Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4([C:26]#[N:27])[CH2:25][CH2:24]4)[CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])=[CH:4][CH:3]=1.[S-:31][C:32]#[N:33].[K+].BrBr>C(O)(=O)C>[NH2:33][C:32]1[S:31][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([NH:15][C:16](=[O:28])[C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]5([C:26]#[N:27])[CH2:25][CH2:24]5)[CH:18]=4)[CH:10]=[CH:11][C:12]=3[O:13][CH3:14])[CH:29]=[CH:30][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.3 %

Procedure:
To a solution (10 mL) of N-[3-(4-aminophenoxy)-4-methoxyphenyl]-3-(1-cyanocyclopropyl)benzamide (1.74 g, 4.36 mmol) in acetic acid was added potassium thiocyanate (1.46 g, 15.0 mmol), and the mixture was stirred at room temperature for 30 min. To the obtained transparent solution was added dropwise bromine (1.20 g, 7.50 mmol) under ice-cooling, and the reaction mixture was stirred at room temperature for 18 hr. The precipitated yellow powder was filtered off through celite, and the filtrate was concentrated under reduced pressure. To the residue was added 0.1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (1.08 g, 54%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([O:16]CC)=O)[C:4]1=[O:19])[CH3:2].Cl.[CH3:21][O:22][C:23](=[O:26])[CH2:24][NH2:25]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[C:5]([C:14]([NH:25][CH2:24][C:23]([O:22][CH3:21])=[O:26])=[O:16])[C:4]1=[O:19])[CH3:2]
Reactant: COC(=O)CN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC)c1=O
Agent: Cl
Solvent: Cc1ccccc1
Product: CCn1c(=O)c(C(=O)NCC(=O)OC)c(O)c2ccccc21
Yield: 11 %

Procedure:
In 4 mL of toluene in a microwave vial, ethyl 1-ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.380 g, 1 mmol), glycine methyl ester hydrochloride (0.5 g, 4 mmol) was microwaved at 180° C. for 3 minutes and then purified by silica flash chromatography (with a 1-5% MeOH/DCM gradient to afford 0.050 g. Yield: 11%
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:7]2[S:6][C:5]3[C:9]([CH3:11])=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[CH:8]=2)[CH:20]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Cc1cc(C)c2sccc2c1
Product: Cc1cc(C)c2sc(Cc3cc(Br)ccc3Cl)cc2c1

Procedure:
5,7-Dimethylbenzo[b]thiophene (see Yoshimura, Y. et al., J. Med. Chem. 43 (2000) 2929-2937) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][O:21][CH2:22][C:23](OC)=[O:24].Cl>C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:6][CH:7]=1
Reactant: COCC(=O)OC
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: COCC(=O)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
To a suspension of 2,5-dibromopyridine (50.0 g) in diethyl ether (1 L) was added under nitrogen atmosphere a 1.6M n-butyllithium hexane solution (140 mL) at −70° C. over 20 min. The reaction mixture was stirred at −70° C. for 30 min, methyl methoxyacetate (44.0 g) was added at −70 to −45° C. over 15 min. The reaction mixture was warmed to room temperature, 2M hydrochloric acid (110 mL) was added, and the diethyl ether layer was separated. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layer was combined with the diethyl ether layer, and the layers were washed with saturated brine, dried (MgSO4) and concentrated. Cold ether was added to the obtained residue, and the resulting crystals were collected by filtration, washed with cold ether and dried to give the title compound (15.85 g, yield 33%) as colorless crystals. melting point 110-112° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.[O:25]=[C:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32](O)=[O:33]>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:17][CH2:18][CH:19]([NH:22][C:32](=[O:33])[CH2:31][N:27]4[CH2:28][CH2:29][CH2:30][C:26]4=[O:25])[CH2:20][CH2:21]3)=[CH:23][CH:24]=2)[CH2:2]1
Reactant: O=C(O)CN1CCCC1=O
Reactant: NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: O=C(CN1CCCC1=O)NC1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 289 is synthesized from Intermediate M and (2-Oxo-pyrrolidin-1-yl)-acetic acid according to the procedure used to synthesize Example 261. (LC/MS method 16: ES+ m/z 451.4 [M+H]+, Rt=2.51 min)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([C:36]2[O:37][CH:38]=[CH:39][CH:40]=2)[O:33][C:34]=1[CH3:35].O>CN(C)C=O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[O:37][CH:38]=[CH:39][CH:40]=4)[O:33][C:34]=3[CH3:35])=[C:19]([O:24][CH3:25])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)c(OC)c2)nc1OCC
Reactant: Cc1oc(-c2ccco2)nc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazol-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 58.0 mg) was added at 0° C., and then the solution was stirred at room temperature for 30 minutes. 4-Chloromethyl-2-(2-furyl)-5-methyloxazole (573 mg) was added to the reaction mixture, which was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyl]-1H-pyrazol-4-yl]propionate (564 mg, yield: 76%) was obtained as a yellow oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]Br)=[CH:18][CH:17]=1.Cl>CO>[CH2:10]([O:9][C:1]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][CH3:13])=[CH:17][CH:18]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COCc1ccc(CCBr)cc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCOC(=O)C(CCc1ccc(COC)cc1)C(=O)OCC

Procedure:
Diethyl malonate (0.32 g) is added to a solution of 0.05 g sodium in 10 ml of methanol. The 1-(methoxymethyl)-4-(2-bromoethyl)benzene (13) (0.5 g) is then added and allowed to react for 8 h. The solution is neutralized with methanolic HCl and is extracted with ether. The ether extract is dried over Na2SO4, and evaporated to yield 1-[3,3-di(ethoxycarbonyl)propyl]-4-methoxymethylbenzene (14). The methyl group is removed by treatment with aqueous HBr in acetic acid, followed by neutralization with aqueous NaOH and extraction with ether. The ether extract is dried over Na2SO4, and evaporated to yield 1-[3,3-di(ethoxycarbonyl)propyl]-4-hydroxymethylbenzene (4).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([O:11][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C(=O)O)c1ccccc1O
Reactant: BrCc1ccccc1
Product: CC(C(=O)OCc1ccccc1)c1ccccc1OCc1ccccc1

Procedure:
2-(2-Hydroxyphenyl)propionic acid was benzylated with two equivalents of benzyl bromide using the process described in Example 85, footnote a to give benzyl 2-(2-benzyloxyphenyl)propionate.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.[Br:12]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:8]1[C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][C:5]([NH2:9])=[N:6][CH:7]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ncc(Br)c(C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 5 h
Yield: 73.9 %

Procedure:
4-(Trifluoromethyl)pyrimidin-2-ylamine (2 g, 12.3 mmol) was suspended in chloroform (70 ml) followed by the addition of N-bromosuccinimide (3.3 g, 18.4 mmol) and the resulting mixture was stirred at 50° C. for 5 hours and then at room temperature for 15 hours. A mixture of methylene chloride (50 ml) and 1 M sodium hydroxide (50 ml) was added, the resulting mixture was stirred, and then the organic layer was fractionated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.2 g, 75%) as a pale orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH:12]([S:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]=[O:10])=[C:6]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,4,6-trichloropyrimidine-5-carbaldehyde (5.0 g, 23.8 mmol) in DCM (50 mL) was added 2-(isopropylsulfonyl)aniline (9.5 g, 47.6 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was warmed to room temperature gradually and stirred overnight. The solid was filtered off, and the filtrate was concentrated in vacuo and purified by silica gel chromatography (DCM/EtOAC/Hexanes: 15/15/70) to afford 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbaldehyde. MS (ES+): 374.0 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.[CH3:25][C:26]1[N:31]=[C:30]2[NH:32][C:33]([CH2:35][CH3:36])=[N:34][C:29]2=[C:28]([CH3:37])[CH:27]=1>>[CH2:21]([O:20][C:18](=[O:19])[CH:17]=[C:7]1[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:32]3[C:30]4=[N:31][C:26]([CH3:25])=[CH:27][C:28]([CH3:37])=[C:29]4[N:34]=[C:33]3[CH2:35][CH3:36])=[CH:4][C:5]=2[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:8]1=2)[CH3:22]
Reactant: CCOC(=O)C=C1c2ccc(CBr)cc2C=Cc2ccc(F)cc21
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Product: CCOC(=O)C=C1c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)cc2C=Cc2ccc(F)cc21
Yield: 14 %

Procedure:
The same procedure as in Step D of Example 1 was repeated using 0.34 g of Compound 4-b and 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine to give 60 mg (14%) of the product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.[NH2:35][C:36]1[CH:41]=[C:40](Br)[CH:39]=[CH:38][N:37]=1>>[NH2:35][C:36]1[CH:41]=[C:40]([C:17]2[CH:18]=[CH:19][C:14]([C@@H:12]([N:8]3[CH2:7][CH2:6][C@:5]([CH2:4][CH2:3][CH2:2][OH:1])([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:10][C:9]3=[O:11])[CH3:13])=[CH:15][CH:16]=2)[CH:39]=[CH:38][N:37]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: Nc1cc(Br)ccn1
Product: C[C@@H](c1ccc(-c2ccnc(N)c2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-amino-4-bromopyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.951, m/z=432; 1H NMR (CDCl3) 1.26-1.40 (m, 1H), 1.48 (d, 3H), 1.59-1.63 (m, 1H), 1.83-1.95 (m, 2H), 2.09-2.20 (m, 1H), 2.21-2.37 (m, 2H), 2.86 (m, 1H), 3.50 (m, 2H), 4.54-4.75 (s, 2H), 5.62 (m, 1H), 6.56 (s, 1H), 6.71 (d, 1H), 6.90 (d, 2H), 7.21-7.33 (m, 7H), 8.00 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[CH:7]=1.CC1C=C(C)C=C(C)N=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C1COCC1>[C:25]1([O:24][C:22](=[O:23])[NH:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[CH:8]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cn2cc(Br)ccc2n1
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(Nc1cn2cc(Br)ccc2n1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-imidazo[1,2-a]pyridin-2-ylamine (Intermediate A1)(6.2 g, 29.2 mmol) in THF (400 ml) is added 2,4,6-trimethylpyridine (5.8 ml, 43.9 mmol). The reaction mixture is cooled to 0° C. (ice-bath) and treated dropwise with a solution of phenyl chloroformate (3.85 ml, 30.7 mmol) in THF (50 ml) over 15 minutes. The reaction mixture is stirred overnight, at room temperature, quenched with water and stirred for a further 5 minutes resulting in a white precipitate. The solid is collected by filtration and dried under vacuum (40° C.) overnight to afford the title compound [MH+ 331.99 and 333.99].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:34](I)[CH3:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:20][N:21]([CH2:34][CH3:35])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])[CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C[C@H](CC(=O)OC(C)(C)C)Nc1ccc(C#N)c(Cl)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the crude 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-{[(2-nitrophenyl)sulfonyl]amino}butanoate from the previous step, ethyl iodide (2.59 mL, 32.4 mmol) and K2CO3 (325 mesh, 6.71 g, 48.6 mmol) in DMF (93 mL) was stirred at room temperature for 60 min. The reaction was diluted with H2O (200 mL) and extracted with Et2O (3×). The organic extracts were washed with H2O (2×), dried over Na2SO4, filtered, and concentrated. The crude product was used directly in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:27]=2[S:28][C:29]=1[CH3:30])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:21][NH:22][C:23]([C:25]1[C:26]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][CH2:15][C@H:14]5[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=34)=[CH:31][C:27]=2[S:28][C:29]=1[CH3:30])=[O:24]
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reactant: CNC(=O)c1c(C)sc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)sc2cc(Oc3ccnc4cc(C(=O)N5CCC[C@H]5COC)sc34)ccc12
Yield: 71.8 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(S)-2-(methoxymethyl)pyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 2a (153 mg, 0.5 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid methylamide 1d (164 mg, 0.7 mmole) and Cs2CO3 (868 mg, 2.7 mmole) in a manner as previously described for example 1 to give 178 mg (73%) of a yellow solid. 1H NMR (DMSO-d6): δ 8.57 (1H, d, J=5.4 Hz), 8.29 (1H, q, J=4.5 Hz), 8.02 (1H, s), 7.95 (1H, d, J=2.2 Hz), 7.85 (1H, d, J=8.8 Hz), 7.32 (1H, dd, J=2.2, 8.8 Hz), 6.75 (1H, d, J=5.4 Hz), 4.37–4.23 (1H, m), 3.95–3.74 (2H, m), 3.60–3.48 (2H, m), 3.27 (3H, s), 2.83 (3H, d, J=4.5 Hz), 2.60 (3H, s), 2.08–1.81 (4H, m). Anal. Calcd. for C25H25N3O4S2: C, 60.58; H, 5.08; N, 8.48; S, 12.94. Found: C, 60.55; H, 5.33; N, 8.27; S, 12.68.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=3)[C:14]([C:25]([OH:27])=O)=[CH:13][N:12]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH2:54]>O.CN(C=O)C>[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53][NH:54][C:25]([C:14]1[C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)=[N:16][C:11]([NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[N:12][CH:13]=1)=[O:27]
Reactant: Cc1cccc(Nc2nc(NCCc3ccc(O)cc3)ncc2C(=O)O)c1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(Nc2nc(NCCc3ccc(O)cc3)ncc2C(=O)NCCN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
A 4 ml portion of DMF solution containing 352 mg of 2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxylic acid was mixed with 223 mg of WSC hydrochloride, 157 mg of HOBt and 103 mg of 2-dimethylaminoethylamine, followed by stirring overnight at room temperature. The reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol:aqueous ammonia) and then recrystallized (hexane-ethyl acetate) to obtain 291 mg of N-(2-dimethylaminoethyl)-2-{[2-(4-hydroxyphenyl)ethyl]amino}-4-[(3-methylphenyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.Cl.Cl.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([NH2:23])[CH2:16]2.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH:17]([NH:23][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12])[CH2:16]2
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: NC1CN2CCC1CC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc(N)c(C(=O)NC2CN3CCC2CC3)nc1Cl

Procedure:
A solution of 3,5-diamino-6-chloropyrazine-2-carboxylic acid (Intermediate 1.1.1, 2.50 g, 13.1 mmol), 1-aza-bicyclo[2.2.2]oct-3-ylamine dihydrochloride (2.87 g, 14.4 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (4.62 g, 14.4 mmol) and triethylamine (6.72 mL, 39.3 mmol) in dry N,N-dimethylformamide (25 mL) is stirred overnight at room temperature under nitrogen atmosphere. The resulting solid is collected by filtration, washed with diethyl ether and dried at 50° C. under vacuum.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>O>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[C:30]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of toluene (35 mL) and water (5 mL) was degassed with nitrogen for 30 minutes. A mixture of sodium carbonate (1.9 g, 18.09 mmol), 4-bromobenzaldehyde (0.7 g, 3.72 mmol), 3-trifluoromethoxyphenylboronic acid (2.86 g, 4.78 mmol) and tetrakis triphenyl phosphene palladium(0) (0.9 g, 0.75 mmol) was added to the above degassed water/toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (0.8 g, 80%).
Reaction SMILES: N[C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:24]([Cu])#[N:25].N(OC(C)(C)C)=O>CS(C)=O.[Cl-].[Na+].O>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[N:6]1[C:5]2[C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:2]([C:24]#[N:25])=[CH:3][C:4]=2[NH:8][C:7]1=[O:9]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1Cl
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1Cl
Temperature: 55 °C
Reaction time: 1.5 h
Yield: 19.4 %

Procedure:
5-Amino-1-(2,4-dichlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (0.7860 g) was dissolved in dimethyl sulfoxide (35 ml), and to the solution was added CuCN (0.5551 g). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.761 ml) was added dropwise during 1.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 1.5 hours. After allowing to cool, to the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (60 g, CHCl3:methanol=10:1) and then by silica gel column (70 g, hexane:ethyl acetate=1:1) to give the title compound (0.1570 g, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:36]=[CH:35][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28]C(C)(C)C)=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:33]#[N:34])=[CH:13][CH:12]=2)=[O:10])=[N:6][CH:7]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:33]#[N:34])=[CH:35][CH:36]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(Cl)cn4)cc3)c(C#N)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)Nc3ccc(Cl)cn3)cc1)OCCC2C(=O)O
Reaction time: 2 h
Yield: 70.9 %

Procedure:
tert-Butyl 7-(4-(5-chloropyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (4 mg, 0.0079 mmol) was diluted with DCM (500 μL) and TFA (500 μL). After stirring for 2 hours, the reaction was concentrated and placed under high vacuum for 1 hour. The residue was purified by preparative TLC, eluting with 10% methanol/DCM to provide the desired product (2.5 mg, 0.0056 mmol, 70% yield) as a white solid. MS (ESI)=450.1 (M+1).