Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([CH3:18])[NH:15][C:16]=1[CH3:17])=[O:10].[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33].N1C=CC=CC=1.O>C(Cl)(Cl)Cl>[S:32]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]([C:11]1[CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:13]([C:19]([O:21][CH3:22])=[O:20])=[C:14]([CH3:18])[NH:15][C:16]=1[CH3:17])=[O:10])([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCO)C1c1cccc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOS(=O)(=O)c2ccc(C)cc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 62.4 %

Procedure:
43.3 g (0.10 mole) of the 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(6-hydroxyhexyl) ester produced in Step i described above was dissolved along with 29.5 g (0.16 mole) of tosyl chloride in 200 ml of chloroform, to which was added dropwise 25.0 g (0.32 mole) of pyridine with stirring under ice cooling. This reaction mixture was allowed to stand at room temperature for 2 hours, then, after adding 100 ml of water, was stirred for 3 hours. The chloroform layer of the obtained liquid was separated, washed with 200 ml of 0.02 N sulfuric acid, 200 ml of water and 200 ml of saturated aqueous sodium bicarbonate successively, and dried over anhydrous sodium sulfate. This chloroform solution was chromatographed on a silica gel column using a mixed solution of benzene-ethyl acetate (the ratio by volume of 8:1) as an eluent to obtain 36.6 g (yield 62.5%) of the 1,4-dihydro- 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid 3-methyl ester 5-(6-tosyloxyhexyl) ester as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CCN(CC)CC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[C:16]1([S:22]([O:1][CH2:2][CH:3]2[CH2:4][CH2:5][C:6](=[O:8])[NH:7]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCC(CO)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCC(COS(=O)(=O)c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 5-(hydroxymethyl)pyrrolidin-2-one (1.0 g, 8.7 mmol) in acetone (80 mL) was added Et3N (1.8 g, 17.4 mmol) and benzenesulfonyl chloride (3.1 g, 17.4 mmol). The mixture was stirred for 3 h at room temperature. Then the reaction mixture was filtered and concentrated, and the crude product was purified by column chromatography to give the desired product. MS (ESI): 256 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([OH:12])[C:5]=1[OH:13].Br[CH2:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:10][C:7]1[C:6]2[O:12][CH2:16][CH2:17][CH2:18][O:13][C:5]=2[C:4]([C:3]([O:2][CH3:1])=[O:14])=[CH:9][CH:8]=1
Reactant: BrCCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1OCCCO2
Reaction time: 7 h

Procedure:
A mixture of 2,3-dihydroxy-4-methoxy benzoic acid methyl ester (0.45 mol), 1,3-dibromopropane (0.72 mol), K2CO3 (155 g) and CuO (3.6 g) in DMF (2500 ml) was stirred at 120° C. to 130° C. for 7 hours, cooled and filtered. The solvent was evaporated. HCl (aqueous solution of 0.5 N, 1000 ml)) was added. The mixture was extracted twice with DCM (750 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent:hexane/ethyl acetate/DCM 70/30/15). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding methyl 3,4-dihydro-9-methoxy-2H-1,5-benzodioxepin-6-carboxylate (intermediate 6).
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:12]([C:23]#[C:22][Si:19]([CH3:21])([CH3:20])[CH3:18])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(C#C[Si](C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.8 %

Procedure:
To a slurry of the compound of Example 239 (0.763 g, 2.0 mmol), bis(triphenylphosphine)palladium dichloride (28 mg, 0.04 mmol) and cuprous iodide (15 mg, 0.08 mmol) in anhydrous triethylamine (10 mL) was added trimethylsilylacetylene (0.236 g, 2.4 mmol). The brown slurry was stirred at RT for 3.5 h, concentrated, slurried in ether and filtered through silica gel (ether). The crude product was further purified by flash chromatography (ethyl acetate/hexanes) followed by recrystallization from hexanes to afford the title compound as white crystals (0.618 g, 88%). m.p. 131°-132° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[F:22])(=[O:11])=[O:10])[S:6][C:5]=1[NH:23][C:24]([C:26]([O:29]C(=O)C)([CH3:28])[CH3:27])=[O:25])(=[O:3])[NH2:2].Cl>O1CCOCC1>[F:22][C:13]1[CH:14]=[C:15]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:17][C:12]=1[S:9]([C:7]1[S:6][C:5]([NH:23][C:24](=[O:25])[C:26]([OH:29])([CH3:28])[CH3:27])=[C:4]([C:1]([NH2:2])=[O:3])[CH:8]=1)(=[O:10])=[O:11]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1sc(S(=O)(=O)c2ccc(C(F)(F)F)cc2F)cc1C(N)=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(O)C(=O)Nc1sc(S(=O)(=O)c2ccc(C(F)(F)F)cc2F)cc1C(N)=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The acetic acid 1-[3-carbamoyl-5-(2-fluoro-4-trifluoromethyl-benzenesulfonyl)-thiophen-2-ylcarbamoyl]-1-methyl-ethyl ester (1.24 g, 2.5 mmol) is dissolved in 1,4-dioxane (35 mL) and an aqueous solution of 6 M HCl (25 mL). This mixture is stirred at 60° C. overnight, after which the mixture is evaporated. Purification by silica chromatography (EtOAc/hexane; 1:1) affords the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C([Li])CCC.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](N(OC)C)=[O:20]>O1CCCC1>[CH3:9][C:4]1[CH:3]=[C:2]([C:19]([CH2:18][CH2:17][CH2:16][Cl:15])=[O:20])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CON(C)C(=O)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)CCCCl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
A solution of 10.2 mL (13.9 g; 72 mmol) 5-bromo-m-xylene in 200 mL of anhydrous tetrahydrofuran was stirred under nitrogen at -78° C. as 35.8 mL (84 mmol) of 2.5 M n-butyllithium in tetrahydrofuran was added dropwise. After 15 minutes at -78° C., a solution of 10.0 g (60 mmol) of 4-chloro-N-methoxy-N-methylbutyramide in 30 mL of anhydrous tetrahydrofuran was added dropwise over 25-30 minutes. The resulting solution was maintained at -78° C. for 45 minutes and then warmed briefly to room temperature. The reaction was quenched by addition of 40 mL of 2 N hydrochloric acid and then partitioned between ethyl acetate and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride solution. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue afforded 8.91 g (70%) of an oil, which had satisfactory purity by 1H NMR (CDCl3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]([F:29])([F:28])[CH2:24][CH:25]1[CH2:27][O:26]1>>[F:22][C:23]([F:29])([F:28])[CH2:24][CH:25]([OH:26])[CH2:27][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: FC(F)(F)CC1CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)CC(F)(F)F)CC1)O2

Procedure:
Compound 160 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(2,2,2-trifluoroethyl)oxirane and conditions outlined in procedure X. M.p.=145-148° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.05 (m, 1H), 3.5 (s, 1H), 2.95 (m, 3H), 2.85-2.7 (m, 2H), 2.6-2.3 (m, 4H), 2.2-2.1 (m, 3H), 2.0-1.9 (m, 2H); LCMS: 428 [M+H].
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:7]=2)=[N:2]1.[F:20][C:21]1([F:30])[CH2:24][N:23]([C:25](=[O:29])/[CH:26]=[CH:27]\I)[CH2:22]1.C1N2CCN(CC2)C1.CO.ClCCl>CN(C=O)C>[F:18][C:16]([F:19])([F:17])[C:8]1[CH:7]=[C:6]([C:3]2[N:4]=[CH:5][N:1](/[CH:27]=[CH:26]\[C:25]([N:23]3[CH2:24][C:21]([F:30])([F:20])[CH2:22]3)=[O:29])[N:2]=2)[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[N:9]=1
Reactant: O=C(/C=C\I)N1CC(F)(F)C1
Reactant: FC(F)(F)c1cc(-c2nc[nH]n2)cc(C(F)(F)F)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)nc(C(F)(F)F)c2)n1)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
In a 3-neck 50 mL round-bottomed flask, 4-(1H-1,2,4-triazol-3-yl)-2,6-bis(trifluoromethyl)pyridine (3) (0.060 g, 1 eq.) and (Z)-1-(3,3-difluoroazetidin-1-yl)-3-iodoprop-2-en-1-one (0.064 g, 1.1 eq) was dissolved in DMF (2 mL). DABCO (0.047 g, 2 eq.) was added at RT. Reaction mixture was stirred for 1 h at RT. Reaction completion was monitored on TLC using MeOH:dichloromethane (0.25:9.75) as mobile phase. The reaction mixture was quenched into the ice-water slurry (50 mL) and was extracted with ethyl acetate (3×25 mL). Organic layer was washed with brine solution (3×25 mL). The organic layer was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the 0.70 g crude compound which was purified by preparative TLC using 2.5% methanol in dichloromethane as mobile phase to afford 0.011 g (12%) title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][O:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][O:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1COC2c1ccc(F)cc1
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1COC2c1ccc(F)cc1

Procedure:
2-chloro-7-(4-fluorophenyl)-N-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-amine (Preparation Ma) (149 mg, 0.533 mmol) and 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (Preparation A) (119 mg, 0.533 mmol) were combined and purified as per Example 75 to give the racemate N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine which was separated by multiple chiral SFC injections (OJ-H 30×250 mm, 5 μM, 35% MeOH (0.1% DEA)/CO2) to give N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine-2,4-diamine (first to elute, enantiomer A) (18.3 mg, 0.039 mmol, 7.36% yield) as a white scrapable foam. LC-MS (M+H)+=467.0. 1H NMR (500 MHz, MeOD) δ ppm 7.89-7.94 (1H, m), 7.65-7.69 (1H, m), 7.36-7.42 (2H, m), 7.20-7.24 (1H, m), 7.13-7.18 (1H, m), 7.03-7.12 (3H, m), 5.79 (1H, br. s.), 5.08-5.16 (1H, m), 4.95-5.03 (1H, m), 3.68-3.73 (3H, m), 3.02-3.07 (3H, m). The absolute stereochemistry of Example 79A was not determined.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].F[C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40].C(N(CC)CC)C.BrC1C=CC=CC=1C#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:39]([C:38]1[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=1[N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)#[N:40]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Reactant: N#Cc1ccccc1F
Agent: N#Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(=O)NC2CCN(c3ccccc3C#N)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 165 °C
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
A solution of the compound of Example 77 (300 mg, 0.59 mmol), 2-fluorobenzonitrile (0.50 mL, 4.6 mmol) and triethylamine (0.50 mL, 3.6 mmol) in DMF (3.5 mL) was stirred under microwave irradiation at 130° C. for 30 min. 2-Bromobenzonitrile (143 mg, 1.2 mmol) and potassium carbonate (208 mg, 1.5 mmol) were added to the reaction mixture, and the mixture was stirred under microwave irradiation at 165° C. for 30 min. The reaction mixture was diluted with water, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate/hexane=50/50-100/0) and recrystallized from ethyl acetate-hexane to give the title compound (74 mg, 22%) as a pale-yellow solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=2)[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.O1CCCC1.[Si:28]([O:35][CH:36]([C:46]1[CH:47]=[CH:48][C:49]([CH:52]=[O:53])=[N:50][CH:51]=1)[CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(N(CC)CC)C>[Si:28]([O:35][CH:36]([C:46]1[CH:47]=[CH:48][C:49]([C:52](=[O:53])[CH2:10][CH2:9][C:8](=[O:11])[CH:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][N:13]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:50][CH:51]=1)[CH2:37][O:38][Si:39]([C:42]([CH3:44])([CH3:45])[CH3:43])([CH3:41])[CH3:40])([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29]
Reactant: C=CC(=O)C(CC1CCCC1)c1ccc(SC)cn1
Reactant: CC(C)(C)[Si](C)(C)OCC(O[Si](C)(C)C(C)(C)C)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2ccc(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)cn2)nc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 5-cyclopentyl-4-[5-(methylsulfanyl)pyridin-2-yl]pent-1-en-3-one (464 mg) in a mixed solvent of ethanol (8 mL) and tetrahydrofuran (8 mL) were added 5-(1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridine-2-carbaldehyde (1.07 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (45.3 mg) and triethylamine (93.7 μL), and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (682 mg, yield 60%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([C:16](=[S:18])[NH2:17])=[C:5]2[C@@H:4]2[CH2:19][CH2:20][N:3]12.[Cl:21][CH2:22][C:23](=O)[CH2:24]Cl>O1CCOCC1>[Cl:21][CH2:22][C:23]1[N:17]=[C:16]([C:15]2[N:14]=[CH:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:2](=[O:1])[N:3]4[CH2:20][CH2:19][C@H:4]4[C:5]=23)[S:18][CH:24]=1
Reactant: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: O=C1c2ccccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCN12
Yield: 41.6 %

Procedure:
A yellow suspension of 4.86 g (0.0171 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-thiocarboxamide in 120 ml of dioxan was treated with 2.38 g (0.0188 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 48 hrs. The solution obtained was cooled and completely freed from the solvents. The product was chromatographed over silica gel with dichloromethane/ethyl acetate 1:1 as the eluent and recrystallized from hot ethyl acetate. There were obtained 2.54 g (42%) of (S)-1-(4-chloromethyl-thiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one as white crystals; m.p. 248-249° and [α]D20 =-186.1° (DMF, c=1%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=2)[N:22]=[C:21]([NH:32][CH2:33][C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[CH:37][NH:38]3)[CH:20]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:38]1[C:39]2[C:35](=[C:34]([CH2:33][NH:32][C:21]3[CH:20]=[C:19]([C:5]4[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)[N:22]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[CH:37]1
Reactant: Cc1cccc(-c2nc(Cl)cc(NCc3cccc4[nH]ccc34)n2)n1
Reactant: COc1cncc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1cncc(-c2cc(NCc3cccc4[nH]ccc34)nc(-c3cccc(C)n3)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 5-methoxypyridine-3-boronic acid pinacolester (1.2 eq, 0.24 mmol, 56.4 mg) in DME (1 ml) under an inert atmosphere of argon is treated with 2M sodium carbonate (2 eq, 0.4 mmol, 0.2 ml) and then stirred at room temperature for 15 minutes. To this mixture is added [6-chloro-2-(6-methyl-pyridin-2-yl)-pyrimidin-4-yl]-(1H-indol-4-ylmethyl)-amine (1 eq, 0.2 mmol, 70 mg) followed by PdCl2(dppf).DCM (0.1 eq, 0.02 mmol, 16.3 mg) and the reaction mixture is heated at 80° C. for 90 minutes. The mixture is dissolved in DCM and washed with water. The solvent is removed in vacuo and the crude product is purified by reverse phase column chromatography and the appropriate fractions are combined and concentrated in vacuo. The resulting residue is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound [M+H]+=423.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])=[CH:4][CH:3]=1.Cl.C[CH2:17][O:18]CC.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[NH:11])[O:18][CH3:17])=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: CC(C)C(C#N)Nc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=N)C(Nc1ccc(Cl)cc1)C(C)C
Temperature: 0 °C

Procedure:
A solution of 3.86 g (20 mmol) of 2-(4-chlorophenylamino)-3-methylbutyronitrile in 10 ml of methanol is saturated at reflux with hydrogen chloride gas. When all of the starting nitrile has been consumed, most of the methanol and excess hydrogen chloride is removed in vacuo. Ether is added to precipitate the hydrochloride of methyl 2-(4-chlorophenyl)-3-methylbutanimidate, which is isolated by filtration under nitrogen. The white solid is added with vigorous stirring to an ice-cold mixture of ether and aqueous sodium bicarbonate. The aqueous layer is discarded, and the ethereal layer is washed with cold water and dried over sodium sulfate. Filtration and concentration in vacuo gives methyl 2-(4-chlorophenylamino)-3-methylbutanimidate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:9]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:10]=2[N:11]=1>CCO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:9]2[O:8][C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[N:11][C:10]=2[CH:12]=1
Reactant: Cn1cccc1-c1nc2cc([N+](=O)[O-])ccc2o1
Agent: [Pd]
Solvent: CCO
Product: Cn1cccc1-c1nc2cc(N)ccc2o1
Yield: 89.9 %

Procedure:
1.5 g of 2-(1-methyl-2-pyrrolyl)-5-nitrobenzoxazole (0.006 mole) and 0.15 g of 10% Pd/C are suspended in 100 ml of 95% EtOH and hydrogenated at 50 psi over a period of 2.5 hr. The catalyst is removed and the EtOH evaporated under vacuum yielding a brown solid. Crystallization from methanol yields 1.15 g of tan crystals, mp 183°-185° (89%).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.I[CH2:17][CH3:18].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:17][CH3:18])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.7 %

Procedure:
A solution of 8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (10 g, 0.044 mol) in anhydrous DMF (100 ml) was treated with iodoethane (5.4 ml, 0.068 mol) and Na2CO3 (4.9 g, 0.046 mol). The reaction mixture was left to stir at rt under nitrogen for 2 days. Iodoethane (0.35 ml, 0.0044 mol) was added and the mixture was left to stir at rt for 1 day. The mixture was partitioned between EtOAc and 2M HCl. The organic layer was separated, washed sequentially with saturated sodium sulphite solution and brine, dried (MgSO4) and concentrated. The crude solid was washed with Et2O to give the title compound as a white solid (8.37 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]([CH2:23][C:24]3([O:30][CH3:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)C(=O)OC(C)(C)C)[N:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:23][C:24]3([O:30][CH3:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:10]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: COC1(CN(C(=O)OC(C)(C)C)c2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Yield: 88.1 %

Procedure:
A solution of tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((4-methoxytetrahydro-2H-pyran-4-yl)methyl)carbamate (32 mg, 0.071 mmol) and TRIFLUOROACETIC ACID (0.982 ml, 12.75 mmol) in DCM (2 ml) was stirred at room temperature for 40 min. The mixture was then concentrated to afford 22 mg of the crude material which was used in the next step without purification. LCMS (m/z): 352.2 [M+H]+; Rt=0.634 min.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][CH:39]=[N:40][N:41]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][CH:39]=[N:40][N:41]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(-c2nnco2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(-c2nnco2)ccc1O
Yield: 90.5 %

Procedure:
A trifluoroacetic acid (5 mL) solution of the obtained tert-butyl 2-(2-hydroxy-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoate (0.034 g) was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.027 g of 2-(2-hydroxy-5-(1,3,4-oxadiazol-2-yl)benzamido)-4-phenylbenzoic acid as a white solid.