Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:12](OC)=[O:13])=[C:5]([CH2:7][C:8](OC)=[O:9])[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[OH:9][CH2:8][CH2:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[CH2:12][OH:13]
Reactant: COC(=O)Cc1nc(Br)sc1C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1ncsc1CO
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of methyl 2-bromo-5-methoxycarbonyl-thiazole-4-acetate (23.4 g) in tetrahydrofuran (500 ml) was added dropwise over 1 hour to a suspension of lithium aluminum hydride (9.03 g) in tetrahydrofuran (500 ml) under ice cooling. After stirring for additional 1 hour under ice cooling, water (9 ml), a 35% aqueous solution (9 ml) of sodium hydroxide and water (27 ml) were successively added, and the mixture was stirred at room temperature for 1 hour. After anhydrous magnesium sulfate was added to the reaction mixture, and the resultant mixture was stirred, insoluble matter was removed by filtration with Celite, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (methanol:dichloromethane=7:93) to obtain the title compound (8.64 g) as a yellow oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33](=[O:36])[N:32]([CH:37]([CH2:48][O:49][CH3:50])[CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>O1CCCC1>[CH2:19]([O:26][C:27]([N:29]1[CH2:35][CH2:34][C:33](=[O:36])[N:32]([CH:37]([CH2:48][O:49][CH3:50])[CH2:38][CH2:39][OH:40])[CH2:31][CH2:30]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COCC(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COCC(CCO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Yield: 76.9 %

Procedure:
3.22 ml (3.22 mmol, 1 M in tetrahydrofuran) tetrabutylammonium fluoride were added to a cooled solution (0° C.) of 1.36 g (2.93 mmol) (rac)-4-[3-(tert-butyl-dimethyl-silanyloxy)-1-methoxymethyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 29 ml tetrahydrofuran. After 50 min water was added and extracted with ethyl acetate (3×). The organic phases were washed with water (2×), dried over Na2SO4 and evaporated. Flash chromatography on silica gel with a gradient 2% to 4% methanol in dichloromethane yielded 0.79 g (77%) of the title compound as a colorless oil, MS: 263 (M).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:21][CH3:22])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=2)[CH:8]=1
Reactant: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Yield: 97 %

Procedure:
A solution of 8-chloro-4-hydroxy-2-(4-isopropylthiazole-2-yl)-7-methoxyquinoline (46, 2.0 g, 5.973 mmol) in POCl3 (10 mL) was heated at 85° C. during 30 min. Then, the reaction mixture was concentrated under reduced pressure. The residue was poured into ice-cooled water (20 mL), the pH was adjusted to 10 with 50% NaOH, and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to give 2.05 g (97%) of the title compound 47 as a yellow solid: m/z=353 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([F:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[Cl:10][C:8]1[C:7]([F:11])=[C:6]([CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]2)[C:5]([O:23][CH3:24])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(C)O)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110 %

Procedure:
To a solution of tert-butyl 3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.17 g, 0.48 mmol) in methanol (3 mL) cooled at 0° C. was added sodium tetrahydroborate (0.022 g, 0.57 mmol). The mixture was stirred at room temperature for 1 hour, then quenched with water, extracted with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated to give the crude alcohol (0.19 g). LCMS calculated for C17H23ClFNO4Na (M+Na)+: m/z=382.1; Found: 382.0.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH3:12])=[O:2].[C:13]1([C:23](Cl)=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.O.CCOC(C)=O>CN(C=O)C.[H-].[Na+]>[CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:23]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[O:24])[C:4]=1[CH3:12])=[O:2]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Cc1[nH]c2ccccc2c1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(C=O)c2ccccc2n1C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
To 3-formyl-2-methylindole (4.30 g; 27.0 mmol) in 70 mL of DMF at r.t. was added NaH 80% (0.861 mg). After 30 min of stirring the solution was cooled to 0° C. and a solution of 1-naphthoyl chloride (5.04 g, 29.3 mmol) in 10 mL of DMF was added dropwise. The mixture was left stirring for 16 h at r.t. and poured into cold water-EtOAc (100mL). The organic phase was washed with H2O (2×25 mL) and brine. The organic phase was dried over Na2SO4 and the solvent removed. Chromatography on silica gel (eluted with 10% EtOAc in toluene) yielded 1.70 g (20%) of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@H](NCc2ccccc2)C1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
Potassium carbonate (462 mg, 3.30 mmol) was added to a solution of (1R,3S)-methyl 3-aminocyclopentanecarboxylate (400 mg, 2.22 mmol) in MeOH (10 ml) and stirred for 1 h. Benzyl bromide (0.2 ml, 1.8 mmol) was added to the reaction mixture and stirred for 15 h at 60-65° C. The reaction mixture was concentrated and the resulting residue was partitioned between water and CHCl3. The organic layer was separated and washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford the crude product. Purification by column chromatography over neutral alumina using 2% MeOH in CHCl3 as eluent afforded 180 mg of (1R,3S)-methyl 3-(benzylamino)cyclopentanecarboxylate with a purity of 75% which was proceeded for the next step.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:10])[CH2:8][CH2:7]1)=[O:5])C.O>CO.[OH-].[Na+]>[C:14]([O:13][C:11]([N:9]([CH3:10])[C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCOC(=O)C1(N(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of 48 mg of 1-(tert-butoxycarbonyl-methyl-amino)-cyclopropane carboxylic acid ethyl ester in 0.4 mL of methanol, 0.1 mL of 5N sodium hydroxide aqueous solution was added and stirred at room temperature overnight. After adding water, the reaction solution was washed with diethyl ether. The aqueous layer was added with 0.7 mL of 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, to afford 36 mg of the title compound as white crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](CCCNC(C3C(C4C=CC=CC=4)=NOC=3C)=O)[CH2:10][CH2:9]2)=[C:4]([CH3:32])[CH:3]=1.[Cl:33]C1C=CC(N)=C(C)C=1>>[Cl:33][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([CH3:32])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: Cc1cc(F)ccc1N1CCN(CCCNC(=O)c2c(-c3ccccc3)noc2C)CC1
Product: Cc1cc(Cl)ccc1N1CCNCC1
Yield: 73 %

Procedure:
The title compound was prepared following the method described for the Compound 31A of Example 31 but starting from 4-chloro-2-methylaniline instead of 4-fluoro-2-methylaniline. Purification by flash chromatography (chloroform-2N ammonia in methanol 100:3 to 100:5) afforded the title compound (73%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[NH2:6].S(Cl)([Cl:17])(=O)=O>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5](=[CH:7][C:8]([O:11][CH3:12])=[C:9]([Cl:17])[CH:10]=1)[NH2:6]
Reactant: COC(=O)c1ccc(OC)cc1N
Reactant: O=S(=O)(Cl)Cl
Product: COC(=O)c1cc(Cl)c(OC)cc1N
Yield: 90 %

Procedure:
Treatment of methyl-4-methoxyanthranilate with sulfuryl chloride as described above afforded methyl-4-methoxy-5-chloroanthranilate, M.P., 197°-200° C. in 90% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10]=1O)=[O:5])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:22]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)[C:10]=1[Cl:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnn(Cc2cc(Cl)cc(Cl)c2)c1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnn(Cc2cc(Cl)cc(Cl)c2)c1Cl

Procedure:
Combine 1-(3,5-dichloro-benzyl)-5-hydroxy-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (1 eq) with PCl5 (2 eq) in toluene and heat at 40–50° C. until reaction is complete. Concentrate the mixture, treat with aqueous NaHCO3, and extract with Et2O. Dry the combined extracts over Na2SO4, concentrate, and purify by chromatography on silica gel. MS (ES) 334.0, 336.0 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[CH2:32]([OH:35])[CH2:33][OH:34]>C1COCC1.[Cl-].[Na+].O>[OH:34][CH2:33][CH2:32][O:35][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCOCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 37 h

Procedure:
4-Chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole (5.57 g) was suspended in 100 ml of THF and 30 ml of ethylene glycol, 1.5 g of sodium hydride was added to the suspension, and the mixture was stirred at 50° C. for 37 hr. Brine was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate) to give 4.87 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[C:16](OS(C2C=CC(C)=CC=2)(=O)=O)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C(#N)C>[N:29]1([C:16]2[C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:4]=3[N:3]=[C:2]([NH2:1])[N:17]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCc2ccccc2-3)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1nc2c(c(N3CCNCC3)n1)CCCCc1ccccc1-2

Procedure:
A solution of Example 20C (80 mg 0.20 mmol), piperazine (26 mg, 0.30 mmol) and triethylamine (0.1 mL, 0.72 mmol) in anhydrous acetonitrile (3 mL) was heated at 160° C. in a microwave reactor for 20 minutes. The mixture was concentrated under reduced pressure and chromatographed on silica gel eluting with NH4OH:MeOH:CH2Cl2 (0.6:6:94) to provide the title compound. 1H NMR (CD3OD) δ 1.45 (m, 2H), 1.86 (m, 1H), 2.00-2.15 (m, 2H), 2.34 (m, 1H), 2.73 (dd, J=14.58, 8.48 Hz, 1H), 2.80-3.02 (m, 5H), 3.37 (m, 4H), 7.22 (m, 1H), 7.24-7.31 (m, 2H), 7.33-7.41 (m, 1H). MS (M+H)+ m/z 310.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:5])[CH3:2].Br[CH2:31][C:32](=[O:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([O:20][C:18]([C:6]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:31][C:32](=[O:34])[CH3:33])=[CH:25][CH:24]=1)([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:19])[CH3:22]
Reactant: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(O)cc1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)C(C(=O)OCC)(C(=O)OCC)c1ccc(OCC(C)=O)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 11.7 g of p-[1,1,2,2-tetrakis(ethoxycarbonyl)ethyl]phenol, 7.9 g of bromoacetone, 7.9 g of potassium carbonate and 100 ml of dimethylformamide, and then purifying the reaction product by column chromatography through silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, the title compound was obtained having an Rf=0.21 (thin layer chromatography over silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20](O)=[O:21])[C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][CH:49]([CH2:58][C:59]1[CH:64]=[C:63]([F:65])[CH:62]=[C:61]([F:66])[CH:60]=1)[C:50]([NH:52][C:53]1[NH:54][CH:55]=[CH:56][N:57]=1)=[O:51]>>[F:65][C:63]1[CH:64]=[C:59]([CH2:58][CH:49]([NH:48][C:20]([C:19]2[C:13]3[N:12]=[C:11]([C:3]4[N:2]=[CH:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)[NH:15][C:14]=3[CH:16]=[CH:17][CH:18]=2)=[O:21])[C:50](=[O:51])[NH:52][C:53]2[NH:54][CH:55]=[CH:56][N:57]=2)[CH:60]=[C:61]([F:66])[CH:62]=1
Reactant: NC(Cc1cc(F)cc(F)c1)C(=O)Nc1ncc[nH]1
Reactant: O=C(O)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NC(Cc1cc(F)cc(F)c1)C(=O)Nc1ncc[nH]1)c1cccc2[nH]c(-c3cc4ccccc4cn3)nc12
Yield: 22.3 %

Procedure:
145 mg (0.5 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid was reacted with 280 mg (0.75 mmol) of HBTU and 2-Amino-3-(3,5-difluoro-phenyl)-N-(1H-imidazol-2-yl)-propionamide HCl salt (152 mg, 0.5 mmol) as described in general procedure A. A solid precipitated from the solution and was collected by filtration, washed with H2O and EtOAc, to give 2-isoquinolin-3-yl-1H-benzoimidazole-4-carboxylic acid [2-(3,5-difluoro-phenyl)-1-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide (60 mg, 22%). LCMS: 538 (M+1)+.
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:43])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH:30]=3)[C:25](O)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:44][C:45]1[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:16]=[C:17]([Cl:43])[C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@@H:32]([CH3:42])[CH2:33][O:34][Si:35]([C:38]([CH3:40])([CH3:41])[CH3:39])([CH3:36])[CH3:37])[CH:30]=3)[C:25]([NH:44][C:45]3[CH:50]=[N:49][C:48]([CH3:51])=[CH:47][N:46]=3)=[O:26])=[N:19][CH:20]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Reaction time: 1 h
Yield: 50.7 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.1 mL, 0.75 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)-3-chloropyridin-2-yl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]benzoic acid (0.3 g, 0.58 mmol) in DCM (10 mL) and stirred for 1 hour. 2-Amino-5-methylpyrazine (126 mg, 1.15 mmol) then pyridine (0.094 mL, 1.15 mmol) were added and the mixture stirred for a further 30 mins before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the title compound as an oil (180 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)[N:10]=2)[N:3]=1.[CH3:25][O-:26].[Na+].CO.[Na]>C(Cl)(Cl)Cl.O>[CH2:23]([O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[N:10]=[C:9]([C:4]3[N:3]=[C:2]([O:26][CH3:25])[CH:7]=[C:6]([CH3:8])[N:5]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:17][CH:18]=1)[CH3:24]
Reactant: C[O-]
Reactant: CCOc1ccc(Oc2cccc(-c3nc(C)cc(Cl)n3)n2)cc1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOc1ccc(Oc2cccc(-c3nc(C)cc(OC)n3)n2)cc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To 4-chloro-2-(6-p-ethoxyphenyloxy-2-pyridinyl)-6-methylpyrimidine (3 g) was added sodium methoxide prepared from methanol (10 ml) and metallic sodium (0.22 g). After the mixture was left to stand at room temperature for 30 minutes, water (30 ml) and chloroform (100 ml) were added thereto, and then extracted. After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain 2-(6-p-ethoxyphenyloxy-2-pyridinyl)-4-methoxy-6-methylpyrimidine (2.7 g, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1.[Br:22][C:23]1[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][C:24]=1[F:32]>>[Br:22][C:23]1[N:28]=[C:27]([C:29]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:9]2)=[O:30])[CH:26]=[CH:25][C:24]=1[F:32]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2N)C1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C1

Procedure:
Following Method 11 (Example 305), (S)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate was coupled to 6-bromo-5-fluoropicolinic acid yielding crude (S)-tert-butyl 1-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)piperidin-3-ylcarbamate (92%) which was used as is. LCMS (m/z): 496.2 (MH+); LC Rt=2.90 min.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1)([O-:15])=[O:14].C(O)(=O)C.O>O1CCCC1.ClC(OCC(C)C)=O.CN1CCOCC1.C(OCC)(=O)C>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]2[N:22]=[C:10]([CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH:23][C:18]=2[CH:17]=1)([O-:15])=[O:14]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1nc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
To a solution of N-Boc-glycine (571 mg) in tetrahydrofuran (16 mL), isobutyl chloroformate (428 μL) and N-methylmorpholine (358 μL) were added under ice cooling, and the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture, 4-nitro-1,2-phenylenediamine (500 mg) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours and 30 minutes. To the reaction mixture, acetic acid (16 mL) was added, and the mixture was stirred at 70° C. for 3 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain tert-butyl ((6-nitro-1H-benzo[d]imidazol-2-yl)methyl)carbamate (C19, 782 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:3][CH:2]=1.[H][H]>C(O)C>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccncc1
Reactant: [H][H]
Solvent: CCO
Product: Nc1cccnc1Nc1ccncc1

Procedure:
A solution of 16.5 g of 2-(4-pyridylamino)-3-nitro-pyridine in 400 ml of 95% ethanol containing 1.6 g of 10% palladized carbon was hydrogenated at 30°-40° C. at atmospheric pressure until 5.8 liters of hydrogen were absorbed and the mixture was filtered to remove the catalyst. The filtrate was evaporated to dryness and the residue was taken up in petroleum ether. The mixture was filtered to obtain 13.5 g (95% yield) of raw product melting at 202°-204° C. which was crystallized from 95% ethanol to obtain 2-(4-pyridylamino)-3-amino-pyridine in the form of a pale yellow, crystalline powder melting at 203°-205° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[S:14]([CH:17]2[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:8][CH:9]=1)=[O:4]>CCO>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][N:13]([S:14]([CH:17]2[CH2:18][CH2:19]2)(=[O:15])=[O:16])[CH2:12][CH2:11][CH2:10][C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)C2CC2)s1
Solvent: CCO
Product: O=C(O)c1ccc(CCCN(CCCc2cccc(Cl)c2)S(=O)(=O)C2CC2)s1

Procedure:
The title compound was prepared following the method described in Example 1, Step C from 5-(3-{[3-(3-chloro-phenyl)-propyl]-cyclopropanesulfonyl-amino}-propyl)-thiophene-2-carboxylic acid methyl ester of Step A except the reaction was performed in EtOH. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 1H, J=3.4 Hz), 7.42-7.00 (m, 4H), 6.62 (d, 1H, J=3.4 Hz), 3.25 (m, 2H), 2.92 (m, 2H), 2.31 (m, 1H), 2.20 (m, 2H), 1.32-0.90 (m, 4H); MS 440 (M−1).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11]>CS(C)=O>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:6]=1[CH2:5][C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CC#N
Reaction time: 1 h

Procedure:
To 5.39 g of NaCN (110 mol), dissolved in 72 ml of DMSO, was added via dropping funnel a solution of 19.57 g of the above prepared 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole in 144 ml of DMSO (slightly exothermic). The reaction mixture was then kept for 1 h at 35° C. and 40° C. for 1 night. The reaction mixture was then poured onto crashed ice/AcOEt, the organic layer washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) delivered 8.81 g of the title compound as light yellow crystals of mp. 85-86°.