Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:30][S:31]([N:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:40][CH:37]2[CH2:38][CH2:39][N:34]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:35][CH2:36]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(C)ccc2OC)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C)cc1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-methoxy-5-methyl-phenyl)-methanone (Example 325) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-5-methyl-phenyl)-methanone. MS (M+H)+, 420
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]([NH2:17])=[S:16])[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].Br[CH2:36][C:37](=O)[C:38]([O:40][Si](C)(C)C)=[O:39].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:18])[C@H:10]2[NH:14][C:15]2[S:16][CH:36]=[C:37]([C:38]([OH:40])=[O:39])[N:17]=2)[C:7]=1[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)OC(=O)C(=O)CBr
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(N)=S)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3nc(C(=O)O)cs3)[C@H]2SC1
Yield: 92.5 %

Procedure:
A mixture of 770 mg of (6R-trans)-3-[(acetyloxy)methyl]-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester, 425 mg of 3-bromo-2-oxopropanoic acid, trimethylsilyl ester, 110 mg of potassium carbonate and 15 ml of acetonitrile was reacted as described in Example 1, giving 810 mg of the desired compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH3:12])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[N:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)[CH2:11][CH3:12]
Reactant: CCCOCCn1c(Cl)nc2ccccc21
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: CCCOCCn1c(N2CCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(n-propoxy)ethyl]benzimidazole (3.00 g), N-methylpiperazine (3.00 g) and fumaric acid (2.53 g), there are obtained crude crystals, which are recrystallized from ethyl acetate-ethanol to give 1-[2-(n-propoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (3.42 g) as colorless prisms, m.p. 165°-166° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](NO)=[O:17])=[O:9])=[CH:5][CH:6]=1.C(O)(=O)CCCCCCC(O)=[O:28].C1(=O)OC(=O)CCCCCC1.NC1C=CC=CC=1>>[C:16]([OH:17])(=[O:28])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]([NH:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:9]
Reactant: O=C(CCCCCCC(=O)Nc1ccccc1)NO
Reactant: O=C(O)CCCCCCC(=O)O
Agent: O=C1CCCCCCC(=O)O1
Solvent: Nc1ccccc1
Product: O=C(O)CCCCCCC(=O)Nc1ccccc1

Procedure:
Another process for the preparation of vorinostat has been reported in OPPI Briefs, 2001, vol. 33(4), pages 391-394. The reported process, illustrated in Scheme 6, involves conversion of suberic acid to suberic anhydride, which on treatment with aniline gives suberanilic acid. Coupling of this suberanilic acid with ethyl chloroformate gives a mixed anhydride which upon treatment with hydroxylamine gives vorinostat in an overall yield of 58%. In the first step, there is competition between the formation of suberic anhydride and the linear anhydride and consequently isolation of pure suberic anhydride from the reaction mixture is very difficult. This process step is also hindered by the formation of process impurities and competitive reactions. In the second step, there is formation of dianilide by reaction of two moles of aniline with the linear anhydride. In the third step, suberanilic acid is an inconvenient by-product as the suberanilic acid is converted to a mixed anhydride with ethyl chloroformate, which is highly unstable and is converted back into suberanilic acid. Consequently, it is very difficult to obtain pure vorinostat from the reaction mixture. Although the reported yield was claimed to be 58%, when repeated a yield of only 38% was obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[C:16]1([Mg]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[OH:15][C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[C:13](=[O:14])[N:5]1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: Cl[Mg]c1ccccc1
Reactant: CCCCN1C(=O)c2cccnc2C1=O
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2cccnc2C1(O)c1ccccc1
Temperature: -65 °C
Yield: 90.5 %

Procedure:
6-(n-Butyl)-pyrrolo[3,4-b]pyridine-5,7-dione(40.4 g, 198 mmoles) was dissolved in toluene (1 L) and cooled to -65° C. Phenylmagnesium chloride (100 mL, 2M in THF, 200 moles) was added over 15 minutes. The cooling bath was then removed and the mixture allowed to warm to -10° C. The reaction was quenched by addition of 25 mL of saturated ammonium chloride solution. The room temperature solution was diluted with 500 mL of ethyl acetate and 500 mL of water. The layers were separated. Removal of most of the organic solvent was accomplished by atmospheric distillation. When the remaining volume reaches 150 mL the mixture was cooled to below 80 C and 1 L of hexanes was added. The resulting crystalline mass was filtered and dried to give 50.6 g of 7-hydroxy-7-phenyl-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]pyridin-5-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([Cl:20])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(I)ccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(I)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
2-chloro-5-iodobenzoic acid (10.0 g, 35.5 mmol) was suspended in methylene chloride (200 mL). To the resulting mixture was added N,N-dimethylformamide (0.05 mL), and then added dropwise oxalyl chloride (11.3 g, 89.0 mmol) at 0° C. After the completion of dropwise addition, the resulting mixture was warmed up to room temperature and stirred for 4 hr. The resulting clear solution was evaporated by rotation to remove the solvent and produce 10.7 g of a product in a yield of 100%, which was directly used in the next reaction without purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[N:38]=[CH:39][S:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[N:38]=[CH:39][S:40][CH:41]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1cscn1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2cscn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-1,3-thiazole hydrochloride (0.58 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.01 g, 66%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]=[C:15]=[S:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C1COCC1>[CH:11]1[CH:12]=[CH:13][C:8]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[S:16])=[CH:9][CH:10]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ccc(S(=O)(=O)Nc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccccc1)c1ccc(NC(=S)Nc2ccccc2)cc1

Procedure:
Triethylamine (0.07 mL, 0.5 mmol) and phenyl isothiocyanate (2.1 mL, 11 mmol) were added sequentially to a solution of 4 (2.48 g, 10 mmol) in dry THF (10 mL). After heating under reflux for 48 h, all volatiles were removed under vacuum, and the resulting crude material was purified by flash chromatography on silica gel (hexanes/acetone, 3:1) to afford N-phenyl-4-[[(phenylamino)thioxomethyl]amino]benzenesulfonamide (5, also called LED209) (1.34 g, 35%) as a white solid, mp 160-162° C. 1H NMR (CD3COCD3, 300 MHz) δ 9.35 (br s, 1H), 9.30 (br s, 1H), 8.98 (br s, 1H), 7.80-7.72 (m, 4H), 7.51-7.47 (m, 2H), 7.38-7.33 (m, 2H), 7.28-7.16 (m, 5H), 7.08-7.04 (m, 1H); 13C NMR (CD3COCD3, 75 MHz) δ 180.2, 143.9, 138.9, 138.2, 135.2, 129.3 (2C), 129.1 (2C), 127.9 (2C), 125.8, 124.6 (3C), 122.8 (2C), 120.8 (2C).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[N:6]=1)=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]=1[S:12]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)(=[O:14])=[O:13]
Reactant: COC(=O)c1ccc(C)c(S(=O)(=O)N2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)nc1S(=O)(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
5-Methyl-6-(piperidine-1-sulfonyl)-pyridine-2-carboxylic acid methyl ester (53 mg, 0.178 mmol) in dioxane (2 mL) was added to a solution of lithium hydroxide monohydrate (CAN 1310-66-3, 0.1 g, 2.38 mmol) in water (2 mL) and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo, water (10 mL) was added, and the pH was adjusted to 3 with 1 N hydrochloric acid. The mixture was extracted by ethyl acetate (2×10 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give the product (36 mg, 71%); MS (EI): m/e=285.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH3:19])[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:1]([C:5]1[N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[C:9](=[O:11])[C:8]([CH2:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH3:19])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nc(C)c(CC(=O)C(C)(C)C)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 2-butyl-5-(3,3-dimethyl-2-oxobutyl)-6-methylpyrimidin-4(3H)-one (0.48 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (0.99 g) in N,N-dimethylformamide (9 mL) was added potassium carbonate (0.75 g), and the mixture was stirred at 80° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.33 g, 40%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:15]1([CH2:14][CH2:13][CH2:12][CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCCc1ccccc1
Reactant: c1c[nH]nn1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Product: c1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
1,2,3-Triazole (1623 mg, 23.5 mmol), sodium iodide (2353 mg, 15.7 mmol) and sodium hydroxide (940 mg, 23.5 mmol) were added to t-amyl alcohol (6.2 ml), and the mixture was refluxed under stirring for 1 hour. 1-Chloro-4-phenylbutane (2648 mg, 15.7 mmol) was dissolved in t-amyl alcohol (6.2 ml) and added dropwise under reflux over 1 hour. The mixture was refluxed under stirring for 2 hours and cooled to room temperature, and toluene (50 ml) was added. The mixture was washed with water (50 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→1/3) to give 1-(4-phenylbutyl)-1H-1,2,3-triazole (2.56 g) as colorless oil. yield 81%. 2-(4-Phenylbutyl)-2H-1,2,3-triazole (360 mg) was obtained as a colorless oil (yield 11%). 1-(4-phenylbutyl)-1H-1,2,3-triazole
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH:10]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:38])=[N-]>C(Cl)Cl>[CH3:38][O:22][C:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:19][CH:18]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Reaction time: 2 h

Procedure:
A solution of 100 mg (0.21 mmol) of (3RS,4RS)-[4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-acetic acid in 5 ml of methylene chloride was treated with 1 ml of ethereal diazomethane solution at room temperature and stirred for a further 2 hours. The reaction solution was evaporated under reduced pressure and the tert-butyl (3RS,4RS)-4-(4-methoxycarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, Rf : 0.5 (hexane:ethyl acetate=2:1), obtained in quantitative yield, was used in the following step without further purification and characterization.
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:49])[C:29]=1[NH:30][C:31]1[C:40]2[C:35](=[C:36]([O:43][CH2:44][C:45]([OH:47])=O)[C:37]([O:41][CH3:42])=[CH:38][CH:39]=2)[O:34][C:33](=[O:48])[CH:32]=1.N>CN(C1C=CN=CC=1)C.C1COCC1.N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:49])[C:29]=1[NH:30][C:31]1[C:40]2[C:35](=[C:36]([O:43][CH2:44][C:45]([NH2:3])=[O:47])[C:37]([O:41][CH3:42])=[CH:38][CH:39]=2)[O:34][C:33](=[O:48])[CH:32]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(N)=O
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
EDC.HCl (85.8 mg, 0.37 mmol), HOBt (49.4 mg, 0.37 mmol), and DMAP (cat.) were sequentially added to a solution of 2-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)acetic acid (100 mg, 0.24 mmol, Example 49) and pyridine (10 mL). After 5 min, a saturated solution of ammonia in THF (10 mL) was added, and the reaction was heated at 40° C. overnight. The reaction was allowed to cool to rt, concentrated to remove THF, and then 2N HCl was added to pH=3. The precipitate was filtered, washed with water, and dried. The crude product was refluxed in ethyl acetate (20 mg/mL) for 10 min, sonicated to break up large particles, refluxed for another 10 min, and then let stand overnight. Filtration and drying gave 2-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)acetamide: 1H NMR (400 MHz, DMSO-d6): δ 9.58 (br s, 1H), 8.79 (s, 2H), 7.97 (d, 1H), 7.57 (s, 1H), 7.41 (s, 1H), 7.23 (d, 1H), 4.62 (s, 1H), 4.40 (s, 2H), 3.94 (s, 3H); MS (ESI): 409.8.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([C:23]1[CH:32]=[C:29]([O:30][CH3:31])[CH:28]=[C:25]([O:26][CH3:27])[CH:24]=1)([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14](O)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:33][C@H:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:35]([CH3:37])[CH3:36].CC1C=CC(S(O)(=O)=O)=CC=1>>[NH:1]([C:17]([O:19][C:20]([C:23]1[CH:24]=[C:25]([O:26][CH3:27])[CH:28]=[C:29]([O:30][CH3:31])[CH:32]=1)([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:33][C@H:34]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)O)c1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cc(OC)cc(C(C)(C)OC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)c1

Procedure:
The peptide coupling is carried out by the PPA method as described for (a). Batch: 13.4 g (30 mmol) of Ddz-Asp(OBzl)-OH and 10.36 g (30 mmol) of H-Val-OBut.TsOH.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:43])[CH2:11][CH2:12][N:13]([C:17](=[O:42])[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:19]=1)[CH:14]([CH3:16])[CH3:15].[OH-].[Na+].Cl>O1CCOCC1>[ClH:24].[C:38]([O:37][C:35]([N:28]([C:29]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1)[CH2:27][CH2:26][O:25][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([Cl:24])[CH:21]=1)[C:17]([N:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]([OH:43])=[O:9])=[O:42])=[O:36])([CH3:40])([CH3:41])[CH3:39]
Reactant: COC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC(C)N(CCC(=O)O)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Yield: 142.4 %

Procedure:
To a solution of 3-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-isopropyl-amino)-propionic acid methyl ester trifluoroacetate (0.33 g) in dioxan (3 ml) was added 2M sodium hydroxide 0.95 ml, and the resultant solution was stirred at room temperature for 3 h. 1M Hydrochloric acid (ca. 4 ml) was added and the resultant suspension extracted with ethyl acetate. The combined, dried (MgSO4) extracts were concentrated under reduced pressure to give the title compound (0.201 g) as a colourless oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:16](OCC)=[O:17].Cl>CN(C)C=O>[CH:16]([CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:17]
Reactant: CCOC(=O)CCC1CCCCC1
Reactant: CCOC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41 %

Procedure:
76.0 g of ethyl 3-cyclohexylpropionate are initially introduced into 200 ml of dimethylformamide at 0° to 5° C., and 24.6 g of sodium hydride (80% strength in oil) are added. After dropwise addition of 235 ml of ethyl formate, the mixture is stirred at 25° C. for 24 hours. The batch is stirred into 1.6 l of 10% strength HCl, extracted with 800 ml of methylene chloride and distilled. 34.2 g (41%) of ethyl 2-formyl-3-cyclohexylpropionate of boiling point 91°-95° C./1.25 mm are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=[CH:6][N:5]2[C:17]=1[CH3:18].C([Li])(C)(C)C.[C:24](Cl)(=[O:26])[CH3:25].CO>C(OCC)C.CCCCC>[C:24]([C:8]1[CH:7]=[CH:6][N:5]2[C:17]([CH3:18])=[C:2]([CH3:1])[N:3]=[C:4]2[C:9]=1[NH:10][C:11](=[O:16])[C:12]([CH3:14])([CH3:15])[CH3:13])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Cc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: CCCCC
Solvent: CCOCC
Product: CC(=O)c1ccn2c(C)c(C)nc2c1NC(=O)C(C)(C)C
Temperature: -40 °C

Procedure:
A vigorously stirred solution of 65.4 g of 2,3-dimethyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 1.4 l of diethyl ether is treated dropwise at −78° C. under argon protective gas with 500 ml of a commercially available, 1.5 molar solution of t-butyllithium in n-pentane such that the temperature does not rise above −70° C. The mixture is then cooled to −90° C. in the course of 15 min and 54 ml of acetyl chloride are added dropwise to the dark-red suspension. The mixture is then allowed to warm to −40° C. (30 min), treated with 60 ml of methanol, the contents of the flask are poured onto 1 l of ice water and the aqueous phase is extracted three times with 150 ml of methylene chloride each time. The combined organic phases are washed three times with 100 ml of water each time, dried over sodium sulfate and the solvent is stripped off in vacuo. The residue is purified on silica gel (eluent: ethyl acetate/petroleum ether=3/7). 23.2 g of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][NH:35][N:36]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48]>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=4)=[O:19])=[CH:16][C:10]=3[CH:9]=2)=[CH:6][C:5]([C:32]2[N:33]=[N:34][N:35]([CH2:44][CH2:45][O:46][Si:47]([C:50]([CH3:53])([CH3:52])[CH3:51])([CH3:49])[CH3:48])[N:36]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Nc1ncc(-c2nn[nH]n2)cc1-c1cc2cc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCn1nnc(-c2cnc(N)c(-c3cc4cc(NC(=O)Nc5ccc(Cl)c(C(F)(F)F)c5)ccc4s3)c2)n1
Temperature: 80 °C

Procedure:
To the mixture of 1-(2-(2-amino-5-(2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea (106 mg, 0.2 mmol, 1 eq) in anhydrous dimethylformamide (2 mL) under nitrogen atmosphere was added potassium carbonate (41.4 mg, 1.5 eq) and (2-bromoethoxy)-tert-butyldimethylsilane (0.06 mL, 1.3 eq). The resulting mixture was stirred and heated at 80° C. for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure with silica gel. Gradient column chromatography (EtOAc-Hex from 1:100 to 3:1) gave 1-(2-(2-amino-5-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea as a fluffy white solid in the amount of 77 mg.