Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)#[N:2].CSC.B>C1COCC1>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[NH:21][S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CC#N)cc2)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@H]1c1ccc(-c2ccc(CCN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(+,−) Trans propane-2-sulfonic acid [2-(4′-cyanomethyl-biphenyl-4-yl)-cyclopentyl]-amide (210 mg, 0.55 mmol, prepared in example 8) was dissolved in 20 mL dry THF. To this solution was added 0.83 mL (1.65 mmol) of a 2.0 M solution of borane dimethyl sulfide in THF. The reaction was heated to reflux for 4 hours then concentrated in vacuo. To this solid was added 30 mL of diethyl ether, 15 mL of concentrated HCl, 10 mL of water, and 5 mL of methanol and stirred at room temperature for 30 minutes. The aqueous layer was separated, and the organic phase washed 1× with water. The combined aqueous phases were made basic with sodium hydroxide at 0° C. and extracted into diethyl ether (2×50 mL) followed by ethyl acetate (1×50 mL). The combined organic phases were dried over sodium sulfate, filtered, and concentrated to a crude oil which was used without further purification.
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[CH2:13](Cl)[CH:14]=[CH2:15]>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]=[CH2:15]
Reactant: COCCOCCOCCO
Reactant: C=CCCl
Agent: [K]
Solvent: O
Product: C=CCOCCOCCOCCOC
Yield: 74 %

Procedure:
540 mls of dried peroxide free tetrahydrofuran and 21.5 g of potassium metal are charged into a 2000 ml three-neck flask equipped with mechanical stirrer and a dry nitrogen inlet. 88.4 ml of triethylene glycol monomethyl ether, available from Chemical Samples Co., is added to the mixture dropwise. After the potassium metal has completely reacted, 48.6 ml of allyl chloride is added dropwise to the mixture at such a rate in order to maintain a gentle reflux. After the reaction is complete, 500 mls of distilled water are added in order to dissolve the precipitated salt. The tetrahydrofuran layer is washed with salt water (270 g NaCl/1 liter water) in order to remove the excess alcohol. The resulting product in tetrahydrofuran is collected and the tetrahydrofuran is removed with a water aspirator. The product is distilled at reduced pressure. 75.5 g (74% yield) of triethylene glycol allyl methyl ether is obtained (b.p. 97° C.-100° C./2 mm). The analytical data is consistent with a product of the general formula:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([N:24]=[C:25]=[S:26])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:28][CH:29]1[CH2:32][NH:31][CH2:30]1>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:24][C:25]([N:31]1[CH2:32][CH:29]([OH:28])[CH2:30]1)=[S:26])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:21])[CH3:22])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N=C=S
Reactant: OC1CNC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=S)N1CC(O)C1
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 3-(t-butyldiphenylsilyloxy)-2-isothiocyanatopropionic acid methyl ester (13.4 g, 33.5 mmol) (obtained as described in Reference Example 70(1)) in tetrahydrofuran (245 ml) was added a solution of 3-hydroxyazetidine (4.90 g, 67.1 mmol) (obtained as described in Reference Example 31(1)) in water (50 ml) at room temperature and the mixture was stirred overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene and toluene:acetonitrile (3:1) as the eluant to afford (2S)-3-(t-butyldiphenylsilyloxy)-2-[(3-hydroxyazetidine-1-carbothioyl)amino]propionic acid methyl ester (9.60 g, yield 61%) as an yellow solid.
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:28])[C@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@H:17]1[C:25](Cl)=[O:26].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:28])[C@H:18]([CH:19]=[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C@H:17]1[C:25]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:26]
Reactant: CC1(C)[C@H](C=C2CCCC2)[C@H]1C(=O)Cl
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C2CCCC2)[C@H]1C(=O)OCc1cnc(Oc2ccccc2)s1
Temperature: 20 °C
Reaction time: 20 h
Yield: 52.7 %

Procedure:
2.74 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of 2 g of (1R,3R) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 74405 published under No. 1,505,423] in 30 ml of benzene and 0.81 ml of pyridine was added dropwise thereto. The mixture was stirred at 20° C. for 20 hours and was poured into dilute aqueous hydrochloric acid. The decanted aqueous phase was extracted with ether and the combined organic phases were dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 1.9 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylate meltingat 67° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:7]=[CH:6][N:5]=1.[SH:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:21]=2[N:22]=1.O.[OH-].[Na+]>C(O)C>[CH3:28][O:27][C:25]1[CH:24]=[CH:23][C:21]2[NH:22][C:18]([S:17][CH2:3][C:4]3[C:9]([CH3:10])=[C:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[N:7]=[CH:6][N:5]=3)=[N:19][C:20]=2[CH:26]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1c(CCl)ncnc1N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2[nH]c(SCc3ncnc(N4CCCCC4)c3C)nc2c1

Procedure:
A mixture of 4-chloromethyl-5-methyl-6-piperidino pyrimidine hydrochloride (4.63 g) and 2-mercapto-5-methoxybenzimidazole (3.18 g) in ethanol (180 ml) were heated at 50° for 5 hours. The solution was stripped to a residual glass, to which water was added, the pH raised to 13 (NaOH), and extracted with chloroform. Extracts were dried (K2CO3) and stripped to a residual glass which crystallised from ethyl acetate to give 5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, 5.67 g, m.p. 94°-96°.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:5]=1[O:6][CH2:7]C(OC)=O)(=O)[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:4]2[C:1]([CH2:2][Br:35])=[CH:7][O:6][C:5]=2[CH:12]=1
Reactant: COC(=O)COc1cc(Br)ccc1C(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: BrCc1coc2cc(Br)ccc12
Yield: 32 %

Procedure:
A solution of the product from Example 58, Part C (1.0 g, 4.74 mmol) and dibenzoyl peroxide (287 mg, 1.19 mmol) in chlorobenzene (24 mL) at reflux was treated in four portions with N-bromosuccinimide (843 mg, 4.74 mmol) over 30 min. The mixture was then stirred at reflux for 2 h. The mixture was cooled, filtered and concentrated and purified by column chromatography on silica gel, eluting with 7-30% chloroform in hexanes. The procedures afforded the title compound as a light yellow oil (438 mg, 32%).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22].Br[CH2:28][CH:29]1[CH2:31][C:30]1([F:33])[F:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:32][C:30]1([F:33])[CH2:31][CH:29]1[CH2:28][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][C:10]3[C:2]([F:1])=[C:3]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:26])[CH3:25])[CH3:22])[CH:4]=[CH:5][C:6]=3[N:7]=2)=[CH:12][C:13]=1[F:18]
Reactant: FC1(F)CC1CBr
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4(F)F)c(F)c3)oc2c1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A suspension of N-((2S)-1-((7-fluoro-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (810 mg), 1-bromomethyl-2,2-difluorocyclopropane (573 mg) and potassium carbonate (463 mg) in DMF (10 mL) was stirred at 70° C. for 1 hr and 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was washed with diethyl ether to give the title compound (880 mg).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].CS([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)(=O)=O>>[CH2:1]([S:3]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)=[O:19])[CH2:13][CH2:12]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 43 %

Procedure:
Ethylsulfonyl chloride (63 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (40 mg, 0.105 mmol, 43% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.77 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.2 Hz, 1H), 3.63 (m, 1H), 3.52 (d, J=12.3 Hz, 2H), 3.05 (m, 5H), 1.89 (d, J=10 Hz, 2H), 1.47 (m, 2H), 1.22 (t, J=4.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH2:27]([N:29]([CH2:30][CH3:31])[C:2]1[CH:7]=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)[N:9]=2)[CH:5]=[C:4]([CH3:20])[N:3]=1)[CH3:28]
Reactant: Cc1cc(-c2noc(-c3cc(C)nc(Cl)c3)n2)ccn1
Reactant: CCNCC
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN(CC)c1cc(-c2nc(-c3ccnc(C)c3)no2)cc(C)n1
Temperature: 90 °C
Reaction time: 72 h
Yield: 23.8 %

Procedure:
To a solution of 2-chloro-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (160 mg, 0.558 mmol, Example 43a)) in dioxane (10 mL), Cs2CO3 (636 mg, 1.95 mmol) and diethylamine (204 mg, 2.79 mmol) is added. The mixture is degassed and put under N2 before Pd(II) acetate (25 mg, 0.112 mmol) and Xantphos (116 mg, 0.201 mmol) is added. The mixture is stirred in a sealed vial at 90° C. for 72 h before it is cooled to rt. The mixture is filtered and the filtrate is evaporated. The crude product is purified on prep. TLC plates with heptane:EA 3:1 to give 2-diethylamino-4-[3-(2-methyl-4-pyridinyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine (43 mg) as a yellow solid; LC-MS: tR=0.66 min, [M+1]+=324.15; 1H NMR δ 1.26 (t, J=7.0 Hz, 6H), 2.51 (s, 3H), 2.71 (s, 3H), 3.63 (q, J=7.0 Hz, 4H), 7.01 (s, 1H), 7.09 (s, 1H), 7.86 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 8.71 (d, J=5.0 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C:13]([NH:15][C:16]1[NH:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:14]>CN(C)C=O>[NH2:12][C:13]([NH:15][C:16]1[NH:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][C:8](=[O:10])[CH3:9])=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:14]
Reactant: CC(=O)Cl
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Triethylamine (80 μL, 0.57 mmol) and acetyl chloride (33 μL, 0.46 mmol) were added to a solution of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 100 mg, 0.39 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the target compound (41 mg) as a green-brown solid (Yield 35%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].C[N+]([O-:14])(C)C>>[O:14]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9]
Reactant: N#CCCCCCCBr
Reactant: C[N+](C)(C)[O-]
Product: N#CCCCCCC=O

Procedure:
7-bromoheptanenitrile and trimethylamine oxide were processed using the method described in Example 137A to afford the title compound. MS (ESI+) m/z 143 (M+NH4)+.
Reaction SMILES: [Cl-].[OH:2][C@H:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C@@H:4]([NH3+:6])[CH3:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27](I)=[C:28]([CH3:31])[CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:2][C@H:3]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=4)[C@@H:4]([NH2:6])[CH3:5])=[C:28]([CH3:31])[CH:29]=3)[CH:24]=[N:23]2)=[CH:20][CH:21]=1
Reactant: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1I
Reactant: COc1cccc([C@@H](O)[C@H](C)[NH3+])c1
Agent: [Cl-]
Product: COc1cccc([C@@H](Oc2cc3cnn(-c4ccc(F)cc4)c3cc2C)[C@H](C)N)c1

Procedure:
Prepared as described in Example 1 from (1R,2S)-1-hydroxy-1-(3-methoxyphenyl)propan-2-aminium chloride (185 mg, 0.85 mmol) and 1-(4-fluorophenyl)-5-iodo-6-methylindazole (300 mg, 0.85 mmol). Yield 224 mg (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N[C:32](=[O:50])[C:33]2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([CH2:33][CH2:32][OH:50])[CH2:18]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@@H]1CCCNC1
Reactant: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@@H]1CCCN(CCO)C1
Yield: 64.7 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (R)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-A, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, was used in the same molar amount (Yield: 64.7%). 1H NMR (CDCl3) δ 8.48 (br, 1H), 8.40 (s, 1H), 8.17 (d, 1H), 7.76 (d, 1H), 7.59 (s, 1H), 7.42 (d, 1H), 7.19 (t, 1H), 7.03 (d, 1H), 6.48-6.40 (m, 1H), 4.35-4.23 (m, 1H), 3.61 (t, 2H), 3.13 (br, 2H), 2.69 (d, 1H), 2.60-2.36 (m, 4H), 1.85-1.58 (m, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.C[N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>O.CN(C)C=O>[Cl:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(F)c(F)c1Cl
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(F)c(F)c1Cl
Reaction time: 40 h
Yield: 52.3 %

Procedure:
To a mixture of 2-chloro-3,4-difluorobenzoic acid (2.50 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.99 g), 1-hydroxybenztriazole (2.39 g) and N,N-dimethylformamide (72 mL) was added 28% aqueous ammonia (1.6 mL) at room temperature, and the mixture was stirred for 40 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane). The obtained solid was washed with dichloromethane to give the title compound as a solid (yield: 1.30 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][N:21]=1>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:19][C:20]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Product: CCOC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)nc1
Yield: 5.4 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methyl ethoxy)benzo[b]thiophene-2-carboxylic acid (1.07 g, 4 mmol ) and ethyl 6-aminonicotinate (690 mg, 4.2 mmol) provides 90 mg (6%) of product; mp 131°-133° C.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][S:15][CH:16]=[C:10]3[C:9]2=[O:17])[CH2:6][CH2:5][C:4](=[O:18])[NH:3]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH3:21][N:3]1[C:4](=[O:18])[CH2:5][CH2:6][CH:7]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][S:15][CH:16]=[C:10]3[C:9]2=[O:17])[C:2]1=[O:1]
Reactant: CI
Reactant: O=C1CCC(N2C(=O)c3cscc3C2=O)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCC(N2C(=O)c3cscc3C2=O)C1=O
Reaction time: 8 h

Procedure:
0.264 g of 5-(2,6-dioxopiperidin-3-yl)-5H-thieno(3,4-c)pyrrole-4,6-dione were dissolved in 10 mL anhydrous DMF, and 0.036 g of NaH (95%) were added. The reaction mixture was reacted at room temperature for 30 min, and 0.2 mL of CH3I were added. The reaction mixture was allowed to stir overnight. 100 mL of water were added, and the aqueous phase was extracted with ethyl acetate (3×30 mL). Organic phases were combined, washed with 30 mL of water and 30 mL of brine, dried over anhydrous MgSO4, filtered, and evaporated to dryness. A white solid (0.196 g) was obtained. 1H NMR (CDCl3): δ 7.91 (s, 2H), 4.93 (d, 1H, J=3 Hz), 3.22 (s, 3H), 3.04-2.94 (m, 1H), 2.83-2.71 (m, 2H), 2.11 (m, 1H); MS (m/z): 278 (M)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>C(Cl)Cl>[C:8]([NH:18][C:19]1[CH:28]=[C:27]([CH2:29][S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(CSc2ccccc2)cc1N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(CSc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.52 mL of triethylamine and 0.16 mL of benzoyl chloride were added to 3.8 mL of methylene chloride suspension containing 0.39 g of methyl 2-amino-4-((phenylthio)methyl)benzoate hydrochloride while ice-cooled and stirred at room temperature for 3 hours and 30 minutes. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent vas evaporated under reduced pressure, Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.29 g of methyl 2-(benzamido)-4-((phenylthio)methyl)benzoate as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25]C(OC(C)(C)C)=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N(CC)C(C)C)(C)C.[O:45]1[CH:49]2[O:50][CH2:51][CH2:52][CH:48]2[CH:47]([O:53][C:54](=[O:63])ON2C(=O)CCC2=O)[CH2:46]1>O1CCOCC1>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:15][CH:16]([OH:33])[CH:17]([NH:25][C:54]([O:53][CH:47]1[CH:48]2[CH:49]([O:50][CH2:51][CH2:52]2)[O:45][CH2:46]1)=[O:63])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][CH:12]([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Reactant: O=C(OC1COC2OCCC12)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.4 %

Procedure:
(3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamic acid benzyl ester 16 (7.54 g, 15 mmol) and 35 ml of 4M HCl in dioxane were stirred 30 min under an argon atmosphere. The mixture was concentrated in vacuo, and co-evaporated twice with dichloromethane. The residue was dissolved in dichloromethane (50ml) and N,N-diisopropylethylamine (6.1 ml, 35 mmol), and carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester 17 (4.88g, 18 mmol) was added. The reaction mixture was stirred overnight, and then concentrated in vacuo. The residue was diluted with dichloromethane, and sequentially washed with brine, 10% KHSO4, brine, saturated NaHCO3, and brine, then dried over MgSO4, and concentrated in vacuo. The oily residue was purified by flash chromatography using 70:30 ethyl acetate hexane as eluant, to give [3-(Hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamic acid benzyl ester 18 (5.8 g, 73%) as a white solid. TLC: Rf 0.56 (7:3 ethyl acetate: hexane). MS m/z 527 (MH)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][C:13]#[N:14])[CH3:2]
Reactant: CCCCCCCNCC
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CC)CC#N
Temperature: 125 °C

Procedure:
Combine 7.95 g (0.055 moles) ethyl(heptyl)amine, 3.5 ml (0.055 moles) chloroacetonitrile, 5.8 g (0.055 moles) sodium carbonate and 25 ml toluene in a sealed pressure tube. Heat to 125° C. for 18 hrs. Follow the progress of the reaction by thin layer chromatography on silica gel (CH3CN+MeOH+NH4OH, 85+10+5). At the completion of the reaction, filter the reaction mixture and evaporate the solvents to provide the title compound.