Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[O:40]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[CH2:53]O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:53][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:6][N:7]=1
Reactant: OCc1ccccc1Oc1ccccc1
Reactant: Oc1ccc(Br)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc(OCc2ccccc2Oc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromopyridin-3-ol (1.76 g) in tetrahydrofuran (20 ml), 3.20 g of triphenylphosphine, 5.52 ml of diethyl azodicarboxylate (45% toluene solution) and 2.43 g of (2-phenoxyphenyl)methanol were added, and the reaction solution was stirred overnight at room temperature. The reaction solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:100-15:85)) to afford the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:17][C:18]1[N:23]=[C:22]([O:24]CCCCCCCCCCCCCCCC)[C:21]([F:41])=[CH:20][N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>[OH-].[K+].C(O)C>[CH2:1]([O:17][C:18]1[NH:23][C:22](=[O:24])[C:21]([F:41])=[CH:20][N:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ncc(F)c(OCCCCCCCCCCCCCCCC)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCOc1ncc(F)c(=O)[nH]1
Yield: 73 %

Procedure:
A 2.9 g portion of the 2,4-di-(n-hexadecyloxy)-5-fluoropyrimidine is dissolved in a mixture of 5 ml of 2N aqueous potassium hydroxide solution and 25 ml of ethanol, and the solution is refluxed for 4 hours. The ethanol is distilled off from the resulting reaction mixture, and 50 ml of ether is added to the residue to remove ether-soluble substances. Dilute hydrochloric acid is added to the remaining mass to adjust the pH to 4-5 and to separate out crystals, which are recrystallized from ethanol to give 1.3 g of white crystalline 2-n-hexadecyloxy-5-fluoropyrimidin-4-one in a yield of 73.0 %, m.p. 97°-98° C.
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[CH2:54][CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:55])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23]O)[CH:16]=2)[N:14]=1)([CH3:9])([CH3:8])[CH3:7].CC[N:58]([CH:62]([CH3:64])C)[CH:59]([CH3:61])C.[OH2:65]>C(Cl)Cl>[CH:40]([OH:39])=[O:65].[C:6]([C:10]1[CH:11]=[C:12]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([N:49]5[CH2:54][CH2:53][CH2:52][CH2:51][C@@H:50]5[CH3:55])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:58]3[CH2:59][CH2:61][CH2:64][CH2:62]3)[CH:16]=2)[N:14]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: O
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCCC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Methanesulfonyl chloride (81 μL, 1.05 mmol) was added to a stirred solution of Intermediate 95e (545 mg, 803 mmol) and DIPEA (420 μL, 2.41 mmol) in DCM (20 mL), under argon and the reaction mixture was stirred at RT for 1.5 h. A further 25 μl, 0.32 mmol of methanesulfonyl chloride was added and the reaction mixture continued to stir at RT for 2 h. Water (20 mL) was added and the two layers were shaken thoroughly before being separated. The aqueous layer was extracted with DCM (2×20 mL) and the combined organics were passed through a phase separator and concentrated in vacuo to afford the title compound as an orange glass (690 mg, >100%). LCMS (Method 3): Rt 3.89 min, m/z 757 [MH+].
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40]>CS(C)=O>[CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5]
Reactant: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reactant: CCCS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(CN(C)S(=O)(=O)N2CCN(c3ncnc4[nH]ccc34)CC23CC3)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
N-methyl-N-(pyrrolidin-3-ylmethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 25) (0.042 mmol) was dissolved in dry DMSO (0.5 mL), added DIPEA (0.25 mL) and propane-1-sulfonyl chloride (0.050 mmol) and then stirred at 40° C. for 1 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[NH:11]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:15][CH2:16][CH2:17][CH2:18]3)[N:11]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:5]([CH2:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: CCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Reactant: BrC1CCCC1
Product: CCc1cc(C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrite was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with triethyl phosphonoacetate according to Method D12a according to afford 2-(2-ethyl-4-((1E)-2-ethoxycarbonylvinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11](=O)[CH:12]=[CH2:13].[NH2:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>>[CH3:10][C:11]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([S:16]([NH2:15])(=[O:17])=[O:18])=[CH:20][CH:21]=2)[C:5]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:9]=[CH:8][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=CC(C)=O
Reactant: Cc1cccc(C=O)c1
Product: Cc1cccc(-c2ccc(C)n2-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Meta-methylbenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-aminosulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 2.15 (3H), 2.05 (3H), 4.90 (2H), 6.10 (1H), 6.30 (1H), 6.89-7.90 (8H); MS (ESI) m/z 327 (M+H).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=1)[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31](C(OC(C)(C)C)=O)[CH2:30]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([F:15])[CH:14]=2)[C@@H:4]([C:5]([NH:24][C:25]2[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=2[CH2:27][CH2:28][C@H:29]2[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:41])([F:43])[F:42])[NH:31][CH2:30]2)=[O:7])[NH:1][C:37]([O:36][CH3:35])=[O:44])=[CH:17][C:18]=1[F:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@H](c1cncc(F)c1)c1ccc(Cl)c(F)c1
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@H](c1cncc(F)c1)c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=732 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:13]=2)[CH:8]=1)[CH3:2].[CH2:27]([I:29])[CH3:28].[CH3:30][C:31](C)=O>C(O)C>[I-:29].[I-:29].[CH2:23]([N+:20]([CH2:27][CH3:28])([CH2:21][CH3:22])[CH2:19][CH2:18][CH2:17][C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH2:30][CH3:31])([CH2:1][CH3:2])[CH2:25][CH3:26])[CH:8]=2)[CH:13]=1)[CH3:24]
Reactant: CCN(CC)CCCc1ccc2cc(CCCN(CC)CC)ccc2c1
Reactant: CCI
Reactant: CC(C)=O
Solvent: CCO
Product: CC[N+](CC)(CC)CCCc1ccc2cc(CCC[N+](CC)(CC)CC)ccc2c1
Product: [I-]
Reaction time: 0.33 h

Procedure:
To a solution of 78 mg of 2,6-bis(3-diethylaminopropyl)naphthalene in 1 ml of absolute ethanol was added 176 μl of ethyl iodide, and the mixture was refluxed for 140 minutes and cooled. After adding 2 ml of acetone, the mixture was stirred for 20 minutes. The resulting crystal was collected by filtration, washed with acetone and dried under a reduced pressure to obtain 117 mg of the title compound as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[C:10]([CH3:25])([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=3)[CH2:11][O:12]2)=[CH:7][CH:6]=1.[O:33]1[CH2:35][CH:34]1[CH2:36][O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:48])([F:47])[F:46].C(#N)C>N1C=CC=CC=1.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:35][C@H:34]([OH:33])[CH2:36][O:37][CH2:38][CH2:39][S:40][CH2:41][CH2:42][CH2:43][C:44]([F:50])([F:49])[C:45]([F:46])([F:47])[F:48])=[CH:30][CH:31]=3)[C:10]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:20]=3)([CH3:25])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: FC(F)(F)C(F)(F)CCCSCCOCC1CO1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OC[C@H](O)COCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Yield: 86.3 %

Procedure:
A mixture of (3RS,4RS)-7-methoxymethoxy-3-methyl-3-(4-methoxymethoxyphenyl)-4-(4-hydroxyphenyl)chroman (31 1 mg, 0.71 mmole), 1-((2-oxiranyl)methoxy)-2-(4,4,5,5,5-pentafluoropentylthio)ethane (568 mg, 1.93 mmole), acetonitrile (9 ml), water (3 ml) and pyridine (5 drops) was refluxed for 10 hours. After cooling, the reaction mixture was diluted with water and the aqueous phase was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (448 mg, yield 86%) as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:14])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[F:15][CH:16]([CH2:18][C:19](Cl)=[S:20])[F:17]>O1CCCC1>[C:8]([O:14][C:19](=[S:20])[CH2:18][CH:16]([F:17])[F:15])(=[O:13])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: FC(F)CC(=S)Cl
Reactant: CC(C)CC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)OC(=S)CC(F)F
Reaction time: 1 h

Procedure:
To a stirred solution of triethylamine (1.4 equivalents) and isovaleric acid (1.3 equivalents) in tetrahydrofuran (5 parts by weight) is dropwise added difluoromethylthioacetyl chloride at -30° C., and the mixture is left standing for 1 hour. After removing separated crystals by filtration, the reaction mixture is concentrated in vacuum to leave difluoromethylthioacetic isovaleric anhydride.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:11]=[C:12]=S)[CH:4]=[N:3]1.[CH2:14]([CH2:16][NH2:17])[OH:15]>CCOCC>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]2[O:15][CH2:14][CH2:16][N:17]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cccc(N=C=S)c21
Reactant: NCCO
Solvent: CCOCC
Product: Cn1ncc2cccc(NC3=NCCO3)c21

Procedure:
The starting material is prepared as follows: 3 g of 1-methyl-7-isothiocyanato-indazole is added to a stirred mixture of 2 ml of ethanolamine and 100 ml of ether, thus forming a white precipitate. After 2 hours the precipitate is filtered off and washed with ether to yield the starting material; M.Pt. 207° - 209°.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(#N)C.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=1>O>[NH2:24][C:22]([C:21]1[CH:25]=[CH:26][C:18]([O:17][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:19][CH:20]=1)=[O:23]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)COc1ccc(C(N)=O)cc1
Temperature: 80 °C

Procedure:
Potassium carbonate (1.04 g) and ethyl bromoacetate (0.610 ml) were added to an acetonitrile (15 ml) solution containing 4-hydroxybenzamide (686 mg), followed by heating at 80° C. for 2 hours. The reaction solution was cooled, water (45 ml) was added thereto, and the precipitated solid was collected by filtration, washed with water and dried to obtain ethyl [4-(aminocarbonyl)phenoxy]acetate (893 mg) as pale brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8]SCC)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([F:17])([F:16])[F:15].[CH:18]1C=C(Cl)C=C(C(OO)=O)[CH:19]=1.[O-:29][S:30]([O-:32])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][S:30]([CH2:18][CH3:19])(=[O:32])=[O:29])[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([F:15])([F:17])[F:16]
Reactant: CCSCc1ccc(OCC(F)(F)F)c(Br)c1
Reactant: O=S([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91 %

Procedure:
To a solution of the title compound from Step 4 (2.10 g, 6.38 mmol) in DCM (210 mL) was added MCPBA (4.41 g, 25.53 mmol) in several portions. The mixture was stirred at 25° C. for 12 hrs. The reaction was poured into sat. aq. Na2SO3 (100 mL) and extracted with DCM (80 mL×3). The combined organic layers were washed with sat. NaHCO3 (100 mL×2) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE:EA=1:0˜2:1) to give the title compound (2.10 g, 91%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.64 (d, J=2.0 Hz, 1H), 7.37 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 4.43 (q, J=8.0 Hz, 2H), 4.15 (s, 2H), 2.91 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[S:15]2)[S:10][C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:40][C:41]1[CH:42]=[C:43]([NH:50][C:51](=[O:55])[CH2:52][O:53][CH3:54])[CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49]>>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:16]([CH3:26])[S:15]2)[S:10][C:9]1=[N:40][C:41]1[CH:42]=[C:43]([NH:50][C:51](=[O:55])[CH2:52][O:53][CH3:54])[CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1ccc(NC(=O)COC)cc1N
Reactant: CC1=C(c2ccccc2)N(C)C(=C2SC(=S)N(Cc3ccccc3)C2=O)S1
Agent: COS(=O)(=O)c1ccc(C)cc1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2SC(C)=C(c3ccccc3)N2C)C(=O)N1Cc1ccccc1

Procedure:
Likewise as described in Example 1, intermediate 3′-benzyl-3,5-dimethyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one was alkylated with methyl p-toluenesulfonate and condensed with N-(3-amino-4-ethylaminophenyl)-2-methoxyacetamide to afford the title compound. 1H-NMR (CDCl3): δ 8.00 (1H, br s), 7.42-7.51 (5H, m), 7.30-7.37 (3H, m), 7.19-7.26 (3H, m), 7.11 (1H, d), 6.53 (1H, br s), 5.18 (2H, s), 3.97 (2H, s), 3.47 (3H, s), 3.42 (3H, s), 2.98 (2H, m), 2.06 (3H, s), 1.02 (3H, br t); MS(ESI): 600 (MH+).
Reaction SMILES: C([CH:4]1[CH2:9][CH2:8][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]#C)=[O:13])[CH2:6][CH2:5]1)(O)=O.[H][H].CC[O:33][C:34]([CH3:36])=[O:35]>[Pd]>[C:34]([CH2:36][CH:4]1[CH2:5][CH2:6][C:7]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:13])[CH2:8][CH2:9]1)([OH:35])=[O:33]
Reactant: [H][H]
Reactant: CCOC(C)=O
Reactant: C#COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(C(=O)O)CC1
Agent: [Pd]
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(CC(=O)O)CC1

Procedure:
A mixture of 1-carboxymethylidenyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohexane (Example 174, 64 mg, 0.17 mmol) and Pd/C (10 mg, 10%), in 5.0 mL of EtOAc was shaken under 50 psi of hydrogen for 24 h. The mixture was filtered through a plug of silica gel and concentrated to give the title compound as a mixture of isomers.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[Na+].[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[CH2:20]>O>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:20][CH2:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: C=Cc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccccn2)CCN(C)CC1
Temperature: 80 °C
Yield: 35.8 %

Procedure:
The title compound was prepared by following general procedure 4. To a solution of 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150 mg, 0.7 mmol) in 50% aq. NaOH solution (7 mL) tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) followed by 2-vinylpyridine (80 mg, 0.77 mmol) was added and the reaction mixture was heated at 80° C. for 14 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 80 mg of 3,9-dimethyl-6-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][O:17][C:16]3([CH3:23])[CH3:22])=[CH:10][CH:11]=1)=[O:4].[C:26](=O)(OC(Cl)(Cl)Cl)[O:27]C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:23][C:16]1([CH3:22])[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([O:12][C:9]3[N:8]=[CH:7][C:6]([N:5]4[C:3](=[O:4])[C@@H:2]([CH2:24][CH3:25])[NH:1][C:26]4=[O:27])=[CH:11][CH:10]=3)[CH:14]=2)[CH2:18][O:17]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc3c(c2)C(C)(C)OC3)nc1
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3ccc4c(c3)C(C)(C)OC4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 167.5 %

Procedure:
To a solution of (2R)-2-amino-N-[6-[(3,3-dimethyl-1H-isobenzofuran-5-yl)oxy]-3-pyridyl]butanamide (Intermediate 61, 18 mg, 0.0527 mmol) in DCM (4 mL) N,N-diethylethanamine (0.022 ml, 0.16 mmol) was added and the reaction mixture was cooled to 0° C. A solution of bis(trichloromethyl) carbonate (7.8 mg, 0.026 mmol) in DCM (1 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was diluted with DCM (5 ml) and washed with an aqueous saturated solution of NH4Cl (10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 80:20 to 10:90 as eluent affording the title compound (16 mg) as white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3OC)nc2n(CC)c1=O
Yield: 46 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.52 g (12.1 mmol) of 2,3dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylsulfoxide/water to give 1.72 g (yield 46%) of Compound 66 as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Br[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:25]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: BrCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2cccc(OCCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
potassium carbonate (0.072 g, 0.52 mmol) was added to a solution of piperazine-1,4-dicarboxylic acid (3-hydroxy)benzyl ester tert-butyl ester (0.16 g, 0.48 mmol) in acetone (5 mL) at 0° C. and the reaction mixture was stirred at 0° C. for 30 min. (2-Bromoethyl)-benzene (0.097 g, 0.52 mmol) was added and the reaction mixture was allowed to warm to room temperature and then heated under reflux for 24 h. After cooling, the reaction mixture was concentrated in vacuo and the residue was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with saturated brine (25 mL), dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography [SiO2; heptane-ethyl acetate (3:1)] to yield the title compound (0.10 g, 48%) as a colourless oil. 1H-NMR (400 MHz, CDCl3): 1.46 (9H, s), 3.10 (2H, t, J=7.0 Hz), 3.40 (4H, m), 3.46 (4H, m), 4.18 (2H, t, J=7.0 Hz), 5.09 (2H, s), 6.84 (1H, m), 6.88 (1H, m), 6.91 (1H, m) and 7.22–7.34 (6H, m).