Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][N:14]=2)=[N:11][N:10]=[C:9]1/[CH:23]=[CH:24]/[C:25]([NH:27][NH:28][C:29]([C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:30])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](/[CH:23]=[CH:24]/[C:25]2[O:30][C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=3)=[N:28][N:27]=2)=[N:10][N:11]=[C:12]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][N:14]=1
Reactant: COc1cc(C(=O)NNC(=O)/C=C/c2nnc(-c3ccc(S(C)(=O)=O)cn3)n2-c2ccccc2Cl)ccn1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2nnc(/C=C/c3nnc(-c4ccc(S(C)(=O)=O)cn4)n3-c3ccccc3Cl)o2)ccn1
Reaction time: 2 h

Procedure:
N′-[(E)-3-[4-(2-chlorophenyl)-5-(5-methylsulfonyl-2-pyridyl)-1,2,4-triazol-3-yl]prop-2-enoyl]-2-methoxy-pyridine-4-carbohydrazide 10 was dissolved into dichloromethane (10 mL), and triphenyl phosphine (0.27 g, 1.0 mmol), carbon tetrabromide (0.34 g, 1.04 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added. The reaction mixture was kept at ambient temperature for 2 h. The final compound was purified by column chromatography (eluting with hexane and ethyl acetate 1:3) to give 2-(4-(2-chlorophenyl)-5-((E)-2-(5-(2-methoxypyridin-4-yl)-1,3,4-oxadiazol-2-yl)vinyl)-4H-1,2,4-triazol-3-yl)-5-(methylsulfonyl)pyridine as a yellow solid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[OH:1][C:2]([C:3]1[O:4][N:62]=[C:61]([NH:60][C:55]2[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]3[C:43](=[O:65])[N:42]([CH3:41])[C:51]4[C:46]([CH:45]=3)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=4)[CH:54]=2)[N:64]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C(C)(C)O)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Hydroxy-2-methylpropanoic acid (16.1 mg, 0.15 mmol), HATU (59 mg, 0.15 mmol), and DIPEA (0.027 mL, 0.15 mmol) were stirred in dry DMF (3 mL) for 1 h before 17 (50 mg, 0.14 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling and filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(2-hydroxypropan-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A32) as a solid. 1H NMR (400 MHz, d4-MeOH) δ 8.90 (s, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.62 (dd, J=8, 4 Hz, 1H), 7.52 (d, J=8, 4 Hz, 1H), 7.35 (d, J=4 Hz, 1H), 7.26 (dd, J=8, 4 Hz, 1H), 7.14 (d, J=8 Hz, 1H), 3.79 (s, 3H), 2.75 (s, 3H), 2.06 (s, 3H), 1.35 (m, 6H). MS m/z 406.2 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Cl:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14]>CO>[Cl-:10].[OH:15][CH:12]([CH2:13][OH:14])[CH2:11][N+:7]1[CH:8]=[CH:9][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=1
Reactant: CCCCn1ccnc1
Reactant: OCC(O)CCl
Solvent: CO
Product: CCCCn1cc[n+](CC(O)CO)c1
Product: [Cl-]
Reaction time: 48 h
Yield: 99.1 %

Procedure:
1-Butylimidazole (12.42 g, 100.0 mmol) and 3-chloro-1,2-propanediol (11.05 g, 100.0 mmol) were stirred in a 130° C. oil bath for 48 h, after which the flask was placed under vacuum and stirring continued at 130° C. for another 48 h. The residue was then dissolved in CH3OH, transferred to a tared flask, and concentrated to afford the product as a viscous brown oil (23.27 g, 92%). 1H NMR: δH ppm (400 MHz; DMSO-d6) 0.89 (t, 3H) 1.17-1.31 (m, 2H) 1.69-1.83 (m, 2H) 3.19-3.28 (m, 1H) 3.37-3.46 (m, 1H) 3.78 (dd, J=7.05, 4.49 Hz, 1H) 4.12 (dd, J=13.83, 7.60 Hz, 1H) 4.20 (t, J=7.14 Hz, 2H) 4.33 (dd, J=13.74, 3.11 Hz, 1H) 5.16 (br. s., 1H) 5.56 (d, J=5.31 Hz, 1H) 7.78 (t, J=1.74 Hz, 1H) 7.83 (t, J=1.74 Hz, 1H) 9.30 (t, J=1.47 Hz, 1H).
Reaction SMILES: [NH:1]([C:8](=[O:47])[CH:9]([C:19]1[CH:46]=[CH:45][C:22]([C:23]([NH:25][C:26]2[C:30]([NH:31]C(=O)OC(C)(C)C)=[CH:29][N:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:27]=2)=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C.CO.O1CCOCC1>[NH2:31][C:30]1[C:26]([NH:25][C:23]([C:22]2[CH:45]=[CH:46][C:19]([CH:9]([C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:11])[C:8]([NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:47])=[CH:20][CH:21]=2)=[O:24])=[N:27][N:28]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cn(-c2ccccc2)nc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of tert-butyl [3-({4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)-1-phenyl-1H-pyrazol-4-yl]carbamate (crude from above) in ethyl acetate (20 mL) and methanol (20 mL) was added 4M HCl in dioxane (10 mL) and the resulting solution was stirred at ambient temperature for 16 hours. The reaction was evaporated to dryness and purified by reverse phase LC to give 0.22 g (52%, 2 steps) of 2-(4-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]-carbonyl}phenyl)-N,N′-diphenyl-malonamide as a white solid. 1H NMR (600 MHz, CD3OD) δ 10.30 (s, 1H), 8.44 (s, 1H), 8.08 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.8 Hz, 21-1), 7.74 (d, J=8.5 Hz, 2H), 7.58 (m, 4H), 7.51 (m, 2H), 7.36 (m, 1H), 7.32 (m, 4H), 7.11 (t, J=7.33 Hz, 2H); ESIMS calcd 531.2 (M++H), found 531.2 (M++H).
Reaction SMILES: [ClH:1].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NC1C=CC([NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=N)=CC=1)=O)(C)C.CC(C1C=C([C:49](=[CH2:61])[C:50]([NH:52][C:53]2[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([NH2:60])[CH:54]=2)=[O:51])C=C(C(C)(C)C)C=1O)(C)C.[CH3:62][C:63]([C:66]1[CH:67]=[C:68]([CH:79]=[C:80]([C:83]([CH3:86])([CH3:85])[CH3:84])[C:81]=1[OH:82])C(NC1C=CC(N)=CC=1)=O)([CH3:65])[CH3:64]>>[ClH:1].[CH3:86][C:83]([C:80]1[CH:79]=[C:68]([CH:61]=[CH:49][C:50]([NH:52][C:53]2[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([NH:60][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[NH:18])[CH:54]=2)=[O:51])[CH:67]=[C:66]([C:63]([CH3:64])([CH3:65])[CH3:62])[C:81]=1[OH:82])([CH3:85])[CH3:84]
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: C=C(C(=O)Nc1ccc(O)c(N)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc(NC(=N)c3cccs3)cc2)cc(C(C)(C)C)c1O
Agent: Cl
Product: CC(C)(C)c1cc(C=CC(=O)Nc2ccc(O)c(NC(=N)c3cccs3)c2)cc(C(C)(C)C)c1O
Yield: 62 %

Procedure:
The experimental protocol used is the same as that described for compound 1, with 3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. The free base is purified on a silica column (eluant: heptane/ethyl acetate: 35/65). The pure fractions are collected and concentrated under reduced pressure. The evaporation residue is diluted in 10 ml of acetone and salified with a molar solution of HCl in anhydrous ether, as described previously. 0.35 g (62%) of a yellow powder is obtained. Melting point: 199-200° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1.[CH2:22]([C@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNC1)O2
Reactant: c1ccc(C[C@H]2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCN(C[C@@H](O)Cc3ccccc3)C1)O2

Procedure:
Compound 196 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione, (2S)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=59-60° C., 400 MHz 1H NMR (CDCl3) δ: 8.05-8.03 (br d, J=7.43 Hz, 1H), 7.73-7.70 (m, 1H), 7.65-7.60 (m, 1H), 7.52-7.44 (m, 1H), 7.31-7.18 (m, 5H), 3.95-3.91 (m, 1H), 3.18-2.91 (m, 3H), 2.78-2.53 (m, 5H), 2.45-2.33 (m, 2H), 2.03-1.71 (m, 4H); LCMS: 436 [M+H].
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4](CC2C=CC=CC=2)[CH2:3]1.[C:16](Cl)(=[O:20])[O:17][CH2:18][CH3:19]>CC1C=CC=CC=1>[CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:16]([O:17][CH2:18][CH3:19])=[O:20])[CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(=O)C(C)C1
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 152 parts of 3-methyl-1-(phenylmethyl)-4-piperidinone in 900 parts of methylbenzene were added dropwise 218 parts of ethyl carbonochloridate at room temperature. Upon completion, stirring was continued overnight at reflux. After cooling the reaction mixture was washed with water and hydrochloric acid, dried, filtered and evaporated. The residue was distilled, yielding 120.5 parts (83%) of ethyl 3-methyl-4-oxo-1-piperidinecarboxylate; bp. 98°-105° C. at 1 mm pressure (intermediate 26).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1)(=[O:4])=[O:3].[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27](=O)[O:28]C2C=CC=CC=2)[N:19]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([NH:26][C:27]([NH:1][S:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)(=[O:3])=[O:4])=[O:28])[N:19]=1
Reactant: COc1cc(Cl)nc(NC(=O)Oc2ccccc2)n1
Reactant: Cn1nnnc1-c1ccccc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(Cl)nc(NC(=O)NS(=O)(=O)c2ccccc2-c2nnnn2C)n1
Temperature: 0 °C
Yield: 87 %

Procedure:
To 0.48 g of 5-(2-aminosulfonylphenyl)-1-methyl-1H-tetrazole and 0.56 g of phenyl N-(4-chloro-6-methoxypyrimidine-2-yl)carbamate in 20 mL of dry acetonitrile at ambient temperature was added, with stirring, 0.3 mL of DBU. After stirring 16 hours the mixture was then poured into 25 g of ice followed by the addition of 10 mL of 2N hydrochloric acid. The precipitate thus formed was removed by filtration, washed with water and dried to yield 0.74 g of the desired product, m.p. 225°-227° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35]([CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:45]2[CH2:46][CH2:47][CH:42]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:43][CH2:44]2)=[O:14])=[CH:11][C:10]=1[C:18]([NH:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=[C:25]([C:27]([F:28])([F:30])[F:29])[CH:26]=1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(=O)N2CCC(Cc3ccccc3)CC2)ccc1OCc1ccccc1
Yield: 76.7 %

Procedure:
Using 4-benzyloxy-N-[3,5-bis(trifluoromethyl)phenyl]isophthalamic acid (compound of Example 84(2)) and 4-benzylpiperidine as the raw materials, the same operation as the Example 84(3) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.C([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)#C.[CH2:40](NCC)[CH3:41]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:40]#[C:41][C:39]4[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=4)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(C#Cc3ccncc3)c21
Reaction time: 8 h

Procedure:
A flame-dried flask under an atmosphere of nitrogen gas containing N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(morpholin-4-ylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Preparation # 15) (0.28 g) is treated with copper (I) iodide (0.01 g), dichlorobis(triphenylphosphine)palladium (II) (0.03 g) and 3-ethynylpyridine (0.10 g). The solids are treated with dimethylformamide (DMF) (3 ML) and diethylamine (3 mL). The resulting suspension is stirred overnight, concentrated under reduced pressure and finally in vacuo. The residue is flash column chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are combined and concentrated under reduced pressure. The resulting material is crystallized from acetonitrile to afford the title compound (0.23 g) as light yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[CH2:36][C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL). Pyridine (1 mL) was added followed by 2-(2-thienyl)ethanoyl chloride (14 uL, 0.113 mmol). After stirring overnight, another 14 uL of 2-(2-thienyl)ethanoyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatogram eluted with dichlormethane/Methanol (95:5) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-(2-thienyl)acetamide (14 mg, 0.031 mmol). 1H NMR (DMSO-d6) 1.89 (m, 6H), 2.25 (m, 2H), 3.82 (s, 3H), 3.99 (s, 2H), 5.19 (bs, 2H), 5.21 (m, 1H), 6.93 (s, 1H), 6.94 (s, 1H), 7.06 (m, 3H), 7.31 (m, 1H), 8.02 (s, 1H), 8.32 (s, 1H), 8.42 (d, J=8.22 Hz, 1H). LC/MS MH+=448.
Reaction SMILES: OCC[N:4]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[N:6]=[CH:5]1.[NH+]1C=CC=CC=1.C([CH2:23][CH2:24][O:25][P:26](=[O:29])([O-:28])[O-:27])#N.[NH+]1C=CC=CC=1>N1C=CC=CC=1.O>[CH3:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]2[N:6]=[C:5]([CH2:23][CH2:24][O:25][P:26](=[O:27])([OH:29])[OH:28])[NH:4][C:8]=2[CH:9]=1
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: Cc1cc2ncn(CCO)c2cc1C
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc2nc(CCOP(=O)(O)O)[nH]c2cc1C
Reaction time: 48 h

Procedure:
A 0.19 g amount of the crude 1-(2-hydroxyethyl)-5,6-dimethylbenzimidazole and 2 ml of 2-cyanoethylphosphoric acid pyridinium salt solution (1 mmol/ml) were dissolved in 20 ml of dry pyridine, and the solution was concentrated to dryness under a reduced pressure. This process was repeated twice more, and further, the dried material was thoroughly dried by a vacuum pump, dissolved in 20 ml of dry pyridine, 1.67 g of dicyclohexylcarbodiimide was added thereto, and the mixture was stored at room temperature for 2 days. After an addition of water to the product, the mixture was concentrated to dryness under a reduced pressure, followed by an addition of 40 ml of an aqueous LiOH solution (0.5 N) to carry out the reaction at 100° C. for 45 minutes. The reaction mixture was filtered to give a filtrate, which was diluted with water, adjusted to a pH of 2.5 to 3, and then the mixture was applied to an ion exchange column (Dowex 50 (hydrogen ion form)). Elution was effected successively with water and 2 N pyridine, and the fractions eluted with the latter were concentrated to dryness under a reduced pressure to give 0.27 g of crude 2-(5,6-dimethylbenzimidazolyl)ethylphosphoric acid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@H:2]2[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: CN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CC=C[C@@H](c2ccccc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 18.4 %

Procedure:
To a solution of (3S,7S)-3-amino-1-methyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (1f) (120 mg) in DCM (6 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (135 mg), HOBt-hydrate (186 mg), EDAC.HCl (160 mg) and N-methyl morpholine (92 mg). The reaction mixture was stirred 1 h at 0° C. and 2.5 h at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1% MeOH/DCM) to afford the title compound as an off-white solid (45 mg, 19%). 1H NMR (300 MHz, CDCl3) δ 1.41 (d, 3H), 2.18-2.29 (m, 1H), 2.54 (s, 3H), 2.79-2.87 (m, 1H), 3.55 (s, 2H), 4.47-4.57 (m, 1H), 5.45-5.54 (m, 1H), 5.86 (m, 2H), 6.14-6.19 (m, 1H), 6.29 (bd, 1H), 6.69-6.76 (m, 1H), 6.84 (bd, 2H), 7.22-7.45 (m, 5H). MS APCI, m/z=464 (M+Na). LC/MS 2.52 min., Method A.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.Cl[C:32]([O:34][CH2:35][CH2:36]Br)=[O:33].[CH2:38]([N:40](CC)[CH2:41][CH3:42])[CH3:39].C(NCC)C>ClCCl>[CH2:38]([N:40]([CH2:41][CH3:42])[CH2:36][CH2:35][O:34][C:32](=[O:33])[NH:1][CH2:2][C@H:3]1[CH2:4][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:6]1)[CH3:39]
Reactant: O=C(Cl)OCCBr
Reactant: CCN(CC)CC
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: CCNCC
Product: CCN(CC)CCOC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.2 g (0.5 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 5 ml of dichloromethane are added 55.4 μl (0.5 mmol) of 2-bromoethyl chloroformate (Fluka, Buchs, Switzerland) and 70 μl (0.5 mmol) of triethylamine. After stirring for 2 h at RT, the solution is concentrated to dryness. The crude compound is dissolved in 5 ml of acetonitrile and 260 μl (2.5 mmol) of diethylamine (Fluka, Buchs, Switzerland) are added thereto. The reaction mixture is refluxed for 16 h and, after concentration, the crude compound is purified by medium-pressure liquid chromatography to provide trans-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamic acid 2-diethylamino-ethyl ester. Analytical HPLC: tR=6.27 min (Grad 2); ES-MS: m/eo=543.3.
Reaction SMILES: Br.[CH:2]1([CH2:5][N:6]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:10]3[CH:20]=[C:21]([OH:26])[C:22]([OH:25])=[C:23]([Cl:24])[C:9]=3[CH2:8][CH2:7]2)[CH2:4][CH2:3]1.[C:27]([Br:30])(=[O:29])[CH3:28]>FC(F)(F)C(O)=O>[BrH:30].[CH:2]1([CH2:5][N:6]2[CH2:12][CH:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][C:27](=[O:29])[CH3:28])=[CH:17][CH:18]=3)[C:10]3[CH:20]=[C:21]([O:26][C:22](=[O:25])[CH3:21])[C:22]([O:25][C:16](=[O:19])[CH3:15])=[C:23]([Cl:24])[C:9]=3[CH2:8][CH2:7]2)[CH2:3][CH2:4]1
Reactant: Oc1ccc(C2CN(CC3CC3)CCc3c2cc(O)c(O)c3Cl)cc1
Reactant: CC(=O)Br
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1ccc(C2CN(CC3CC3)CCc3c2cc(OC(C)=O)c(OC(C)=O)c3Cl)cc1

Procedure:
A mixture of 1 g of 3-cyclopropylmethyl-6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, 1.3 ml of acetyl bromide and 200 ml of trifluoroacetic acid is heated at reflux for 2 hours. After evaporation to dryness, the residue is purified, if necessary, by recrystallization to give 3-cyclopropylmethyl-6-chloro-7,8-diacetoxy-1-(p-acetoxyphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide. Similarly tri-isobutyryloxy, -propionyloxy, -isovaleryloxy, -n-butyryloxy and -n-heptanoyloxy ester derivatives are prepared.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1([CH3:24])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][OH:21])=[CH:16][CH:15]=2)[O:8]1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH3:1][S:2]([O:21][CH2:20][CH2:19][O:18][C:17]1[CH:22]=[CH:23][C:14]([B:9]2[O:8][C:7]([CH3:24])([CH3:6])[C:11]([CH3:12])([CH3:13])[O:10]2)=[CH:15][CH:16]=1)(=[O:4])=[O:3]
Reactant: CC1(C)OB(c2ccc(OCCO)cc2)OC1(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(OCCOS(C)(=O)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.33 mL) was added to a mixture of 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]ethanol (0.92 g) and triethylamine (0.73 mL) in methylene chloride (18 mL), and the mixture was stirred at room temperature for 1 hr. 1 mol/L hydrochloric acid was added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (1.28 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2>>[Cl-:1].[CH2:12]([O:11][C:4]1[N:5]=[C:6]([O:8][CH2:9][CH3:10])[N:7]=[C:2]([N+:14]23[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)[N:3]=1)[CH3:13]
Reactant: C1CN2CCC1CC2
Reactant: CCOc1nc(Cl)nc(OCC)n1
Product: CCOc1nc(OCC)nc([N+]23CCC(CC2)CC3)n1
Product: [Cl-]

Procedure:
The operation was carried out in the same manner as in Preparation Example 1 but using 4.07 g (0.02 mols) of a 2-chloro-4,6-diethoxy-1,3,5-triazine and 2.22 g (0.02 mols) of a quinuclidine to obtain 5.73 g (yield, 91.0%) of white crystals of a 1-(4,6-diethoxy-1,3,5-triazin-2-yl)quinuclidinium chloride represented by the following general formula (XI)