Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[I:3][C:4]1[CH:5]=[N:6][C:7]([C:10]2([NH:13][C:14]([C:16]3([NH2:19])[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11]2)=[N:8][CH:9]=1.C(N(CC)CC)C.[C:27]([C:29]1[CH:57]=[CH:56][C:32]([CH2:33][C@@:34]2([CH3:55])[N:38]3[C:39]([C:42](Cl)=[O:43])=[CH:40][N:41]=[C:37]3[N:36]([C:45]3[CH:50]=[C:49]([Cl:51])[C:48]([F:52])=[C:47]([Cl:53])[CH:46]=3)[C:35]2=[O:54])=[CH:31][CH:30]=1)#[N:28]>C1COCC1>[I:3][C:4]1[CH:9]=[N:8][C:7]([C:10]2([NH:13][C:14]([C:16]3([NH:19][C:42]([C:39]4[N:38]5[C@@:34]([CH2:33][C:32]6[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:57][CH:56]=6)([CH3:55])[C:35](=[O:54])[N:36]([C:45]6[CH:46]=[C:47]([Cl:53])[C:48]([F:52])=[C:49]([Cl:51])[CH:50]=6)[C:37]5=[N:41][CH:40]=4)=[O:43])[CH2:18][CH2:17]3)=[O:15])[CH2:12][CH2:11]2)=[N:6][CH:5]=1
Reactant: NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)Cl)n21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ncc(I)cn5)CC4)CC3)n21
Reaction time: 2 h
Yield: 101.7 %

Procedure:
To 1-amino-cyclopropanecarboxylic acid[1-(5-iodo-pyrimidin-2-yl)-cyclopropyl]-amide dihydrochloride (400 mg, 0.96 mmol) was added 1 mL of dry THF and triethylamine (0.71 ml, 3.98 mmol). Crude (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl chloride (476 mg, 1.0 mmol) was dissolved in 2 mL of dry THF and transferred to the reaction flask. After 2 h, the solvent was removed at 55° C. under a stream of N2. The resulting slurry was diluted with EtOAc (75 mL) and washed with 10% aq citric acid (75 mL) and saturated aq NaHCO3 (75 mL). The organic layer was dried over Na2SO4 and concentrated to give a light orange foam. This solid was purified by normal phase flash chromatography on silica gel (1→3% MeOH/CH2Cl2) to give 767 mg of the title compound as a tan powder, m/z 785.5.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23](Br)[O:22][C:18]=2[N:19]=[CH:20][N:21]=1.[CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O)=[CH2:36]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH:35]=[CH2:36])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: C=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: C=Cc1ccccc1-c1oc2ncnc(NCCCCCC(=O)OC)c2c1-c1ccc(OC)cc1
Reaction time: 15 h

Procedure:
Add 0.5 ml of 2 M aqueous potassium carbonate solution to a mixture of 224 mg (0.50 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 29 mg (0.03 mmol) tetrakis(triphenylphosphine)palladium(0) in 2.5 ml 1,2-dimethoxyethane. Next, add 92 mg (0.63 mmol) (2-vinylphenyl)boronic acid and stir the mixture for 15 h under reflux. Filter the reaction mixture and purify directly by preparative RP-HPLC (gradient: water/acetonitrile). 82 mg (35% of theor.) of the desired product is obtained.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=1.[CH3:17][NH:18][CH3:19].CO>>[CH2:12]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[CH:8]=2)[N:3]=[C:2]([N:18]([CH3:19])[CH3:17])[CH:11]=1)[CH3:13]
Reactant: CNC
Reactant: CCc1cc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: CO
Product: CCc1cc(N(C)C)nc2ccc([N+](=O)[O-])cc12

Procedure:
The product was obtained from the product of Step B and a solution of 2N dimethyl-amine in methanol (5 mL, 25 mmol) according to the procedure of Example 1, Step C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][C:18]([NH:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCN
Reactant: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)CCNC(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)acetic acid and ethyl 3-aminopropionate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-3-aminopropionate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-3-aminopropionic acid (M.P. 129° to 131°).
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]3[CH2:17][CH2:18][NH:19][C:12]3=[N:11][C:10]=2[N:9]([CH3:20])[C:8]1=[O:21].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C)C=O>[CH3:20][N:9]1[C:10]2[N:11]=[C:12]3[NH:19][CH2:18][CH2:17][N:13]3[C:14]=2[C:15](=[O:16])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]([O:1][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH3:22])[C:8]1=[O:21]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CCCCn1c(=O)c2c(nc3n2CCN3)n(C)c1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.2 %

Procedure:
To the stirring solution of (R)-7,8-dihydro-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (CT-13430) (200 mg, 0.65 mmol) and imidazole (68 mg, 1.0 mmol) in dimethylformamide (1 ml) was added tert-butyldimethylsilyl chloride (127 mg, 1.30 mmol). After stirred at room temperature for 16 hours, the reaction mixture was treated with water and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water (2×5 ml), with saturated aqueous sodium chloride solution (5 ml), and dried over magnesium sulfate. Concentrating under reduced pressure to provide (R)-7,8-dihydro-1-methyl-3-(5-tert-butyldimethylsilyloxyhexyl)-1H-imidazo[2,1-f]-purine-2,4(3H, 6H)-dione (280 mg, 100% yield) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][CH:29]=3)[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:37]=[O:38]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[CH:37]=[O:38])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(COc2ccc(-c3cnc4ccnn4c3C3CCCCC3)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice cold solution of 300 mg (0.78 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine in 2 mL of dimethylformamide (DMF) and 1 mL of dichloromethane (DCM) was added 0.085 mL (0.9 mmol) of phosphorus oxychloride (POCl3) and the resulting mixture was allowed to warm up to rt and stirred at rt for 4 h when analysis by thin layer chromatography (TLC) indicated complete conversion of starting material to product. The reaction mixture poured into ice-water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 335 mg of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (436) as a beige solid as indicated by 1H NMR; LC-MS—calcd for C26H25N3O2 [M++H]+: 412.19, found: 412.1.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Br:2].[F:6][C:7]([F:15])([F:14])[C:8]([C:10]([F:13])([F:12])[F:11])=[O:9]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:6][C:7]([F:15])([F:14])[C:8]1([C:10]([F:13])([F:12])[F:11])[O:5][CH:3]([CH2:1][Br:2])[CH2:4][O:9]1
Reactant: BrCC1CO1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Product: FC(F)(F)C1(C(F)(F)F)OCC(CBr)O1

Procedure:
This compound was prepared from epibromohydrin and hexafluoroacetone (HFA) (1:1 mole ratio) in the presence of catalytic amounts of tetrabutylammonium bromide and water at 125° C. in 95% isolated yield. Compound 7 has a boiling point 56° C./2 mm. 1H NMR (neat): δ4.88 (m, IH), 4.73 (t, J =7.5 Hz, IH), 4.22 (t, J=7.5 Hz, lH), 3.60 (m, 2H); 19F NMR (neat): -80.5 (q, J=8.5 Hz, 3F), -81.0 (q, J=8.5 Hz, 3F). Anal. Calc. for C6H5BrF6O2 : C: 23.78, H: 1.66, Br: 26.37, F: 37.62; Found: C: 23.91, H: 1.64, Br: 26.87, F: 37.84.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[I:28]N1C(=O)CCC1=O>O1CCCC1>[I:28][C:3]1[CH:4]=[C:5]([N+:12]([O-:14])=[O:13])[C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=1[NH2:1]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I

Procedure:
5-Amino-2-nitrobenzotrifluoride (16.25 g, 78.8 mmol) was dissolved in tetrahydrofuran (100 mL) and methanol (100 mL) and to this solution was added p-toluenesulfonic acid (0.18 g, 0.95 mmol) and N-iodosuccinimide (17.8 g, 78.8 mmol). The solution was stirred all day. N-iodosuccinimide (0.78 g, 3.47 mmol) and p-toluenesulfonic acid (0.2 g, 1.05 mmol) were then added and the solution stirred overnight at room temperature under nitrogen. The solution was concentrated under vacuum to a small volume. Water (200 mL) was added to the reaction mixture and and a brown solid precipitated out. The solid was filtered- and washed with water, then dissolved in ethyl acetate (100 mL) and diethyl ether (60 mL). The organic solution was washed with 10% sodium thiosulfate solution (50 mL). This created an emulsion which was alleviated by adding diethy! ether and water and filtering undissolved material. The layers were separated and the organic layer was washed with 10% sodium thiosulfate solution (50 mL), water was then added to the aqueous layer and the layers separated. The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered, and evaporated to yield the title compound as a brown solid that was dried under vacuum.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([CH2:44][N:45]2[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]2)=[CH:14][N:13]=1.[NH2:55][C:56]1[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[N:60][CH:61]=1>C1COCC1>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:20]2[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([C:17]3[C:12]([NH:55][C:56]4[CH:57]=[CH:58][C:59]([NH:62][C:63](=[O:69])[O:64][C:65]([CH3:67])([CH3:66])[CH3:68])=[N:60][CH:61]=4)=[N:13][CH:14]=[C:15]([CH2:44][N:45]4[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][CH2:46]4)[CH:16]=3)[N:19]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cn1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
LiHMDS (Aldrich) (2.44 mL, 2.44 mmol) was added dropwise at 0° C. to a stirred solution of 4-(2-fluoro-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.507 g, 0.815 mmol) and tert-butyl 5-aminopyridin-2-ylcarbamate (0.204 g, 0.976 mmol) in THF (2 mL). The dark red mixture was stirred at 0° C. for 2 h. More LiHMDS (1.6 mL, 1.6 mmol) was added dropwise at 0° C. and stirring was continued for another 30 min. The reaction was quenched by adding 0.3 mL of sat'd NH4Cl. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The aqueous phase was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated aqueous sodium chloride (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (100 g, eluent: iPrOH (w/10% NH4OH) in CHCl3 0%-10%) to give tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)pyridin-2-ylcarbamate (0.306 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 11.76 (s, 1H); 8.71 (d, J=2.54 Hz, 1H); 8.42 (d, J=2.35 Hz, 1H); 8.23 (d, J=2.35 Hz, 1H); 7.94 (dd, J=9.00, 2.54 Hz, 1H); 7.83 (d, J=9.00 Hz, 1H); 7.15-7.25 (m, 5H); 6.86 (dd, J=11.15, 8.61 Hz, 4H); 4.83 (d, J=10.17 Hz, 4H); 3.76-3.85 (m, 6H); 3.50 (s, 2H); 3.18 (br s., 4H); 2.71 (s, 3H); 2.59 (s, 3H); 2.55 (t, J=4.50 Hz, 4H); 1.53 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([N:27]3[CH2:30][CH:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:28]3)[O:26][C:22]=2[C:21](F)=[C:20]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:19]=1[CH3:46])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([N:27]3[CH2:28][CH:29]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30]3)[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:19]=1[CH3:46])#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Temperature: 130 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (180 μl, 1.42 mmol) and triethylamine (238 μl, 1.70 mmol) were added to a dimethyl sulfoxide (5 ml) solution of tert-butyl [1-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)azetidin-3-yl]carbamate (I-194) (400 mg, 0.947 mmol), followed by stirring in an oil bath at 130° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml) and washed with saturated brine (100 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=10:1) to obtain the entitled compound (260 mg, 53.2%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])=[C:20]([CH2:30][CH3:31])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.N1(C2C=CN=CC=2)CCCC1.[C:43]([O:47][C:48]([NH:50][CH2:51][C:52](O)=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44].C(N=C=NC(C)C)(C)C.O.NN>C(Cl)Cl>[C:43]([O:47][C:48]([NH:50][CH2:51][C:52]([O:29][C:26]([CH3:27])([CH3:28])[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([N:13]2[C:14](=[O:17])[C:15]3[S:16][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[N:11]=[CH:12]2)=[CH:19][C:20]=1[CH2:30][CH3:31])=[O:53])=[O:49])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)O
Agent: CC(C)N=C=NC(C)C
Agent: NN
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: O
Product: CCc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCC(C)(C)OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.1 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(3-ethyl-4-(2-hydroxy-2-methylpropoxy)-phenyl)thieno[3,2-d]pyrimidin-4(3H)-one (0.96 g, 2.11 mmol), 4-pyrrolidinopyridine (0.31 g, 2.11 mmol) and N-(tert-butoxycarbonyl)glycine (1.11 g, 6.33 mmol) in 20 mL of CH2Cl2 heated at reflux was added diisopropylcarbodiimide (0.98 mL; 6.33 mmol) over 3 h via syringe pump. The suspension was heated at reflux for 1 h and additional N-(tert-butoxycarbonyl)glycine (0.55 g, 3.17 mmol) was added followed by diisopropylcarbodiimide (0.55 mL, 3.17 mmol) over 2 hrs via syringe pump. The suspension heated at reflux for 1 h and cooled to rt. Hydrazine monohydrate (0.34 mL, 7.01 mmol) was added and the suspension stirred at rt for 2 h. The suspension was cooled to 0° C., filtered and the filtrate washed with cold, 1N HCl, cold, dilute NaHCO3 solution, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, EtOAc/Hexanes, 0:100 to 1:1 gradient) to afford 1.37 g (100%) of the title compound as an off-white solid. 1H NMR (CDCl3) δ 1.24 (t, 3H), 1.45 (s, 9H), 1.64 (s, 6H), 2.68-2.73 (m, 2H), 3.85 (d, J=4.95 Hz, 2H), 4.18 (s, 2H), 4.98 (br s, 1H), 6.92 (d, J=9.35 Hz, 1H), 7.20-7.22 (m, 2H), 7.44 (d, J=8.79 Hz, 2H), 7.53 (s, 1H), 7.66 (d, J=8.25 Hz, 2H), 8.13 (s, 1H); 13C NMR (CDCl3) δ 13.68, 23.39, 23.67, 28.28, 42.87, 72.72, 79.86, 81.86, 111.48, 120.82, 123.25, 125.42, 127.62, 129.42, 129.67, 131.54, 134.25, 135.59, 148.29, 151.50, 155.58, 156.69, 156.92, 157.37, 169.47; HPLC (Method #1) 4.80 min retention time; LCMS (ES): m/z 612 [M+H]+.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].C(O)CCCCCCCC(O)C>>[CH2:10]([OH:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: OCCCCCCCCCCO
Agent: CC(O)CCCCCCCCO
Product: CCCCCCCCCCO
Yield: 25.7 %

Procedure:
5.22 g (30.0 mmol) of 1,10-decanediol (with a yield of 52%); 1.23 g (7.1 mmol) of 1,9-decanediol (12%); and 1.23 g (7.7 mmol) of 1-decanol (13%) were obtained.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1COC(=O)N1CCCCSc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1OC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 3.66 g (12 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]oxazolidine-2,4-dione and 1.08 ml (12 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.12 ml (1.2 mmol) of piperidine was added, followed by refluxing for 16 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/2) to yield 1.05 g (24.3%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][OH:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH2:18][O:19][C:29]1[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:14])([F:15])[F:16])[CH:6]=1
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)CN(CCO)c1ccc(C#N)c(C(F)(F)F)c1
Product: CC(C)(C)CN(CCOc1ccc(S(C)(=O)=O)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1C from 4-[(2,2-dimethylpropyl)(2-hydroxyethyl)amino]-2-(trifluoromethyl)benzonitrile and 4-methanesulfonylphenol: MS (ESI) m/z 455 (M+1).
Reaction SMILES: FC1C(O[C:9](=[O:33])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])=[C:13]([O:31][CH3:32])[CH:12]=2)=C(F)C(F)=C(F)C=1F.[CH:38]1([C:45]2[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=2)[NH2:48])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(OCC)(=O)C>[CH:38]1([C:45]2[CH:46]=[C:47]([NH:48][C:9](=[O:33])[CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[C:24](=[O:25])[C:23]5=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]5[C:21]4=[O:30])=[C:13]([O:31][CH3:32])[CH:12]=3)[CH:49]=[CH:50][CH:51]=2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1OCCN1C(=O)c2ccccc2C1=O
Reactant: Nc1cccc(C2CCCCCC2)c1
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)Nc2cccc(C3CCCCCC3)c2)ccc1OCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 71.7 %

Procedure:
3-Methoxy-4-(2-phthalimidoethoxy)phenylacetic acid pentafluorophenyl ester (690 mg) and 3-cycloheptylaniline (500 mg) are dissolved in ethyl acetate (10 ml), and the mixture is heated with stirring at 60° C. for 18 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give N-(3-cycloheptylphenyl)-3-methoxy-4-(2-phthalimidoethoxy)phenylacetamide (500 mg). This product is dissolved in ethanol (10 ml), and thereto is added hydrazine monohydrate (610 mg), and the mixture is heated under reflux for 2 hours. The insoluble materials are removed by filtration, and the solvent is evaporated under reduced pressure. To the residue is added water, and the mixture is extracted with chloroform. The organic layer is dried over sodium sulfate, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 30% chloroform/methanol), and treated with 10% hydrogen chloride-methanol to give the desired compound (170 mg).
Reaction SMILES: [CH2:1]([N:8]([C@H:13]1[C@H:17]([OH:18])[CH2:16][CH2:15][C:14]1([F:20])[F:19])[C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1COCC1>CC(O)(C)C>[CH2:1]([N:8]1[C:9](=[O:12])[CH2:10][O:18][C@@H:17]2[CH2:16][CH2:15][C:14]([F:20])([F:19])[C@@H:13]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)N(Cc1ccccc1)[C@H]1[C@H](O)CCC1(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C1CO[C@@H]2CCC(F)(F)[C@H]2N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-N-benzyl-2-chloro-N-(2,2-difluoro-5-hydroxycyclopentyl)acetamide (750 mg, 2.46 mmol) in t-BuOH (20 mL) was added a 1M solution of KOtBu in THF (4.93 mL, 4.93 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 hours and then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (20 mL), washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification of the residue on a silica gel column (0 to 40% EtOAc/hexanes) afforded trans-4-benzyl-5,5-difluorohexahydrocyclopenta[b][1,4]oxazin-3(2H)-one. MS ESI calc'd. for C14H15F2NO2 [M+H]+ 268. found 268.