Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(Cl)=CC=1OC1N=CC=CC=1C(O)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[F:36])[O:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=O.CC1CCC2C(=CC=CC=2)N1.[NH:48]1[C:57]2[C:52](=[N:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][CH2:50][CH2:49]1>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][C:35]=1[F:36])[O:23][C:24]1[C:25]([C:26]([N:53]2[C:52]3[C:57](=[N:48][CH:49]=[CH:50][CH:51]=3)[CH2:56][CH2:55][CH2:54]2)=[O:28])=[CH:29][CH:30]=[CH:31][N:32]=1
Reactant: c1cnc2c(c1)NCCC2
Reactant: O=C(O)c1cccnc1Oc1ccc(F)c(Cl)c1
Agent: CC1CCc2ccccc2N1
Agent: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Product: O=C(c1cccnc1Oc1ccc(F)c(Cl)c1)N1CCCc2ncccc21

Procedure:
The title compound was prepared in analogy to Example 67 replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(3-chloro-4-fluoro-phenoxy)-nicotinic acid (Example 77, Step 1) and 2-methyl-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-[1,5]naphthyridine ([CAS RN 13993-61-8]). MS (ISN): 383.9 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2.[CH3:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C@H:28]([OH:36])[CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:22][C:20]=2[N:21]=1.CCN(C(C)C)C(C)C>CCO>[CH2:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]3[CH2:34][CH2:35][N:30]([CH2:29][C@@H:28]([OH:36])[CH2:27][O:26][C:23]4[CH:24]=[CH:25][C:19]5[S:18][C:17]([CH3:16])=[N:21][C:20]=5[CH:22]=4)[CH2:31][CH2:32]3)=[CH:15][CH:14]=2)[CH2:10][CH2:11]1
Reactant: BrCCCCOc1ccc2c(c1)CCC2
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCCCOc4ccc5c(c4)CCC5)CC3)ccc2s1
Temperature: 25 °C

Procedure:
A solution of 4-bromo-1-indan-5-yloxybutane (934 mg, 3.46 mmol, crude) in EtOH (10 mL) was treated with (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol as prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (0.57 mL, 3.3 mmol) and refluxed for 14 hours. Upon cooling to RT, the solution was then concentrated under reduced pressure and purified via an Isco™ (100% EtOAc 4 min, 10 min gradient to 25% MeOH/EtOAc, hold 6 min.) to afford (2R)-3-[4-(4-indan-5-yloxybutyl)piperazinyl]-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[F:27][C:23]([F:28])([C:15]1[CH:16]=[CH:17][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:2][F:1])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=2[CH:14]=1)[C:22]([F:30])([F:29])[F:21]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21

Procedure:
In the same manner as described in Example 3 (6) but using ethyl 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylate, potassium pentafluoropropionate, cuprous iodide, toluene and N,N-dimethylformamide, ethyl 6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylate was obtained as an oily substance.
Reaction SMILES: [NH:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]([C:9]2[NH:10][N:11]=[CH:12][CH:13]=2)=[N:2]1.[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:6]([C:5]3[NH:1][N:2]=[C:3]([C:9]4[NH:10][N:11]=[CH:12][CH:13]=4)[CH:4]=3)=[O:8])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cc(-c2ccn[nH]2)n[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cc(-c2ccn[nH]2)n[nH]1
Yield: 15.6 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1H,2′H-3,3′-bipyrazole-5-carboxylic acid (2.245 mmol, 0.4 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.871 mmol, 0.521 g) and using DMF (10 ml) as the solvent. Water was added to the reaction mixture and the mixture was extracted with EtOAc. The organic phase was washed with 2M Na2CO3, water and brine. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography and preparative HPLC, respectively. 0.1277 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.19 (d, 3H), 4.27-4.56 (m, 3H), 6.64 (bs, 1H), 6.84 (bs, 1H), 6.98 (d, 1H), 7.77 (bs, 1H), 7.81-7.87 (m, 2H), 7.93-7.6 (m, 1H), 8.07 (br. s, 1H), 12.57-13.78 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 1.1 g, 5.00 mmol) was dissolved in DCM (10 mL) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol) added. The mixture was cooled in an ice/water bath and 4-(2-aminoethyl)morpholine (Aldrich; 0.66 mL, 5.00 mmol) in DCM (5 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. The reaction mixture was washed with brine, 2N NaOH, dried (MgSO4) and concentrated. Column chromatography of the residue (2% MeoH/DCM) gave the title compound as a yellow solid. (1.2 g, 76%)
Reaction SMILES: C1CC(N)(C(O)=[O:6])C1.[OH-].[K+].C1NC1.[CH2:14]([C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17]C)[OH:15]>>[CH2:14]([C:16]([CH2:21][OH:22])([CH3:17])[C:19]([OH:6])=[O:20])[OH:15]
Reactant: NC1(C(=O)O)CCC1
Reactant: CCC(CO)(CO)CO
Agent: C1CN1
Agent: [K+]
Agent: [OH-]
Product: CC(CO)(CO)C(=O)O

Procedure:
Examples of polyester polyols selected for the ACBC layer, and, in embodiments, for reaction with the polyisocyanate are known, and can be obtained from Perstorp Specialty Chemicals (Perstorp, Sweden) as BOLTORN® P500 (OH value of 560 to 630 milligram KOH/gram, Mw (GPC)=1,800), P1000 (OH value of 430 to 490 mg KOH/grams, Mw (GPC)=1,500), H20 (OH value of 490 to 520 mg KOH/grams, Mw (GPC)=2,100, Tg=25° C.), H2003 (OH value of 280 to 310 mg KOH/grams, Mw (GPC)=2,500, Tg=−5° C.), H2004 (OH value of 110 to 130 mg KOH/grams, Mw (GPC)=3,200, Tg=−35° C.), H30 (OH value of 490 to 510 mg KOH/grams, Mw (GPC)=3,500, Tg=35° C.), H40 (OH value of 470 to 500 mg KOH/grams, Mw (GPC)=5,100, Tg=40° C.), U3000 (OH value of 77 mg KOH/grams, Mw (GPC)=6,500), and W3000 (OH value of 45 mg KOH/grams, Mw (GPC)=10,000). In embodiments, a dendritic polyester polyol selected for the ACBC layer formation can be formed by, for example, the polymerization of a core such as trimethylolpropane and branches extending therefrom of 2,2-dimethylol propionic acid (Bis-MPA), and which resulting products can be referred to as hydroxyl-functional dendritic polyesters.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:24]>C(Cl)Cl>[C:4]1([N:7]2[CH2:8][CH2:9][N:10]([C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:24])[CH2:11][CH2:12]2)[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of phenylpiperazine (12.0 g, 74.0 mmol) and DIPEA (13.5 mL, 81.6 mmol) in DCM (70 mL) at 0° C. add 4-nitrophenyl chloroformate (16.5 g, 81.71 mmol). The reaction mixture was stirred for 30 minutes at 0° C. and then washed with saturated sodium hydrogen carbonate solution (3×200 mL), dried (MgSO4) and concentrated in vacuo to give a 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (24.8 g, 102%) as a yellow solid which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:17]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[CH:7]([NH:14][S:17]([C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24])(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)C(N)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(S(=O)(=O)NC(C(=O)OC(C)(C)C)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a stirred solution of tert-butyl-2-amino-2-phenylacetate (1.34 g, 6.45 mmol) and methyl 3-(chlorosulfonyl)benzoate (1.53 g, 6.51 mmol) in tetrahydrofuran (15 mL) was added triethylamine (0.90 mL, 6.45 mmol) in one portion at ambient temperature. The reaction mixture was stirred for 30 minutes, after which time, the reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (30 mL) and 10% citric acid solution (10 mL). The resulting organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield a crude solid. The solid was triturated in diethyl ether (5 mL) and cold methanol (5 mL) to yield the title compound as a white solid (1.13 g, 43%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:25])[CH3:24])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:26].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([C:23](=[O:25])[CH2:24][Br:26])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CBr)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reaction time: 24 h

Procedure:
To a stirred solution of 1-[3,5-bis(benzyloxy)phenyl]ethanone (5 g, 15.04 mmol) in tetrahydrofuran (60 mL) and methanol (35 mL) was added tetrabutylammonium tribromide (7.25 g, 15.04 mmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred for 24 hours and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with water (2×50 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to afford the desired compound as a yellow oil in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)#[N:25].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([CH3:21])[N:6]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([C:24]#[N:25])=[CH:27][CH:28]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
5,5-Dimethyl-3-naphthylcarbonylimidazolidine -2,4-dione (35 mg) was dissolved in DMF (0.4 mL) and sodium hydride (60%, in oil) (5 mg) was added. Then, 4-cyanobenzyl bromide (25 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 24 mg of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][NH:7][N:6]=1)=[O:4].[H-].[Na+].Cl[C:13]1[CH2:17][C:16]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=1.N1C=CC=N1>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:19])([F:20])[F:21])[O:15][N:14]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc[nH]n1
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(Cl)=NO1
Agent: [H-]
Agent: [Na+]
Agent: c1cn[nH]c1
Solvent: CC#N
Product: COC(=O)c1ccn(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of pyrazole-3-carboxylic acid methyl ester (504 mg) in acetonitrile (25 ml) under argon was added sodium hydride (160 mg). The reaction mixture was stirred at room temperature for 1 h. 15 mf of this solution was added dropwise to a solution of chloroisoxazoline of example 17.2 (630 mg) in acetonitrile (10 ml). It was then stirred at room temperature for 1 h; 10 ml of pyrazole solution was added again and the mixture was stirred for 1.5 hour. The reaction was quenched by adding water and dichloromethane. The two layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was purified by column chromatography (from c-Hex (100%) to c-Hex:EtOAc (80:20)) to afford the title intermediate (680 mg). 1H-NMR (CDCl3, 400 MHz): 8.15 (s, 1H), 7.5 (m, 2H), 7.45 (m, 1H), 4.45 (d, 1H), 4.10 (d, 1H), 3.95 (s, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1)=O.C([BH3-])#N.[Na+].O>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][C@H:13]2[CH2:14][CH2:15][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H](CN[C@@H]2C[C@H]2c2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of trans-2-phenylcyclopropanamine (80 mg, 0.601 mmol) in methanol (10 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (102 mg, 0.601 mmol) and the reaction was heated to reflux for 2 minutes. After cooling back to the room temperature, sodium cyanoborohydride (75 mg, 1.201 mmol) was added to the reaction mixture and was stirred for 1 hour. Water (20 mL) was added. The reaction was concentrated and 20 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, and dried over MgSO4, filtered and evaporated. The resulting oil was purified on preparatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier). 0.5 mL of 6 M HCl was added into each fraction and the product was evaporated. trans-Methyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)cyclohexanecarboxylate (95 mg, 0.250 mmol, 41.7% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.38 (m, 2H), 7.22-7.29 (m, 1H), 7.11-7.22 (m, 2H), 3.68 (s, 3H), 3.09 (d, J=7.07 Hz, 2H), 2.99 (dt, J=4.11, 7.45 Hz, 1H), 2.49 (ddd, J=3.79, 6.57, 10.36 Hz, 1H), 2.35 (tt, J=3.63, 12.28 Hz, 1H), 2.07 (dd, J=3.54, 13.39 Hz, 2H), 1.93 (dd, J=3.28, 13.14 Hz, 2H), 1.66-1.83 (m, J=3.57, 3.57, 7.70, 7.70, 15.36 Hz, 1H), 1.50-1.58 (m, 1H), 1.36-1.50 (m, 3H), 1.15 (qd, J=3.54, 12.72 Hz, 2H); LC-MS Rt=0.83 min; MS (ESI): 288.2 [M+H]+.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:4](=[O:14])[CH:3]=1.P(Cl)(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>O>[Cl:17][C:2]1[N:7]=[CH:6][N:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[C:4](=[O:14])[CH:3]=1
Reactant: O=c1cc(O)ncn1C1CCOCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=c1cc(Cl)ncn1C1CCOCC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 6-hydroxy-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-4(3H)-one obtained in Reference Example 25 (210 mg) and phosphorus oxychloride (6 mL) was stirred at 100° C. for 2 hr. The mixture was allowed to be cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was subjected to azeotropy with toluene to give a residue. The residue was dissolved in water (10 mL), and the solution was basified with saturated aqueous sodium hydrogen carbonate solution (30 mL) under ice-cooling. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a residue. The residue was purified by chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: [C:1]([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:16][Mg]Cl.O>O1CCCC1>[CH3:2][C:1]([CH3:16])([C:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1)[OH:3]
Reactant: CC(=O)C1=CCCCCCCCCCC1
Reactant: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)C1=CCCCCCCCCCC1
Yield: 96 %

Procedure:
52 g (0.25 mole) of 1-acetyl-1-cyclododecene, prepared as described in Example 2, are added over 30 minutes to 200 ml of a 1.5-molar solution of methyl-magnesium chloride in tetrahydrofuran at from 0° to +10° C. After completion of the addition, the reaction mixture is hydrolyzed with 20 ml of water and the tetrahydrofuran solution is filtered to remove the salt which has precipitated. After destilling off the tetrahydrofuran under reduced pressure (50° C./20 mbars) the product which remains is fractionated. 52 g of dimethyl-cyclododecenyl-carbinol (96% yield) of boiling point=108°-112° C./0.01 mm Hg and refractive index nD25 =1.5000 are obtained.
Reaction SMILES: C(OC/C=C\COC(=O)C)(=O)C.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([NH:24][C:25]1([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[NH2:46])[CH2:36][CH:35]2[OH:47])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23].[CH2:48]([N:50](CC)[CH2:51][CH3:52])[CH3:49]>ClCCl.CN(C)C=O>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([NH:24][C:25]1([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[NH:46][N:50]3[CH2:51][CH:52]=[CH:49][CH2:48]3)[CH2:36][CH:35]2[OH:47])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: CCN(CC)CC
Agent: CC(=O)OC/C=C\COC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3NN3CC=CC3)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of cis-2-buten-1,4-diol diacetate (1.15 g) in 30 ml of dichloromethane, was added the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-aminophenyl)piperidin-3-ol (1.5 g) obtained in Step 2 of Example 43 in 20 ml of dimethylformamide. 0.44 ml of triethylamine was added to the reaction mixture, which was then stirred overnight at room temperature. 20 ml of ice water was added to the reaction mixture. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 0.7 g of the titled compound.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(#N)C>[C:25]1([S:31]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:19]([C:17]([NH:16][C@H:13]3[CH2:12][CH2:11][C@H:10]([O:9][C:6]4[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[O:18])[CH2:20]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S)—N-[trans-4-(pyridin-4-yloxy)cyclohexyl]piperidine-3-carboxamide dihydrochloride (28 mg, purity: 40%, 0.03 mmol), benzenesulfonyl chloride (6.3 mg, 0.036 mmol), triethylamine (16 μL, 0.12 mmol) in acetonitrile (1 mL) was stirred at r.t. overnight. the mixture was purified with prep. HPLC. 5.9 mg (45%) of final product was obtained. LCMS: m/z 444.1 (M+H)+; 466.1 (M+Na)+.
Reaction SMILES: Cl.Cl.Cl[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=[O:26])[NH:18][C:17]3[CH:27]=[CH:28][CH:29]=[N:30][C:16]2=3)=[O:14])[CH2:8][CH2:7]1.[NH4+:31].[OH-]>>[NH2:31][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=[O:26])[NH:18][C:17]3[CH:27]=[CH:28][CH:29]=[N:30][C:16]2=3)=[O:14])[CH2:8][CH2:7]1
Reactant: [NH4+]
Reactant: O=C1Nc2cccnc2N(C(=O)CN2CCN(CCCl)CC2)c2ccccc21
Agent: Cl
Agent: [OH-]
Product: NCCN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound 26 (8.6 mg,0.017 mmol) was dissolved in concentrated NH4OH (0.4 mL) and stirred overnight. The crude product was extracted into CHCl3, and the organic layer was evaporated to dryness. The remaining residue was recrystallized from chloroform/petroleum ether to yield 7.2 mg of 27 (97%); mp 188°-190 ° C.: 1H NMR (CDCl3) δ 2.00-2.70 (m, 12 H), 3.20 (d, J=14 Hz, 1 H), 3.60 (br d, J=14 Hz, 1 H), 7.26 (dd, J= 7.8, 4.7 Hz, 1 H), 7.40 (m, 1 H), 7.55 (dd, J= 7.9, 1.4 Hz, 1 H), 7.58-7.62 (br s, 1 H), 7.92 (d, J= 7.7 Hz, 1 H), 8.26 (br s, 1 H), 9.35 (br s, 1 H); MS (CI/NH3) m/e 381 (MH+base) , 338, 252, 212.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[N:13](C(OC(C)(C)C)=O)[C:12]2=[CH:21][S:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[C:33]5[C:37]=4[NH:36][C:35](=[O:38])[N:34]5C(OC(C)(C)C)=O)=[CH:26][CH:25]=3)=[C:11]2[NH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[O:8]=[C:9]1[NH:13][C:12]2=[CH:21][S:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[C:33]5[C:37]=4[NH:36][C:35](=[O:38])[NH:34]5)=[CH:26][CH:25]=3)=[C:11]2[NH:10]1
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2c(-c3ccc(-c4scc5c4[nH]c(=O)n5C(=O)OC(C)(C)C)cc3)scc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2csc(-c3ccc(-c4scc5[nH]c(=O)[nH]c45)cc3)c2[nH]1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid in an amount of 40 equivalents relative to the obtained tert-butyl 4-[4-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)phenyl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was added and a reaction was carried out at 25° C. for 3 hours. The resulting reaction liquid was dropped slowly to a saturated aqueous sodium carbonate solution to neutralize, thereby stopping the reaction. Ethyl acetate was added to the reaction liquid and stirred, and then an organic layer was taken and the solvent was distilled off. The residue was purified by silica gel column chromatography using an ethyl acetate/hexane solvent, so that 4-[4-(2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazol-4-yl)phenyl]-2,3-dihydro-1H-thieno[3,4-d]imidazol-2-one was obtained. The yield based on the charged tert-butyl 4-[4-(2,3-dihydro-2-oxo-1-tert-butoxycarbonyl-1H-thieno[3,4-d]imidazol-4-yl)phenyl]-2,3-dihydro-2-oxo-1H-thieno[3,4-d]imidazole-1-carboxylate was 90%.