Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C1(N)CCCCC1.O>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: NC1CCCCC1
Solvent: CCO
Solvent: O
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
Triethyl orthoformate (3 ml, 18 mmol) and p-Toluenesulfonic acid (30 mg, 0.16 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (3 g, 8.72 mmol) in ethanol (20 ml). The mixture was stirred at room temperature for 1 h. Cyclohexylamine (1 ml, 8.75 mmol) was added and the mixture was heated at 30° C. for 2 h, cooled to 10° C. and water (20 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (2.0 g yield: 80%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4]=2[N:3]=1.[CH3:20][NH:21][CH3:22]>CO>[Cl:1][C:2]1[N:11]=[C:10]([N:21]([CH3:22])[CH3:20])[C:9]2[CH2:8][CH2:7][CH2:6][CH:5]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:4]=2[N:3]=1
Reactant: Fc1ccc(C2CCCc3c(Cl)nc(Cl)nc32)cc1
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCCC2c1ccc(F)cc1
Yield: 99.7 %

Procedure:
A solution of 2,4-dichloro-8-(4-fluorophenyl)-5,6,7,8-tetrahydroquinazoline (115 mg, 0.387 mmol) and excess dimethylamine (1.935 mL, 3.87 mmol) in MeOH (1 mL) was stirred at room temperature for 1 h. The solvent was removed in vacuum to afford 2-chloro-8-(4-fluorophenyl)-N,N-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine (118 mg, 0.386 mmol, 100% yield). LC-MS (M+H)+=306.2.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][C@H:6]([OH:23])[C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]([OH:22])[CH2:10][C:11]2=[O:21])[CH2:3]1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[OH:23][C@H:6]1[CH:5]=[C:4]2[C@:17]([CH3:20])([CH2:18][CH2:19][C@H:2]([O:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3]2)[C@@H:16]2[C@@H:7]1[C@H:8]1[C@@:12]([CH2:14][CH2:15]2)([CH3:13])[C:11](=[O:21])[CH2:10][C@@H:9]1[O:22][C:11](=[O:21])[C:12]([CH3:14])([CH3:13])[CH3:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@H]1[C@@H]3[C@@H](O)CC(=O)[C@@]3(C)CC[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H](OC(=O)C(C)(C)C)CC(=O)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
One gram of 3β,7β,15α-trihydroxy-5-androsten-17-one is dissolved at room temperature in 20 ml of pyridine; 2 ml of pivalic acid chloride as well as 100 mg of 4-dimethylaminopyridine are added to the reaction mixture, and the latter is agitated at room temperature for 48 hours. The reaction mixture is then poured into 250 ml of ice water, stirred for 2 hours at room temperature, the resultant precipitate is vacuum-filtered, washed with water, and dried for 8 hours in a vacuum drying cabinet at 50° C., yielding 1.38 g of 7β-hydroxy-3β,15α-dipivaloyloxy-5-androsten-17-one, mp 195°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20]I)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.C(NC(C1N=C[N:34]2[C:40]3[CH:41]=[CH:42][C:43](F)=[CH:44]C=3C(=O)N(C)CC=12)=O)C#C.IN1C(=O)CCC1=O.N1CCCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[O:16][C:17]([CH2:20][N:34]5[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]5)=[CH:18][N:19]=4)=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: CN1Cc2c(-c3ncc(CI)o3)ncn2-c2ccc(F)cc2C1=O
Agent: O=C1CCC(=O)N1I
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1Cc2c(-c3ncc(CN4CCCCC4)o3)ncn2-c2ccc(F)cc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
125 ml of a crude THF solution of 8-fluoro-3-(5-iodomethyl-oxazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one (prepared from 15.6 g (0.050 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-carboxylic acid prop-2-ynylamide and 16.9 g (0.075 mol) of N-iodosuccinimide, subsequently completely freed from the solvents, dried azeotropically several times with toluene and dissolved in 500 ml of THF) were treated with 10.7 ml (0.109 mol) of piperidine and stirred at room temperature for 3 hrs. The suspension obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the beige-brown product was chromatographed over silica gel with ethyl acetate/methanol 4:1 as the eluent and recrystallized from hot ethyl acetate. There was obtained 0.85 g (17%) of 8-fluoro-5-methyl-3-(5-piperidin-1-ylmethyl-oxazol-2-yl)-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 191°-193°.
Reaction SMILES: C([Li:5])CCC.[CH3:6][C:7]1[CH2:11][C:10]([CH3:12])=[C:9]([CH3:13])[C:8]=1[CH3:14]>C1COCC1>[CH3:6][C:7]1[CH:11]([Li:5])[C:10]([CH3:12])=[C:9]([CH3:13])[C:8]=1[CH3:14]
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: [Li]C1C(C)=C(C)C(C)=C1C
Reaction time: 2 h
Yield: 76 %

Procedure:
Meanwhile, n-butyl lithium (26 ml, 0.042 mol) was slowly added to a solution of 1,2,3,4-tetramethylcyclopentadiene (5 g, 0.041 mol) in 100 ml of THF at −78° C. and the mixture was stirred for 2 hours. Then, the solvent was removed and the resultant product was washed with hexane and dried to obtain tetramethylcyclopentadienyl lithium (yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[F:8].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:42][CH2:43][C:44]1[CH:59]=[CH:58][C:47]([C:48]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[NH2:57])=[O:49])=[CH:46][CH:45]=1>CN(C=O)C>[NH2:57][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[NH:50][C:48](=[O:49])[C:47]1[CH:46]=[CH:45][C:44]([CH2:43][NH:42][C:11](=[O:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[CH:59][CH:58]=1
Reactant: NCc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: O=C(O)C(=Cc1ccc(F)c(F)c1)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(CNC(=O)C(=Cc2ccc(F)c(F)c2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
To a solution of 3-(3,4-difluorophenyl)-2-(4-fluorophenyl)acrylic acid (0.5 g, 1.7 mmol) in DMF (5 mL) was added TEA (0.75 mL, 5.4 mmol), EDCI (0.68 g, 3.5 mmol), HOBt (0.25 g, 1.8 mmol) followed by the 4-(aminomethyl)-N-(2-aminophenyl)benzamide (0.52 g, 1.9 mmol). The reaction mixture was stirred at room temperature for 12 hours. Subsequently it was concentrated under reduced pressure to half the volume and the resulted solution was poured into water. Upon standing a white precipitate formed, was filtered, washed with water followed by ether gave the pure product (0.3 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 4.41 (2H, d, CH2), 4.88 (2H, s, NH2), 6.59 (1H, t, Ar—H), 6.77 (1H, d, Ar—H), 6.88 (1H, s, Ar—H), 6.96 (2H, m, Ar—H), 7.16 (1H, d, Ar—H), 7.24-7.38 (7H, m, Ar—H), 7.47 (1H, s, ═CH), 7.92 (2H, d, Ar—H), 8.14 (1H, t, NH), 9.61 (1H, s, NH). MS m/z: 502.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH2:19])[CH:5]=1.C([C:23]1[C:24]([N:30]=[CH:31][N:32]([CH3:34])C)=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)#N>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH:19][C:34]2[C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[N:25][C:24]=3[N:30]=[CH:31][N:32]=2)[CH:5]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(N)c1
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Yield: 44.8 %

Procedure:
The product from Example 136B (2.67 g, 9.23 mmol) and the product from Example 9B (1.72 g, 9.23 mmol) were reacted according to the procedure from Example 136C substituting the product from Example 9B for the product from Example 8E to give a residue which was purified by silica gel chromatography using 4% methanol in dichloromethane as eluent to provide the title compound as a white solid (1.79 g, 45%).
Reaction SMILES: [OH:1][C:2]([C@@:5]1([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1)([CH3:4])[CH3:3].[ClH:36]>CCOCC.O1CCCC1>[ClH:36].[ClH:36].[NH2:10][C@H:7]1[CH2:8][CH2:9][C@@:5]([C:2]([OH:1])([CH3:3])[CH3:4])([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1CC[C@](C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)(C(C)(C)O)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)[C@@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
tert-Butyl [(3R)-3-(1-hydroxy-1-methylethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (75 mg, 0.15 mmol) was mixed with a 2.00 M solution of hydrogen chloride in ether (2 mL) and tetrahydrofuran (1 mL). After being stirred for 1 h at room temperature, the reaction solution was concentrated to provide the desired product (70 mg, 98.7%). LCMS calculated for C17H28F3N4O2: (M+H) 473.2; found 473.2.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14]([OH:16])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[O:46]=[C:47]([N:64]1[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]1)[CH2:48][NH:49][C:50]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)=[O:51]>CN(C=O)C.O>[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[C:14]([N:67]1[CH2:66][CH2:65][N:64]([C:47](=[O:46])[CH2:48][NH:49][C:50]([C:52]2[CH:57]=[CH:56][C:55]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:54][CH:53]=2)=[O:51])[CH2:69][CH2:68]1)=[O:16]
Reactant: O=C(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)cc(C(F)(F)F)c2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
DIPEA (149.8 mg, 1.15 mmol) was added to a stirred solution of 3-fluoro-5-trifluoromethyl-benzoic acid (53.6 mg, 0.26 mmol) in DMF (3 mL), HOBt (38.2 mg, 0.28 mmol) and EDCI.HCl (123.4 mg, 0.64 mmol) at room temperature. After 2 minutes biphenyl-4-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.31 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added, and the resulting precipitate was filtered. The residue was purified by column chromatography (using 60-120 mesh silica gel and 60% EtOAc in hexane as eluent) to afford 60 mg (45.3% yield) of biphenyl-4-carboxylicacid {2-[4-(3-fluoro-5-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide, LC-MS purity: 99.64%, 1H NMR: (DMSO) δ 8.7-8.62 (t, 1H), 8.02-7.94 (d, 2H), 7.86-7.66 (m, 7H), 7.54-7.46 (m, 2H), 7.44-7.38 (m, 1H), 4.26-4.12 (bs, 2H), 3.74-3.44 (m, 6H), 3.42-3.34 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=O)[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.Cl.[CH:12]1([CH2:16][NH2:17])[CH2:15][CH2:14][CH2:13]1.[S-:18][C:19]#[N:20].[K+].II>C(N(CC)CC)C>[CH:12]1([CH2:16][N:17]2[C:5]3[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]=3[S:18][C:19]2=[NH:20])[CH2:15][CH2:14][CH2:13]1
Reactant: NCC1CCC1
Reactant: N#C[S-]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Agent: Cl
Agent: II
Agent: [K+]
Solvent: CCN(CC)CC
Product: CC1(C)OC(C)(C)c2c1sc(=N)n2CC1CCC1

Procedure:
Commercially available 2,2,5,5-tetramethyldihydrofuran-3(2H)-one (Aldrich), triethylamine, cyclobutylmethanamine hydrochloride (prepared from cyclobutanecarbonitrile as described in WO2005075464), potassium thiocyanate (Aldrich) and iodine (EMD chemicals) were processed using the method described in Example 91A to afford the title compound. MS (ESI+) m/z 267 (M+H)+
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[F:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH2:14][CH2:15][O:16]2)=[CH:11][CH:10]=1.CS([Cl:24])(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:24][C:13]1([CH:6]=[CH2:7])[C:12]2[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[O:16][CH2:15][CH2:14]1
Reactant: O=C1CCOc2cc(F)ccc21
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1(Cl)CCOc2cc(F)ccc21
Reaction time: 1.5 h

Procedure:
Triethylamine (0.19 ml) was added to a solution of the compound 5-1 synthesized from 7-fluorochroman-4-one according to Example 4 (200 mg) in tetrahydrofuran (3.0 ml), cooled in an ice bath. A solution of methanesulfonyl chloride (177 mg) in tetrahydrofuran (2.0 ml) was added dropwise at the same temperature, followed by stirring for 1.5 hours. After confirming disappearance of the raw material, the reaction mixture was added to aqueous sodium bicarbonate to terminate the reaction. The aqueous layer was extracted with ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (214 mg), which was used for the next reaction as a crude product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:25])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([OH:22])=O)=[C:14]([O:23][CH3:24])[CH:13]=2)[CH2:4][CH2:3]1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[N:42]1([CH:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([N:51]3[CH2:52][CH2:53][CH:48]([N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)[CH2:49][CH2:50]3)=[O:22])=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:25])[CH2:6][CH2:7]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)O
Reactant: C1CCN(C2CCNCC2)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)N1CCC(N2CCCCC2)CC1

Procedure:
Using 1.9 g of N-(trans-4-methylcyclohexyl)-4-(carboxymethoxy)-3-methoxycinnamamide (Example 172), 1.2 ml of diethyl chlorophosphate, 2.3 ml of triethylamine, 0.92 g of 4-piperidinopiperidine, 0.04 g of 4-dimethylaminopyridine, and 100 ml of methylene chloride, a reaction similar to that conducted in Example 188 was carried out. As a result, 1.51 g of 1-{4-{2-[N-(trans-4-methylcyclohexyl)carbamoyl]vinyl}-2-methoxyphenoxyacetyl}-4-piperidinopiperidine (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([B:13]([OH:15])[OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.C[Si](Cl)(C)C.[CH3:30][C:31]1[CH:39]=[C:38]([CH3:40])[CH:37]=[C:36]([CH3:41])[C:32]=1[C:33](Cl)=[O:34]>C(Cl)Cl>[B:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:2]([NH:1][C:33](=[O:34])[C:32]2[C:36]([CH3:41])=[CH:37][C:38]([CH3:40])=[CH:39][C:31]=2[CH3:30])[C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1)([OH:15])[OH:14]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: NC(Cc1ccc(B(O)O)cc1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(C(=O)NC(Cc2ccc(B(O)O)cc2)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (7.18 mmol) of 2-amino-3-(4-boronophenyl)propionic acid were suspended in 50 ml DCM and 7.4 ml (43.1 mmol) DIPEA and refluxed for 20 min together with 4.5 ml (35 mmol) TMSCl. The solution was cooled in an ice bath and a solution of 1.44 g (7.9 mmol) 2,4,6-trimethylbenzoyl chloride in 5 ml DCM were added dropwise. The reaction mixture was stirred 2 h at room temperature, diluted with 100 ml DCM and washed with 2 N aqueous HCl. During this washing some product precipitated which was collected. The organic phase was extracted with 2 N NaOH twice. Upon acidifying of the combined basic phases the product precipitated, which was collected and dried together with the first precipitate. The crude product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.O1CCCC1.[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>O>[Br:7][C:5]1[S:4][C:3]([C:8]([NH2:10])=[O:9])=[C:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH:6]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: O=C(Cl)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1sc(Br)cc1NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 3-amino-5-bromothiophene-2-carboxamide (200 mg) produced in Example 1, step D, triethylamine (0.19 mL) and tetrahydrofuran (4.0 mL) was added cyclohexanecarbonyl chloride (0.18 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was poured into the reaction system, the mixture was extracted with ethyl acetate, and the extract was washed with brine, and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide. To 5-bromo-3-[(cyclohexylcarbonyl)amino]thiophene-2-carboxamide produced above were added 2M aqueous sodium hydroxide solution (0.90 mL) and ethanol (2.0 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction system was neutralized with 1M hydrochloric acid at 0° C. Water (2 mL) was added, and the precipitate was collected by filtration to give the title compound (252 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:28])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 100 °C

Procedure:
To a 500 mL round-bottom flask was added tert-butyl 4′-methylbiphenyl-2-carboxylate (7.04 g, 26.23 mmol), NBS (5.14 g, 28.85 mmol), AIBN (0.43 g, 2.62 mmol) and CCl4 (200 mL). The reaction mixture was refluxed for 2 h at 100° C. The completion of the reaction was monitored by analytical HPLC. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0→30%) to obtain the title compound.
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)=[N:12][CH:13]=2)[CH:5]=1.O[CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]1[CH3:33]>>[N:14]1([C:11]2[N:12]=[CH:13][C:8]([O:7][CH2:6][C:4]3[CH:5]=[N:1][N:2]([CH:20]4[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH:21]4[CH3:33])[N:3]=3)=[CH:9][CH:10]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCC1O
Product: CC1CN(C(=O)OC(C)(C)C)CCC1n1ncc(COc2ccc(-n3cnnn3)nc2)n1

Procedure:
The title compound was synthesized from Intermediate 13 and tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate in a manner similar to that described in Example 69. The compounds were isolated as a mixture of four stereoisomers. Characterized by LCMS (ES+-MS found: 464 (M+Na), 442 (M+H)).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][N:17]([S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])(=[O:22])=[O:21])[CH2:16][CH2:15]3)[C:11]2=[O:30])=[CH:6][CH:5]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33].[Cl-].C[Al+]C.O>C1(C)C=CC=CC=1.CCCCCC>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([N:17]1[CH2:18][CH2:19][C:12]2([C:11](=[O:30])[N:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:31])=[CH:9][CH:8]=3)[CH2:14][CH2:13]2)[CH2:15][CH2:16]1)(=[O:22])=[O:21]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
4-[8-(2-Chloro-benzenesulfonyl)-1-oxo-2,8-diaza-spiro[4.5]dec-2-yl]-benzoic acid methyl ester (0.149 g), compound of example 150), was suspended in toluene under an argon atmosphere at RT, isopropylamine (0.057 g) and dimethylaluminium chloride in hexane (1 molar, 1.61 ml) were added and the mixture stirred 10 minutes at 130° than overnight at 95° C. The reaction mixture was cooled to RT, water (0.05 ml) was added, and the mixture was stirred for 10 minutes. Then the solvent was carefully evaporated off in vacuo, the residue was adsorbed on silica gel and chromatographed over silica gel (eluents: AcOEt/heptane, gradient from 0 to 50%) to give the desired compound (0.048 g) as white solid. MS (ESI): 490.15 MH+).
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[CH3:32]>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[C:4](=[O:13])[CH2:5][CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]=1[OH:1])=[C:26]2[CH3:32]
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: Cc1c[nH]c2ccc(F)cc12
Product: Cc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure D, rac-3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a red solid. MS: 412.0 ([M+H]+).