Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=O)[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33].CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:15])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CCN
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
To a stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.3 g, 1.234 mmol) in DCM (5 ml) EDCI (0.284 g, 1.48 mmol) and HOBt (0.2 g, 1.48 mmol) were added at about 0° C., after 10 minutes methyl 3-aminopropanoate hydrochloride (0.254 g, 2.47 mmol) and Et3N (0.9 ml, 6.17 mmol) in DCM (5 ml) were added drop wise and the reaction mass was allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM and washed with water and saturated NaHCO3 solution, then washed with aqueous 1N HCl, then washed with water and saturated brine, and the organic layer was concentrated under reduced pressure, the resulting crude was purified by silica gel column (100-200 mesh, elution 70% EtOAC in hexane) to afford the title compound as solid. Wt: 0.336 g; Yield: 88.9%; 1H NMR (300 MHz, CDCl3): δ 5.89 (brs, 1H), 4.79 (d, 1H, J=8.1 Hz), 3.88-3.73 (m, 1H), 3.70 (s, 3H), 3.59-3.42 (m, 2H), 2.54-2.51 (m, 2H), 2.39-2.20 (m, 2H), 2.11-1.99 (m, 1H), 1.43 (s, 9H), 1.26 (s, 3H), 0.87 (s, 3H); Mass: [M+Na]+ 351 (100%); IR (KBr, cm−1): 3359, 3319, 2973, 1737, 1696, 1667, 1539, 1454, 1366, 1271, 1254, 1176, 1051, 1024, 782, 683; M.R: 98.6° C.-100.2° C.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=O)[CH:11]=[CH:12][CH:13]=1.[CH3:26][NH:27][NH2:28]>CO>[ClH:1].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]2[N:27]([CH3:26])[N:28]=[C:16]3[C:17]4[C:22]([CH2:23][CH:15]23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCCOc1cccc(C=C2Cc3ccccc3C2=O)c1
Reactant: CNN
Agent: Cl
Solvent: CO
Product: CN(C)CCCOc1cccc(C2C3Cc4ccccc4C3=NN2C)c1
Yield: 10.8 %

Procedure:
A stirred solution of 8.6 g (0.024 mole) of 2-[[3-[3-(dimethylamino)propoxy]phenyl]methylene]-2,3-dihydro-1H-inden-1-one hydrochloride from part B and 1.3 g (0.028 mole) of methyl hydrazine in 50 ml of methanol is heated at reflux for 2 hours. After cooling, the solvent is evaporated to give 1.0 g of an amber oily residue.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[C:17]([C:24](O)=[O:25])[CH:16]=2)=[C:11]([C:27]([N:29]2[C@H:38]([CH2:39][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.C1(C)C=CC=CC=1.[Si:61]([O:68][C:69]1[CH:74]=[CH:73][C:72]([NH:75][C:76]2[CH:77]=[C:78]3[CH:84]=[CH:83][N:82]([CH3:85])[C:79]3=[N:80][CH:81]=2)=[CH:71][CH:70]=1)([C:64]([CH3:67])([CH3:66])[CH3:65])([CH3:63])[CH3:62]>ClCCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[C:17]([C:24]([N:75]([C:72]3[CH:71]=[CH:70][C:69]([O:68][Si:61]([C:64]([CH3:67])([CH3:65])[CH3:66])([CH3:63])[CH3:62])=[CH:74][CH:73]=3)[C:76]3[CH:77]=[C:78]4[CH:84]=[CH:83][N:82]([CH3:85])[C:79]4=[N:80][CH:81]=3)=[O:25])[CH:16]=2)=[C:11]([C:27]([N:29]2[C@H:38]([CH2:39][N:40]3[CH2:41][CH2:42][O:43][CH2:44][CH2:45]3)[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:28])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc2cc(Nc3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN2CCOCC2)n2c1CCCC2
Agent: CC(C)=C(Cl)N(C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: Cn1ccc2cc(N(C(=O)c3cc(-c4ccc(OCc5ccccc5)cc4C(=O)N4Cc5ccccc5C[C@H]4CN4CCOCC4)n4c3CCCC4)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The acid obtained in Step B (9 g, 11.8 mmol) is dissolved in 90 mL of 1,2-dichloroethane. 1.9 mL of 1-chloro-N,N,2-trimethylpropenylamine (14 mmol) are added thereto. After stirring for 3 hours at ambient temperature, 90 mL of toluene and 4.62 g of N-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-1-methyl-1H-pyrrolo[2,3-b]pyridin-5-amine (Preparation 3″, 13 mmol) are added. The reaction mixture is heated at 110° C. for 20 hours. After returning to ambient temperature, the reaction mixture is washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue obtained is purified by chromatography over silica gel (dichloromethane/ethanol gradient) to yield the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5[NH:33][C:34]([CH:37]6[CH2:41][CH2:40][CH2:39][N:38]6[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:46])[CH3:45])=[N:35][CH:36]=5)=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[C:9]1=[O:53])(C)(C)C.COC(=O)N[CH:59](C(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(CN5CCCC(N)C5=O)=NC=4)=CC=3)=CC=2)=CN=1)=O)[CH:60](C)C>>[CH3:1][O:5][C:6](=[O:54])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]2[N:10]([CH:14]([C:15]3[NH:16][C:17]([C:20]4[CH:21]=[CH:22][C:23]([C:26]5[CH:31]=[CH:30][C:29]([C:32]6[NH:33][C:34]([CH:37]7[CH2:41][CH2:40][CH2:39][N:38]7[C:42](=[O:52])[CH:43]([NH:47][C:48]([O:50][CH3:51])=[O:49])[CH:44]([CH3:45])[CH3:46])=[N:35][CH:36]=6)=[CH:28][CH:27]=5)=[CH:24][CH:25]=4)=[CH:18][N:19]=3)[CH2:59][CH2:60]2)[C:9]1=[O:53]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(N)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(CN5CCCC(NC(=O)OC(C)(C)C)C5=O)[nH]4)cc3)cc2)[nH]1)C(C)C
Product: COC(=O)NC1CCC2CCC(c3ncc(-c4ccc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)C(C)C)[nH]6)cc5)cc4)[nH]3)N2C1=O

Procedure:
{3-[5-(4′-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid methyl ester was prepared following method 804 followed by method 805, substituting {3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-5-oxo-octahydro-indolizin-6-yl}-carbamic acid tert-butyl ester for {1-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-ylmethyl]-2-oxo-piperidin-3-yl}-carbamic acid tert-butyl ester in method 804, and substituting {1-[2-(5-{4′-[2-(6-Amino-5-oxo-octahydro-indolizin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester for {1-[2-(5-{4′-[2-(3-amino-2-oxo-piperidin-1-ylmethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester in method 805. C39H46N8O6 calculated 722.4 observed [M+1]+ 723.4; rt=1.62 min. 1H (DMSO-d6): δ=8.10 (m, 1H), 7.90 (m, 8H), 7.31 (m, 2H), 5.12 (m, 2H), 4.11 (m, 2H), 3.84 (m 21-1), 3.74 (m, 1H), 3.53 (s, 6H), 2.38 (m, 2H), 2.14 (m, 3H), 2.05 (m, 5H), 1.82 (m 3H), 0.81 (dd, J=8.8 Hz, J=17.6 Hz, 6H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[CH:61]=[C:60]1[CH2:68]O>C(OCC)(=O)C.O1CCCC1>[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[CH:61]=[C:60]1[CH2:68][N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27]
Reactant: OCc1cc2ccccc2s1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2cc3ccccc3s2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.23 g), tributylphosphine (1.52 mL), 1-benzothien-2-ylmethanol (0.56 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.55 g, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
A solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-methoxyphenyl)piperidine (2.59 g) in dichloromethane (45 mL) was treated with trifluoroacetic acid (8.6 g) followed by triethylsilane (17.5 g). The resulting brown reaction mixture was stirred for 5 minutes and then poured into a saturated solution of sodium bicarbonate. The bicarbonate solution was extracted with dichloromethane. The dichloromethane solution was dried and evaporated to give the des-hydroxy compound (2.1 g); NMR (CDCl3): 1.55-1.66 (m, 2), 1.78-1.82 (br, 2), 2.91, (m, 2), 3.11 (m, 1), 3.8 and 3.82 (s, 3), 4.32 (br, 2), 5.12-5.28 (m, 2), 6.84 (d, 4, J=9), 6.87-6.95 (m, 1), 7.11-7.25 (m, 2), 7.29-7.38 (m, 5); MS: m/z=326(M+1). This material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])(=O)=O)=CC=1>CCO.O>[OH:12][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:24][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[CH:3]=1)[CH2:9][C:10]#[N:11]
Reactant: N#CCC(O)c1cccc(N)c1
Reactant: CCCC(CCC)COS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Solvent: O
Product: CCCC(CCC)CNc1cccc(C(O)CC#N)c1

Procedure:
To a stirred solution of aniline 12 (1.0 g, 6.1 mmol) in EtOH:H2O (9:1) was added 2-propylpentyl 4-methylbenzenesulfonate (0.87 g, 3.08 mmol). The reaction mixture was heated under reflux for 4 days, concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc three times. Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. Purification by flash chromatography (25% EtOAc—hexanes) gave 3-hydroxy-3-(3-(2-propylpentylamino)phenyl)propanenitrile as a colorless semi-solid. Yield (0.3 g, 18%); 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J=7.6 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 6.57 (dd, J=2.0, 8.0 Hz, 1H), 4.95 (dt, J=3.2, 6.0 Hz, 1H), 3.72 (bs, 1H), 3.02 (d, J=6.0 Hz, 2H), 2.80 (d, J=6.8 Hz, 2H), 2.89 (d, J=3.2 Hz, 1H), 1.64-1.57 (m, 1H), 1.37-1.20 (m, 8H), 0.84 (t, J=6.8 Hz, 6H).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:28])[CH:10]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:3][CH:2]=1.ClC(Cl)(Cl)C(=N)O[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>O1CCCC1.B(F)(F)F.CCOCC>[C:1]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([O:28][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[CH:10]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:22])[CH3:23])[C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])=[CH:3][CH:2]=1
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(-c2ccccc2)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(COC(CCc2ccc(-c3ccccc3)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.4 %

Procedure:
Boron trifluoride etherate (8.0 μL, 65 μmol) was added to a stirred solution of tert-butyl 5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-hydroxypentanoate (7.88 g, 16.3 mmol) and 4-methoxybenzyl 2,2,2-trichloroethanimidoate (6.88 g, 24.5 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. A further portion of boron trifluoride etherate (8.0 μL, 65 μmol) was then added and stirring was continued at room temperature for a further 2 h. Two further additions of boron trifluoride etherate (8.0 μL, 65 μmol) followed by stirring at room temperature for 2 h were carried out before evaporation of the solvent. The residue was chromatographed on silica gel (5% to 10% diethyl ether: cyclohexane) to give the title compound (3.39 g, 34%) as a pale yellow oil which was a mixture of diastereomers. LC/MS: 4.81 min; z/e 605, calcd (M+1) 605. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.45 (4H), 7.35-6.80 (7H), 4.50 (2H), 3.80 (3H), 3.60 (3H), 2.95 (1H), 2.80 (1H), 2.65 (1H), 1.85 (4H), 1.45 (9H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: S(O)(O)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[NH:8])[NH2:7].[OH-].[Na+].[CH2:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[C:28](=[CH:33]OC)[C:27]1=[O:36])[CH3:25]>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[CH:33][C:28]3[C:27](=[O:36])[N:26]([CH2:24][CH3:25])[CH2:31][CH2:30][C:29]=3[N:8]=2)[CH2:10][CH2:11]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCN1CCC(=O)C(=COC)C1=O
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN1CCc2nc(N3CCN(Cc4ccccc4)CC3)ncc2C1=O
Yield: 80.8 %

Procedure:
To a suspension which had been obtained by adding 1.56 g of 1-amidino-4-benzylpiperazine sulfate to an ethanol solution of 0.23 g of sodium hydroxide, 1.07 g of 1-ethyl-3-methoxymethylenepiperidine-2,4-dione (Referential Example 37) was added. The resultant mixture was refluxed for 2 hours. After distilling off ethanol, water was added to the residue, followed by extraction with chloroform. After drying the chloroform layer, it was concentrated to obtain 1.4 g of 2-(4-benzylpiperazino)-6-ethyl-5-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (yield: 69%).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][C@H:28]([CH3:32])[C:29](O)=[O:30]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:29](=[O:30])[C@H:28]([O:27][CH3:26])[CH3:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CO[C@H](C)C(=O)O
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (19 mg, 65.2%), MS (ISP) m/z=417.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and (R)-2-methoxypropanoic acid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][CH:26]([F:27])[C:24]1[CH:23]=[C:22]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=2)[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=2)[N:25]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.2 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butylamide (0.24 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash-chromatography on silica gel (ethyl acetate/hexane) and crystallization (dichloromethane) yielded the title compound as an off-white solid (0.1 g, 20%). MS (ISP) 513.3 [(M+H)+]; mp 242° C.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22]I)[CH:17]=[CH:18][C:4]1=2)[CH3:2].[NH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CO>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: NCCc1cccnc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNCCc3cccnc3)ccc21
Temperature: 50 °C
Reaction time: 9 h
Yield: 69.8 %

Procedure:
1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (5.3 mmol) was added to a methanol solution (100 ml) of 3-(2-aminoethyl)pyridine (3.3 g, 26.7 mmol), and stirred at 50° C. for 9 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the residue, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1→10:1). The purified product was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate:methanol=1:0→10:1) again. The purified product was concentrated under reduced pressure to thereby obtain 1.57 g (yield: 70%) of 1-ethyl-3,3,5-trimethyl-7-[3-(2-pyridin-3-ylethylamino)propoxy]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione as a yellow oil.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7].O>C(O)(=O)C>[CH2:6]([O:8][N:9]=[C:10]([C:16](=[O:18])[CH2:17][Cl:4])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCON=C(C(C)=O)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCON=C(C(=O)CCl)C(=O)OCC
Yield: 93.1 %

Procedure:
Sulfuryl chloride (35.2 g.) was added all at once to the stirred solution of ethyl 2-ethoxyimino-3-oxobutyrate (syn isomer) (48.9 g.) in acetic acid (49 ml.) at room temperature, and stirred at the same temperature for an hour. After adding the resultant solution into water (200 ml.), the solution was extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, neutralized with an aqueous solution of sodium bicarbonate and washed with water. The solution was dried over magnesium sulfate and concentrated under reduced pressure to give ethyl 2-ethoxyimino-3-oxo-4-chlorobutyrate (syn isomer) (53.8 g.), pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH2:5].[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:27]=1[C:28](Cl)=[O:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:22])[N:15]([CH3:21])[C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:9]([CH3:23])[CH:8]=1)[NH:5][C:28]([C:27]1[C:26]([Cl:25])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:35])=[O:29]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
To a suspension of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.128 mmol, 47 mg) and 2,6-dichlorobenzoyl chloride (0.153 mmol, 32 mg) in dichloromethane (1 mL) was added diisopropylethylamine (0.45 mmol, 77 uL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 15 h at room temperature. The resulting brown solution was diluted with dichloromethane (25 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×25 mL), saturated sodium bicarbonate solution (25 mL), and brine solution (25 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 52 mg (81% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C24H23Cl2N3O5 (M+Na) 526.0907, found 526.0912.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:14][Mg]Br>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])([CH3:14])[CH3:12])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(OC(C)C)cc1
Product: CC(C)Oc1ccc(C(C)(C)O)cc1

Procedure:
Reaction of 1-isopropoxy-4-acetylbenzene with methyl magnesium bromide afforded 1-isopropoxy-4-(1-hydroxy-1-methylethyl)benzene. A solution of 35 g. of 1-isopropoxy-4-(1-hydroxy-1-methylethyl)benzene in 65 ml. of ethyl alcohol and 300 ml. of liquid ammonia was stirred while 5 g. of Lithium metal in the form of small pieces was added portionwise over thirty minutes. The reaction mixture was stirred for an additional thirty minutes, and then was diluted with 150 ml. of toluene and 35 g. of ammonium chloride. The reaction mixture was stirred at room temperature for twelve hours, and then was further diluted with 200 ml. of water. The aqueous layer was separated and extracted with 100 ml. of fresh toluene. The toluene layers were combined, washed with water, dried, and concentrated by evaporation under reduced pressure. Distillation of the residue provided 22.8 g. of 1-isopropoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene. B.P. 85°-87° C. at 0.02 torr.