Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:10](=[O:21])[CH2:9]1)=[O:7])(C)(C)C.Cl.C(N(CC)CC)C.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1/[CH:40]=[CH:41]/C(O)=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1/[CH:40]=[CH:41]/[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:10](=[O:21])[CH2:9]1)=[O:7]
Reactant: O=C(O)/C=C/c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCN(CCN2CCCC2)C(=O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc2ccccc2c1)N1CCN(CCN2CCCC2)C(=O)C1
Reaction time: 1 h

Procedure:
3-Oxo-4-(2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 6; 0.03 g, 0.1 mmol) was treated with a hydrogen chloride solution (4 M in 1,4-dioxane, 1 ml) for 15 minutes after which time the solvent was evaporated. The crude salt was dissolved in N,N-dimethylformamide (0.8 ml) with triethylamine (0.06 ml, 0.4 mmol) and (E)-3-naphthalen-2-yl-acrylic acid (0.02 g, 0.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) were added. The mixture was shaken for 1 h after which time it was directly purified by preparative HPLC. MS (ISP)=378.6 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[C:11]([C:17]([OH:19])=O)[CH:10]=1.C(C1N[CH:29]=[CH:30][N:31]=1)(C1NC=CN=1)=O.[CH2:32]1COCC1>>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[C:11]([C:17]([NH:31][CH:30]([CH3:32])[CH3:29])=[O:19])[CH:10]=1
Reactant: C=Cc1cc(C(=O)O)cc(-c2ccc(C)cc2F)c1
Reactant: C1CCOC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: C=Cc1cc(C(=O)NC(C)C)cc(-c2ccc(C)cc2F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
In a 500 mL flask charged with carboxylic acid from step D (12 g, 46.8 mmol) in THF (300 mL) at 0° C. was added carbonyl diimidazole (9.1 g, 56.2 mmol) portionwise. Upon complete addition (10 min.) the ice bath was removed and the reaction stirred for 1 h. At this time the mixture was re-cooled to 0° C. and isopropylamine added dropwise (4.98 g, 84 mmol). The mixture was warmed to rt and the reaction complete within 2 h as indicated by LC-MS. The mixture was concentrated and treated with EtOAc and aq. Na2HCO3. The organic layer was washed with brine; dried over Na2SO4 and concentrated to via rotary evaporation and further dried in vacuo. The crude product was re-crystallized from EtOAc/hexanes to give 11.7 g of final product as a colorless solid (84%): LC-MS (M+H)=298.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.[Cl-].[Al+3].[Cl-].[Cl-].[I:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>[N+](C)([O-])=O.C(OCC)C>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[I:23])[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(Cl)c1ccccc1I
Reactant: CC1(C)CC(c2ccccn2)c2ccccc2O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3I)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
250 mg of 3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of nitromethane and cooled in an ice-bath under a nitrogen atmosphere. 280 mg of finely powdered aluminum chloride were added followed, after 5 minutes, by 700 mg of 2-iodobenzoyl chloride. After stirring at 0° C. for 30 minutes and at room temperature for 1 hour the mixture was diluted with diethyl ether and washed with sodium hydroxide solution. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (1:2) for the elution to give 230 mg of 3,4-dihydro-2,2-dimethyl-6-(2-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran.
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1.[OH-].[Na+]>C(O)C.O>[O:18]1[C:10]2[CH:9]=[CH:8][C:13]([CH:14]=[CH:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]=2[O:16][CH2:17]1
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
To a mixture of pinacolone (55 g) and piperonal (75 g) in ethanol (200 ml) was added a sodium hydroxide (5.0 g) in water (115 ml) solution. The mixture solidified after stirring at room temperature for 2 days. Filtration collected 137 g of solid which was then dissolved in ethyl acetate (500 ml), washed with water (500 ml), and dried over anhydrous magnesium sulfate. Concentration and trituration in hexane yielded 104.5 g of colorless solid product, mp 94°-96° C. Using essentially the same procedures, additional alpha, beta-unsaturated ketones were prepared as intermediates and are listed in Table 5. [see Pace, E, Atti Acad Lincei, [6], 9, 778 (1929); Chemical Abstracts, 23, 4942, 1929].
Reaction SMILES: Cl.O1CCOCC1.Cl[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:12]([F:24])=[CH:11][N:10]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([CH2:33][S:34][CH3:35])[CH:32]=1)[NH2:29]>C(O)CCC.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[C:28]([NH:29][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[O:22][CH3:23])[C:12]([F:24])=[CH:11][N:10]=2)[CH:30]=[C:31]([CH2:33][S:34][CH3:35])[CH:32]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CSCc1cc(N)cc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: COc1cc(F)ccc1-c1nc(Nc2cc(Br)cc(CSC)c2)ncc1F
Temperature: 140 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A 4N solution of hydrogen chloride in dioxane (0.54 mL; 2.15 mmol) was added to a stirred solution of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (553 mg; 2.15 mmol) and 3-bromo-5-[(methylsulfanyl)methyl]aniline (500 mg; 2.15 mmol) in 1-butanol (4.8 mL). The batch was stirred at 140° C. for 8 hours. After cooling the batch was diluted with ethyl acetate and washed with sodium bicarbonate and saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 4:1) to give the desired product (450 mg; 0.99 mmol).
Reaction SMILES: C(N(CC)CC)C.CS(Cl)(=O)=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=[CH2:15].O[CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:15][C:14](=[CH2:16])[C:13]([O:18][CH2:20][CH2:21][CH2:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:17]
Reactant: C=C(C)C(=O)O
Reactant: O=Cc1ccc(-c2ccc([C@H]3CC[C@H](CCCO)CC3)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C=O)cc3)cc2)CC1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
Firstly 9.4 ml of triethylamine and then 2.63 ml of methanesulphonyl chloride were added dropwise at −25° C. to a solution of 2.9 ml of methacrylic acid in 30 ml of tetrahydrofuran. Thereafter, the mixture was stirred at −25° C. for 1 hour and then a solution of 9.9 g of trans-4′-[4-(3-hydroxy-propyl)-cyclohexyl]-biphenyl-4-carboxaldehyde and 1.1 g of 4-dimethylamino-pyridine in 50 ml of tetrahydrofuran was added dropwise. Thereafter, the mixture was left to react at 0° C. for 2.5 hours and then at room temperature for 18 hours. Thereupon, the reaction mixture was filtered over Celite, the filtrate was partitioned between ether and water, the ether phase was dried over magnesium sulphate and evaporated. This gave 11.5 g of crude trans-4′-[4-[3-(2-methyl-acryloyloxy)-propyl]-cyclohexyl]-biphenyl-4-carboxaldehyde in solid form.
Reaction SMILES: [N:1]([C@@H:4]([CH:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:6])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:10][CH:11]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=729 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([O:21][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2O)CC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccnc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
A stirring solution of 1.4 g (0.0048 mol) of 4-(3-hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in THF (24 mL) was cooled to 0° C., and 0.13 g (0.0052 mol) of NaH was added. After 30 min, 0.8 g (0.0052 mol) of ethyl bromoacetate was added, and reaction was allowed to warm to room temperature and stirred overnight. Saturated NaHCO3 (20 mL) was added and the reaction mixture was partitioned between EtOAc (200 mL) and saturated NaHCO3 (75 mL). The organic layer was washed with water (50 mL) and NaCl (50 mL), dried over Na2SO4, and concentrated to afford 0.9 g (49%) of a white powder. MS (electrospray): exact mass calculated for C19H29N3O5, 379.21. m/z found, 380.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.74 (d, J=5.3 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.46 (dd, J=7.8 Hz, 5.3 Hz, 1H), 5.05 (d, J=7.33 Hz, 1H), 4.59 (s, 2H), 4.26 (q, J=7.3 Hz, 2H), 4.18-3.92 (m, 3H), 2.97 (t, J=11.6 Hz, 2H), 2.06 (d, J=12.1 Hz, 2H), 1.46 (s, 9H), 1.46-1.34 (m, 2H) 1.29 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Li][CH3:2].[N:3]1[C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1C(Cl)=O.CC[O:17][CH2:18][CH3:19]>C1COCC1.[Cu]I>[C:9]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([C:18](=[O:17])[CH3:19])[N:3]=1)(=[O:10])[CH3:2]
Reactant: [Li]C
Reactant: CCOCC
Reactant: O=C(Cl)c1cccc(C(=O)Cl)n1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(C)=O)n1
Temperature: -20 °C
Reaction time: 2.5 h

Procedure:
MeLi in ether (185 ml, 259 mmol) was added over one hour into the cooled (-78° C.) suspension of CuI (I) (47.5 g, 249 mmol) in ether (100 ml) and THF (300 ml). The resulting yellow suspension was slowly warmed up to -20° C. over about one hour, then cooled to -78° C. again. 2,6-pyridinedicarboxylic acid dichloride (Example 22, 19.1 g, 93.6 mmol) in THF (100 ml) was added over 30 minutes. The resulting orange-yellow suspension was stirred at temperature lower than -30° C. for 2.5 hours and then hydrolyzed with saturated NH4Cl--H2 O. After warmed up to room temperature, the color of the aqueous phase changed from light orange to blue. The mixture was filtered through Celite, and washed consecutively with ether and CH2Cl2. The organic phase was separated off. The aqueous phase was extracted consecutively with ether (2×80 ml) and CH2Cl2 (80 ml). The combined organic solutions were dried over Na2SO4, and then filtered. After removal of solvents, the residue was subjected to chromatography on a silica gel column, eluted with hexane/AcOEt (16:1), giving white or pale yellow solid. Yield: 14.2 g (93%). 1H-NMR (CDCl3): dH=8.18 (d, 3J(HH)=7.7 Hz, 2 H, H3,5), 7.96 (dd, 3J(HH)=8,2 and 7.3 Hz, 1 H, H4), 2.76 (s, 6 H, CH3). 13C-NMR (CDCl3): dC=199.17 (C=O), 152.46 (C2,6), 137.74 (C4), 124.51 (C3,5), 25.32 (CH3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1>O1CCCC1>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[CH:26]([NH:25][C:10]([C:6]1[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:27]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NC1CN2CCC1CC2)c1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
Tetrahydrofuran (50 ml) was added to a mixture of indole-5-carboxylic acid (2.42 g, 0.016 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole). The mixture was stirred for 1 hr while nitrogen was bubbled through the solution to remove the carbon dioxide that was evolved. Then 3-aminoquinuclidine (1.89 g, 0.015 mole) was added in one portion, and the mixture was stirred for 60 hr at room temperature. The solid product was collected by filtration to yield 3.75 g (86.8%). Recrystallization from methanol-isopropyl ether (with chilling) gave 1.89 g of the product as an off-white solid; m.p. 293°-295° C. The solid was vacuum dried at 82° C. for 16 hr, m.p. 293°-295° C.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6](N)[CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.[C:19]1(=O)[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[CH2:20]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:18]=[C:17]2[C:5]3=[C:4]([O:9][CH2:8][CH:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[N:6]3[C:19]3[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:20]2=3)[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)N2N
Reactant: O=C1CCCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc2c3c(c1)c1c(n3C(c3ccccc3)CO2)CCCC1=O
Temperature: 106 °C
Yield: 51.6 %

Procedure:
To a mixture of 7-methyl-3-phenyl-2,3-dihydro-4H-1,4-benzoxazin-4-amine (5.95 g, 24.8 mmol) in toluene (175 mL) is added while stirring 1,3 cyclohexandione (2.86 g, 25.5 mmol). The mixture is heated to 95° C. for 20 min, at which time p-toluenesulfonic acid monohydrate (4.71 g, 24.8 mmol) is added and the temperature is increased to 106° C. for 1 h. The mixture is refluxed for 12 h, then cooled to room temperature and concentrated. The residue is partitioned between CH2Cl2/1N NaOH. The organic layer is washed with brine, dried over magnesium sulfate and concentrated to dryness. Column chromatography (100 g silica gel) using acetone/hexane (25/75) as eluent gave 4.06 g (51%) of 5-methyl-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one; mp 171° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH2:14]([O:16][C:17]([C:19]#[C:20][C:21](OCC)=[O:22])=[O:18])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]([C:19]1[N:6]2[N:5]=[C:4]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[S:3][C:2]2=[N:1][C:21](=[O:22])[CH:20]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: Nc1nnc(-c2ccc(Cl)cc2)s1
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(-c3ccc(Cl)cc3)nn12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 5.5 g of 2-amino-5-(p-chlorophenyl)-1,3,4-thiadiazole, 100 ml of absolute ethanol and 4.5 g of acetylene dicarboxylic acid diethyl ester is heated to about 50° C. until a clear solution has formed and then left standing for 2 days. The product is filtered off, washed with ethanol and dried. Thus 2-(p-chlorophenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 220°-222° C. with decomposition is obtained in a yield of 3.5 g (40.2% of the theoretical).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N:26]2[CH:30]=[N:29][N:28]=[N:27]2)=[C:15]([CH:25]=1)[CH2:16][NH:17][C:18](=[O:24])[C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.[CH2:31](Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:31][C:4]([CH3:5])([CH3:6])[CH2:3][C@H:2]([C:7]([N:20]1[CH2:21][CH2:22][CH2:23][C@H:19]1[C:18]([NH:17][CH2:16][C:15]1[CH:25]=[C:11]([Cl:10])[CH:12]=[CH:13][C:14]=1[N:26]1[CH:30]=[N:29][N:28]=[N:27]1)=[O:24])=[O:9])[NH2:1]
Reactant: ClCCCl
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H](N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-4-methyl]-D-leucine (32 mg, 0.13 mmol), N-[5-chloro-2-(1H-1,2,4-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 50 mg, 0.21 mmol, 1.0 equiv), EDC (38 mg, 0.20 mmol, 1.5 equiv) and HOAt (9 mg, 0.07 mmol, 0.5 equiv) in DMF (1 mL) followed by deprotection in TFA-CH2Cl2 essentially according to the procedure described in Example 27, Step C. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)] followed by lyophilization of the fractions afforded the title compound as a white powder. 1H NMR (400 MHz, CDCl3): δ 9.18 (s, 1 H), 8.45 (br s, 2 H), 8.00 (t, J=5.2 Hz, 1 H), 7.73 (d, J=2.0 Hz, 1 H), 7.41 (dd, J=2.0, 8.4 Hz, 1 H), 7.19 (d, J=8.4 Hz, 1 H), 4.41–4.34 (m, 2 H), 4.25 (dd, J=4.8, 14.8 Hz, 1 H), 4.00–3.94 (m, 1 H), 3.89–3.85 (m, 1 H), 3.53–3.46 (m, 1 H), 2.25–2.22 (m, 1 H), 2.09–1.85 (m, 5 H), 1.00 (s, 9 H). HRMS (APCI) M+H: calculated for (C20H28N7O2Cl)+ 434.2066, found 434.2065.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:16]C)=[N:5][C:6]([CH3:15])=[C:7]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)[CH:8]=1)[CH3:2].[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>O.CCOCC>[CH2:1]([C:3]1[C:4](=[O:16])[NH:5][C:6]([CH3:15])=[C:7]([C:9]2[N:13]=[C:12]([CH3:14])[O:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-c2noc(C)n2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CCc1cc(-c2noc(C)n2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 56.5 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)-pyridine (47 mg, 0.202 mmol) and sodium iodide (91 mg, 0.607 mmol) under a nitrogen atmosphere is added anhydrous acetonitrile (4 mL) followed by drop-wise addition of chlorotrimethylsilane (76 μL, 0.605 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 15 hr. The reaction mixture is allowed to cool, diluted with water and the resulting mixture is extracted with four portions of dichloromethane. The combined extracts are dried over magnesium sulfate and evaporated to leave an orange residue. The crude product is purified by flash chromatography on a 2-gram silica gel cartridge by elution with heptane:dichloromethane: (1:1). Fractions containing the product are combined, the solvent evaporated and the residue triturated with ether to 3-ethyl-6-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)-1H-pyridin-2-one (25 mg, 58% yield) as a light yellow powder. LC/MS: RT: 2.39 min, MS: m/e=220 (M+H); 1H NMR (CDCl3, δ, ppm): 12.14 (1H, s), 7.89 (1H, s), 2.70 (3H, s), 2.64 (3H, s), 2.61 (2H, q), 1.24 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:21](=[O:35])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)=[O:13])=[CH:4][CH:3]=1.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl.[O:50]1CCOC[CH2:51]1>>[N:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:51]=[O:50])=[CH:37][CH:36]=2)=[O:35])=[CH:33][CH:32]=1)=[C:39]=[O:41]
Reactant: C1COCCO1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OCCCCCC(=O)OCCOCCOC(=O)CCCCCOc2ccc(N)cc2)cc1
Product: O=C=Nc1ccc(OCCCCCC(=O)OCCOCCOC(=O)CCCCCOc2ccc(N=C=O)cc2)cc1
Temperature: 80 °C

Procedure:
6-(4-Aminophenoxy)-hexanoic acid 2-{2-[6-(4-aminophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (5 g) was dissolved in dry 1,4-dioxane (80 ml) under nitrogen atmosphere. The solution was cooled to below 10° C. A solution of triphosgene (4.8 g) in dry 1,4-dioxane (20 ml) was added. The mixture was heated slowly to 80° C. and maintained at that temperature for 2 hours. The condenser was then arranged for distillation and the solvent was removed by distillation at atmospheric pressure until the volume of the reaction mixture had been reduced to approximately one third. Fresh dry 1,4-dioxane (25 ml) was added. The solvents were distilled off under vacuum. The residue was re-evaporated from dry 1,4-dioxane (50 ml) and dry toluene (30 ml) and charcoal (2 gram) was added. The solution was filtered hot. The toluene was distilled off under vacuum to give pure 6-(4-isocyanatophenoxy)-hexanoic acid 2-{2-[6-(4-isocyanatophenoxy)-hexanoyloxy]-ethoxy}-ethyl ester (4.5 g) as a light yellow oil. The product was characterized by 1H NMR (CDCl3) δ 1.48 (m, 2H, CH2), 1.68 (m, 2H, CH2), 1.78 (m, 2H, CH2), 2.37 (t, 2H, CH2), 3.68 (t, 2H, CH2), 3.92 (t, 2H, CH2), 4.24 (t, 2H, CH2), 6.78 (d, 2H, Ar), 6.97 (d, 2H, Ar).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:34])([CH3:33])[CH2:9]2)=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:18]2[CH:19]=[C:20]([F:22])[CH:21]=[C:16]([CH:11]3[C:10]([CH3:34])([CH3:33])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=2)=[CH:28][CH:27]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cc(F)cc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 81.4 %

Procedure:
A mixture of 2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.17 g, 0.37 mmol) in ethanol (3 mL) and tetrahydrofuran (5 mL), 30% sodium hydroxide in water (1 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(4′-tert-butyl-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.13 g, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C28H30FNO2 (M+H)+: 432.6, observed: 432.3;