Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4](Cl)[N:3]=1.[S:11]([F:21])(=[O:20])([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)=[O:12]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([S:11]([F:21])(=[O:20])=[O:12])=[CH:14][CH:15]=2)[N:3]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnc(Nc2ccc(S(=O)(=O)F)cc2)nc1N
Yield: 35.7 %

Procedure:
A solution of 4-amino-2-chloro-5-cyanopyrimidine (8.0 g, 52 mmol) and sulphanilyl fluoride (9.07 g, 52 mmol) in NMP (155 ml) was heated at 120° C. for 24 hours. The mixture was allowed to cool and was diluted with water. The resulting precipitate was collected by filtration, washed with water and dried under vacuum at 60° C. for 2 hours. The crude product was recrystallized from ethyl acetate/hexane to give the title compound (5.45 g, 37%). NMR: 7.70 (s, 24H), 7.93 (d, 2H), 8.15 (d, 2H), 8.45 (s, 1H); m/z: 292 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2>O1CCOCC1.[Ag]=O>[N:4]1[C:3]2[C:2](=[O:1])[CH:11]=[CH:10][C:9](=[O:12])[C:8]=2[N:7]=[CH:6][CH:5]=1
Reactant: Oc1ccc(O)c2nccnc12
Agent: O=[Ag]
Solvent: C1COCCO1
Product: O=C1C=CC(=O)c2nccnc21

Procedure:
A 9.2 g portion of 5,8-dihydroxyquinoxaline in 300 ml of p-dioxane was heated at reflux with 16.2 g of silver oxide for 6 hours. The mixture was cooled, then filtered and the filtrate concentrated in vacuo. The residue was slurried with 75 ml of acetone, cooled and the solid collected, washed with acetone and dried, giving 8.0 g of the desired product, mp 172°-173° C.
Reaction SMILES: [C:1]([CH:3]1[N:8]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH2:7][CH2:6][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1)#[N:2]>CO.[Ni]>[NH2:2][CH2:1][CH:3]1[N:8]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])[CH2:7][CH2:6][N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCCO)C(C#N)C1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCOCCO)C(CN)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-cyano-4-(2-(2-hydroxyethoxy)ethyl)piperazine-1-carboxylate, prepared as described in the previous step, (9.9 g, 33.1 mmol) in methanol (20 mL) was added Raney Ni (15 g). The reaction solution was stirred at room temperature overnight under hydrogen atmosphere (50 psi). The mixture was filtered and concentrated to provide the product, which was used in the next step without additional purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](OC)=[O:15])[CH2:3]1.[Li+].[BH4-].O.Cl>C1COCC1>[OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of compound 236 (6.4 g, 26.09 mmol) in THF (80 mL) at 0° C. was added a solution of LiBH4 (2.063 g, 94.76 mmol) in one shot. The suspension was stirred at 0° C. for 1 h then at room temperature overnight. The mixture was cooled to 0° C. and water (52 mL) then 6N HCl (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×70 mL). The combined organics were washed with 2N NaOH, 2N HCl and brine (20 mL each). The organic layers were dried over Na2SO4 filtered and concentrated to afford title compound 237 (5.4 g, 95%) as clear oil. LRMS (ESI): (calc.) 217.13 (found) 256.3 (M+K).
Reaction SMILES: [NH:1]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@H:2]([C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14](O)=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.[NH2:31][C@H:32]([C:37]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([C:55]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH2:60][S:61][CH3:62])=[O:56])[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[NH:48][CH:47]=1)=[O:42])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35].CC(O)C.O(C(C)C)C(C)C>CO.C(OCC)(=O)C>[NH:1]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[C@H:2]([C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([NH:31][C@H:32]([C:37]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([C:55]([NH:57][C@H:58]([C:63]([O:65][CH3:66])=[O:64])[CH2:59][CH2:60][S:61][CH3:62])=[O:56])[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[NH:48][CH:47]=1)=[O:42])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Yield: 80 %

Procedure:
Starting from 9.10 g (22.12 mmol) of BOC-Val-Pro-Pro-OH (X) and 12.30 g (22.12 mmol of HCl.H-Leu-Gly-Trp-Met-OMe (VI) and operating as described in Step 5, but using as an eluant system ethyl acetate containing an increasing amount of methanol from 5 to 30 percent during the chromatographic purification, 16.16 g (80% yield) of compound XI were obtained from iPrOH/iPr2O: m.p. 184°-190° C. [α]D20 =-98.9° (c=1, MeOH); RfB 0.13; RfC 0.58.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:29]=[C:30]([C@@H:33]4[CH2:37][CH2:36][CH2:35][N:34]4[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.C1COCC1.[Pt](=O)=O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:9]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([C@@H:33]5[CH2:37][CH2:36][CH2:35][N:34]5[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)[CH2:10][CH2:11]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc([N+](=O)[O-])cc4)N3c3ccc(F)cc3)cc2)c[nH]1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(C3CCC(c4ccc(N)cc4)N3c3ccc(F)cc3)cc2)c[nH]1
Yield: 100 %

Procedure:
Dissolved the product from Example 39F (300 mg, 0.502 mmol) in ethanol (5 mL) and THF (5 mL) then added platinum(IV) oxide (22.8 mg, 0.1 mmol) and a hydrogen balloon and stirred the solution at room temperature for 2.5 h. Solution was filtered through celite and washed with methanol (10 mL), then concentrated to give the title compound (285 mg, 100%) as a colorless semi-solid and a 1/1 mixture of stereoisomers.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:5]=[C:6]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][N:16]=2)[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[O:3].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:4]1[CH:5]=[C:6]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][N:16]=2)[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH:10]=[CH:9]2)(=[O:29])=[O:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1ncnc1-c1cc(S(C)=O)c2[nH]c(=O)ccc2c1
Solvent: ClC(Cl)Cl
Product: Cn1ncnc1-c1cc(S(C)(=O)=O)c2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 8-methylsulphinyl-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolone (0.097 g) and m-chloroperbenzoic acid (0.088 g) in chloroform (10 cm3) was stirred for 18 hours at room temperature. The mixture was then concentrated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]), eluting with ethyl acetate:methanol, 19:1. Combination and evaporation of the appropriate fractions afforded a solid which was recrystallised from dichloromethane/hexane to give 8-methylsulphonyl-6-[1-methyl-1,2,4-triazol-5-yl]-2-(1H)-quinolone, m.p. 226°-232° (0.051 g).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.O=S(Cl)[Cl:17]>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([Cl:17])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCOc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCCOc1ccc(Br)cc1
Yield: 67 %

Procedure:
4-(4-Bromophenoxy)butanoic acid (39 g, 25.6 mmol) was dissolved in SOCl2(100 ml) mixture was heated to refluxed overnight. the mixture was concentrated in vacuo to give 4-(4-bromophenoxy)butanoyl chloride (27.6 g, 67%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][C:13](=S)[CH2:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[CH:23]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:14][CH:13]([NH:2][NH2:3])[CH2:12][CH2:11][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:9]=2[CH:23]=1
Reactant: NN
Reactant: Fc1ccccc1C1CCC(=S)Nc2ccc(Cl)cc21
Solvent: C1CCOC1
Solvent: O
Product: NNC1CCC(c2ccccc2F)c2cc(Cl)ccc2N1
Reaction time: 2 h

Procedure:
A solution of 17.5 ml of hydrazine hydrate in 1.75 l of tetrahydrofuran is treated with 22 g of 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione. The solution is stirred under a stream of argon for 2 hours and then evaporated at 40° in vacuo. The residue is crystallized from ether and there is obtained 7-chloro-5-(2-fluorophenyl)-2-hydrazino-4,5-dihydro-2H-1-benzazepine of melting point 213°-215°.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@@:11]([OH:27])([CH3:26])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>O1CCOCC1>[CH3:26][C@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:27][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C[C@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
Tert-butyl (R)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]-piperazine-1-carboxylate prepared in Example 368 (376 mg, 0.93 mmol) was dissolved in 1,4-dioxane (10 ml). To the solution, sodium hydride (45 mg, 1.12 mmol) was added with cooling on ice-bath, and the resulting solution was stirred at room temperature for 30 minutes and then stirred under reflux for 24 hours. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added slowly, and the solution was extracted with ethyl acetate twice. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=3/1) to afford tert-butyl (R)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-carboxylate (239 mg, yield 70%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH:27]([NH:31][C:32]([O:34][CH2:35][CH:36]1[C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[C:37]1=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C:28](O)=[O:29])=[O:22])([CH3:19])([CH3:18])[CH3:17].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:28](=[O:29])[CH:27]([NH:31][C:32]([O:34][CH2:35][CH:36]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:42]=2[C:43]2[C:48]1=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:33])[CH2:26][CH2:25][CH2:24][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CC(C)(C)OC(=O)NCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Temperature: -15 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
In anhydrous pyridine (30 ml), 2-amino-terephthalic acid dimethyl ester (manufactured by Merck Ltd.) (1.46 g) and 5-t-butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-valeric acid (manufactured by Watanabe Chemical Industries, Ltd.) (3.18 g) were dissolved. The whole was cooled to −15° C. and added with phosphorus oxychloride (0.718 ml), followed by stirring at room temperature for 1 hour. After completion of the reaction, the whole was poured in ice-cold water and subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution and dried with magnesium sulfate. After the solvent was distilled off, the resultant was subjected to azeotropic distillation with toluene. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (3.33 g) as a white crystal.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>C(Cl)Cl>[CH3:4][C:3]([OH:5])([CH3:6])[CH2:2][NH:1][C:10]([NH:9][CH2:7][CH3:8])=[O:11]
Reactant: CC(C)(O)CN
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCC(C)(C)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-amino-2-methyl-2-propanol (4.0 g, 45 mmol) in CH2Cl2 (25 mL) at 0° C. was added a solution of ethyl isocyanate (3.2 g, 45 mmol) in CH2Cl2 (5 mL) dropwise. The mixture was stirred at ambient temperature for 18 hours, then concentrated of all volatiles in vacuo to afford a quantitative yield of N-(2-methyl-2-hydroxypropyl)-N'-ethylurea as a yellow solid; NMR (DMSO-d6 /TFA) 5.9 (m. 1), 5.7 (m, 1), 3.0 (m, 2), 2.9 (d, 2), 1.0 (s, 6), 0.9 (t, 3) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13]O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])C>>[CH2:31]([O:30][C:27](=[O:29])[CH2:13][CH2:12][CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:32]
Reactant: COc1cc(CCCO)cc(OC)c1
Reactant: CCOC(C)=O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 3-(3,5-dimethoxyphenyl)propan-1-ol (24.3 g) in ethyl acetate (500 ml) were sequentially added triethylamine (16.3 g) and methanesulfonyl chloride (16.3 g) on an ice bath, and the solution was stirred for 25 minutes at room temperature. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To a solution of the total amount of the resulting 3-(3,5-dimethoxyphenyl)propyl methanesulfonate (crude product) in N,N-dimethylformamide (150 ml) was added sodium cyanide (15.2 g), and the solution was stirred for 8.5 hours at 80° C. The solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To a solution of the total amount of the resulting 4-(3,5-dimethoxyphenyl)butyronitrile (crude product) in ethylene glycol (100 ml) was added an aqueous solution of 5N sodium hydroxide (75 ml), and the solution was refluxed for 9.5 hours. The reaction solution was acidified with concentrated sulfuric acid, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, then the solvent was evaporated in vacuo. To a solution of the resulting residue in ethanol (400 ml) was added concentrated sulfuric acid (4 ml), and the solution was stirred for 1 hour and 20 minutes at 70° C. The reaction solution was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (25.3 g).
Reaction SMILES: [O:1]=[C:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)/[CH:3]=[CH:4]/[C:5]([O:7][CH:8]1[CH:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][CH:10]([CH3:17])[CH2:9]1)=[O:6]>CC(C)=O>[O:1]=[C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)/[CH:3]=[CH:4]\[C:5]([O:7][CH:8]1[CH:13]([CH:14]([CH3:16])[CH3:15])[CH2:12][CH2:11][CH:10]([CH3:17])[CH2:9]1)=[O:6]
Reactant: CC1CCC(C(C)C)C(OC(=O)/C=C/C(=O)c2ccccc2)C1
Solvent: CC(C)=O
Product: CC1CCC(C(C)C)C(OC(=O)/C=C\C(=O)c2ccccc2)C1
Reaction time: 3 h

Procedure:
A solution of 3.0 g (0.009 mole) of (-)-menthyl (E)-4-oxo-4-phenyl-2-butenoate in 100 ml of anhydrous acetone is irradiated with ultraviolet light. After an irradiation lasting 3 hours the solution is evaporated and the residue is recrystallized from n-hexane to give the named compound in a yield of 1.9 g, m.p.: 85°-87° C. [α]D25 =-74.7° (c=1, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][CH:5]=1.C1COCC1.[CH2:17]([Mg]Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: CCCCCC[Mg]Br
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CCCCCCc1ccc(C(=O)OC)cc1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
A flame-dried two-necked flask is charged under argon with 4-chlorobenzoic acid methyl ester (0.5 g, 2.93 mmol), FeCl2 (19 mg, 0.15 mmol), THF (7 mL) and N-methylpyrrolidone (NMP, 1 mL). A solution of n-hexylmagnesium bromide (2M in Et2O, 1.9 mL, 3.8 mmol) is added via syringe to the resulting red solution, causing an immediate color change to dark brown and finally to violet. The resulting mixture is stirred for 5 min. Work-up as described above provides 4-hexylbenzoic acid methyl ester as a colorless syrup (90%). The spectroscopic and analytical data are identical to those compiled above.
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][N:9](C(OC(C)(C)C)=O)[CH2:10][CH2:11][N:6]2[C:5]1=[O:20].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]1[CH2:19][CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:20]
Reactant: CC(C)(O)CN1CC2CN(C(=O)OC(C)(C)C)CCN2C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)CN1CC2CNCCN2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-hydroxy-2-methyl-propyl)-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazine-7-carboxylate (compound 106-C-1) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. After the reaction mixture was stirred at rt for 1 hour, the solvent was removed in vacuum to give the crude product 106-C, which was used directly in the next step.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[C:7]([O:14]C)=[N:8][C:9]([O:12]C)=[N:10][CH:11]=2)[CH:3]=[N:2]1.[ClH:16]>O1CCOCC1>[ClH:16].[S:1]1[CH:5]=[C:4]([C:6]2[C:7](=[O:14])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)[CH:3]=[N:2]1
Reactant: COc1ncc(-c2cnsc2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]cc(-c2cnsc2)c(=O)[nH]1
Reaction time: 1 h

Procedure:
5-(4-isothiazolyl)-2,4-bis(methyloxy)pyrimidine (Prep22, 686 mg, 2.427 mmol) was suspended in 4M HCl solution in 1,4-dioxane (25 ml). After 1 h at 90° C., the solvent was evaporated. 696.8 mg of the title compound were isolated as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(C(F)(F)F)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-trifluoromethyl-phenol via the same procedure used for the preparation of (2S)-3-{4-[2-(Biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3) to produce a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[C:13]([NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[C:13]([NH:15][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(NC(=O)c1cccc(-c2ccncc2[N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(NC(=O)c1cccc(-c2ccncc2N)c1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution containing 3-(3-nitropyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide (2.0 g, 5.5 mmol) and methanol (18.5 mL) was added 10% Pd/C (1.6 g, 0.76 mmol, wet, 50% water) in one portion under a nitrogen atmosphere. The reaction mixture was stirred for 2 h under an atmosphere of hydrogen gas (balloon), filtered and concentrated to afford 3-(3-aminopyridin-4-yl)-N-(2-phenylpropan-2-yl)benzamide as a pale yellow oil which was used without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.47 (s, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.85 (d, J=4.77 Hz, 1H), 7.81 (ddd, J=7.65, 1.63, 1.51 Hz, 1H), 7.52-7.61 (m, 2H), 7.36-7.41 (m, 2H), 7.24-7.30 (m, 2H), 7.15 (t, J=7.28 Hz, 1H), 7.04 (d, J=5.02 Hz, 1H), 5.15 (s, 2H), 1.64-1.70 (m, 6H). LCMS: retention time: 1.240 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 332 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.ClC1C=CC([N+]([O-])=O)=CC=1O>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:10]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=[N+]([O-])c1ccc(Cl)c(O)c1
Product: Brc1ccc(-c2cccnc2)cc1

Procedure:
The title compound was prepared from 3-bromopyridine (5 g) and 4-bromophenylboronic acid by the method described in Description 15 (2.6 g, 35%).