Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](/[C:3](=[C:7](/OCC)\[CH3:8])/[C:4]([NH2:6])=[S:5])#[N:2].C(O)C.[NH3:15].C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH2:15]/[C:7](/[CH3:8])=[C:3](/[C:1]#[N:2])\[C:4]([NH2:6])=[S:5]
Reactant: CCO/C(C)=C(/C#N)C(N)=S
Reactant: N
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: C/C(N)=C(\C#N)C(N)=S
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 3 liter multi-neck flask was equipped with air stirrer, gas inlet, thermometer and condenser. To the flask was charged 2-cyano-3-ethoxythiocrotonamide (68 g, 0.4 mole) and 74 OP ethanol (2 liters). The mixture was then stirred at room temperature. Very little of the solid appeared to dissolve. Ammonia was then bubbled through the reaction mixture. After approximately 15 minutes it became apparent that the starting material was reacting, evidenced by the increased solubility, and after 30 minutes a homogeneous solution resulted. Passage of ammonia through the solution was continued until no more gas was taken up. TLC showed the reaction to be complete, as evidenced by the disappearance of the starting material (silica, eluent 30% ethyl acetate in toluene, Rf product: 0.5, Rf starting material: 0.1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:18](=[O:19])[CH:17]2[CH2:20][CH2:21][CH2:22][C:16]2=[N:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]1=2>C(OCC)(=O)C.CCCCCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:18](=[O:19])[C@H:17]2[CH2:20][CH2:21][CH2:22][C@H:16]2[NH:15][C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]1=2
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccc2ccccc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc2ccccc2c1
Yield: 81 %

Procedure:
Using 9-(2-naphthylmethyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[1,4]diazepin-10(1H)-one, the titled compound was synthesized in substantially the same manner as in yield of 81%, m.p. 148.0°-148.5° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[F:10][C:11]1[N:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13](NC1C=CC=CC=1C)=[O:14]>>[F:10][C:11]1[N:26]=[CH:25][CH:24]=[CH:23][C:12]=1[C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:9])=[O:14]
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Reactant: Cc1cc(F)ccc1N
Product: Cc1cc(F)ccc1NC(=O)c1cccnc1F
Yield: 99 %

Procedure:
4-Fluoro-2-methylaniline (Aldrich, 0.18 mL, 1.6 mmol) was converted to the desired compound (0.098 g, 99%) in a manner similar to the preparation of 2-fluoro-N-o-tolylnicotinamide (Step A of Example 8). MS(ESI+) m/z 249 (M+H)+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([O:10][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)=[O:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
Combine 4-fluorobenzonitrile (3.96 g, 32.7 mmol), 4-hydroxybenzaldehyde (3.99 g, 32.7 mmol), dimethyl acetamide (100 mL), and potassium carbonate (6.8 g, 49 mmol), stir, and heat to 130° C. After 18 h, cool to ambient temperature, partially remove the solvent in vacuo, and dilute with 100 mL of water. Extract the aqueous solution with diethyl ether (3×150 mL), wash the organic phase with water (2×100 mL), and brine (100 mL). Dry the organic phase over magnesium sulfate, filter, and concentrate under vacuum. Purify via a Biotage Flash 40L system, using a gradient: 5:95 hexanes/ethyl acetate to 50:50 hexanes/ethyl acetate to give the title compound (3.6 g, 49%) as a white solid: 1H NMR (chloroform-d): 9.95 (s, 1H), 7.92 (d, 2H), 7.68 (d, 2H), 7.14 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]1[CH2:14][CH2:13][N:12](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH2:10]1.C1(O)C=CC=CC=1.[OH-].[Na+]>Br>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3ccccc3Cl)CC2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: Cl
Product: Clc1ccccc1SC1CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 88.76 g (0.23 mole) of 4-[(2-chlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine, 47.0 g (0.50 mole) of phenol and 200 ml of 48% hydrobromic acid was refluxed for 1.5 hr. The reaction mixture was cooled to room temperature and diluted with ice water. The mixture was made alkaline with 50% sodium hydroxide and extracted with diethyl ether. The ether phase was extracted with 1N sulfuric acid. The acidic layer was made alkaline and extracted with methylene chloride. The methylene chloride layer was dried over sodium sulfate, filtered and evaporated to give an oil, the free base of the title compound. The free base was converted to 4.30 g (36.5%) of a white crystalline hydrochloride salt, m.p. 202°-210° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH3:18])=[C:9]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][O:6][CH2:5][CH2:4][OH:3])[C:9]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[C:10]2[CH3:18]
Reactant: CCOC(=O)COCn1c(-c2cccnc2)c(C)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(COCCO)c2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask is charged with (5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethoxy)-acetic acid ethyl ester (Example 72b, 1.00 g, 2.79 mmol) and THF (10 mL). The reaction mixture is cooled to 0° C. and lithium aluminum hydride (1M in THF, 6.98 mL, 6.98 mmol) is added. After stirring for 1 h at room temperature, the mixture is quenched with water (0.3 mL), followed with 16% aqueous NaOH (0.3 mL). Water (1 mL) is added and stirring is continued for 10 min. The solids are filtered off and the filtrate is concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-acetonitrile, 3:1), followed by a purification on Chiralcel® IA column (heptane-EtOH, 9:1) to afford 2-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethoxy)-ethanol as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 2.27 (s, 3H), 3.42-3.49 (m, 2H), 3.60 (t, J=4.8 Hz, 2H), 5.47 (s, 2H), 7.27 (dd, J=8.7, 1.9 Hz, 1H), 7.57-7.62 (m, 2H), 7.64 (dd, J=8.0, 4.9 Hz, 1H), 8.10 (dt, J=7.8, 1.9 Hz, 1H), 8.66 (dd, J=4.9, 1.6 Hz, 1H), 8.74 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 317.1056 [(M+H)+ Calcd for C17H17ClN2O2: 317.1507].
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:9]=[N:10]NC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[CH:16][N:15]=1.[CH2:21]([N:23](CC)CC)C>C(#N)C>[Cl:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]([N:10]2[CH:21]=[N:23][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9]2)[CH:19]=1
Reactant: CCN(CC)CC
Reactant: Clc1cc(Cl)ncn1
Reactant: c1ccc(Nc2c[nH]nn2)cc1
Solvent: CC#N
Product: Clc1cc(-n2cnc(Nc3ccccc3)n2)ncn1

Procedure:
A suspension of phenylaminotriazole (3.12 mmol), 4,6-dichloropyrimidine (4.1 mmol, 1.3 equivalents) and triethylamine (4.7 mmol, 1.5 equivalents) in acetonitrile (20 ml) was stirred at reflux for eighteen hours. The reaction mixture was partitioned between ethyl acetate and brine. A white precipitate formed and was removed by filtration to afford the the title compound which was used without purification in the next step. LC-MS: [MH+] 274.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([Br:14])[CH:4]=1.N1C=CN=C1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOCC>[Si:20]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([Br:14])[CH:4]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc(Br)cc(CO)n1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Br)cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1
Reaction time: 3 h
Yield: 125.4 %

Procedure:
Predried ethyl 6-hydroxymethyl-4-bromopyridine-2-carboxylate (1.4 g, 5 4 mmol) and imidazole (1.1 g, 6.5 mmol) were dissolved in dry DMF (1.7 mL). TBDPS-chloride (1.78 g, 6.5 mmol) was added portionwise, and the reaction was allowed to proceed for 3 h at r.t. The reaction mixture was diluted with Et2O (50 mL) and washed with water and sat. NaHCO3. The organic phase was dried over Na2SO4 and evaporated to dryness. Purification on silica gel (petroleum ether, by 40-60° C./ethyl acetate 5:2) yielded 2.5 g (92%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[NH2:25][CH2:26][CH:27]([OH:30])[CH2:28][CH3:29]>C(O)C.[Hg](Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=[N:25][CH2:26][CH:27]([OH:30])[CH2:28][CH3:29])[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Reactant: CCC(O)CN
Agent: Cl[Hg]Cl
Solvent: CCO
Product: CCC(O)CN=C1NC[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.5 %

Procedure:
Mercury(II) chloride (174 mg, 0.640 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (190 mg, 0.533 mmol) and 1-aminobutan-2-ol (152 μL, 1.60 mmol) in ethanol (5 mL) at 55° C. After 30 min, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated. Saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound (238 mg). MS 412.2 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].Cl.[C:8]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12]1)(=[NH:10])[NH2:9].[OH-].[Na+]>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:10][C:8](=[NH:9])[N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12]1)=[O:3])[CH3:6]
Reactant: N=C(N)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)NC(=N)N1CCC[C@@H](CNC(=O)OCc2ccccc2)C1

Procedure:
0.55 ml of ethyl chloroformate is added dropwise to a solution of 2.0 g of benzyl [[(S)-1-amidino-3-piperidinyl]methyl]carbamate hydrochloride in 200 ml of methylene chloride. The reaction mixture is cooled to 0°. 113 ml of 0.1N sodium hydroxide solution are added dropwise while stirring. Subsequently, the mixture is stirred in an ice bath. The phases are separated. The organic phase is washed with water, dried and evaporated. There are obtained 1.5 g of benzyl (S)-1-(ethoxycarbonylamino-imino-methyl)-piperidin-3-ylmethylcarbamate, MS (FAB): 363.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][NH:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1>>[C:17]1([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:13][NH:12][S:11](=[O:15])(=[O:14])[NH:10][CH2:9]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: Nc1ccc(C2CNS(=O)(=O)NC2)cc1Br
Reactant: OB(O)C1=CCCCC1
Product: Nc1ccc(C2CNS(=O)(=O)NC2)cc1C1=CCCCC1
Yield: 65 %

Procedure:
2-Bromo-4-(1,1-dioxo-1λ6-[1,2,6]thiadiazinan-4-yl)-phenylamine (as prepared in the previous step, 46.9 mg, 0.153 mmol) was reacted with cyclohexane-1-enyl boronic acid (24.1 mg, 0.191 mmol) according to the Suzuki coupling procedure of Example 4, step (e) and purified on silica (20-100% EtOAc-hexane) to afford the title compound (30.7 mg, 65%): Mass spectrum (ESI, m/z): Calcd. for C15H21N3O2S, 308.1 (M+H). found 308.1.
Reaction SMILES: [NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([O:22]C)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO.O>[NH:1]([C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1
Reactant: COC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)O

Procedure:
To a solution of Z-Tyr-D-Ala-Gly-OMe (27) (4.57 g, 0.01 mol) in MeOH (10 ml) was added 1 N NaOH (20 ml, 0.02 mol) at 0° with stirring. The suspension was stirred for 2 hr at 0° C., diluted with water (80 ml), and neutralized with 1 N HCl (20 ml). The precipitated crystals were collected by suction, washed with water and dried under reduced pressure to give Z-Tyr-D-Ala-Gly.OH (28) (3.59 g, 81.0%), mp 102°-104° C. (AcOEt) (lit.* mp 124° C.); [α]D22 18.0° (C=1.0, DMF), (lit.* [α]D22 16.7° (c=0.54, DMF)); NMR (DMSO-d6)δ: 1.16 (3H, d, J=7 Hz, CH3), 2.60-2.90 (2H, m, CH2), 3.80 (2H, d, J=6 Hx, CH2PhOH), 4.10-4.45 (2H, m, 2CH), 5.02 (2H, s, CH2O), 6.63-7.20 (4H, m, HOPh-), 7.40 (5H, s, ArH), 8.10-8.30 (2H, br, 2 NH), 9.10-9.40 (1H, br, OH). Rf (IV)=0.20.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([B:20]2[O:28][CH:27]3[C:22]([CH3:32])([CH:23]4[CH2:29][CH:25]([CH2:26]3)[C:24]4([CH3:31])[CH3:30])[O:21]2)[NH:15][Si](C)(C)C)[C:8]=1[O:33][CH3:34])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:40][C:41]([NH:43][CH2:44][CH:45]1[CH2:50][CH2:49][C:48]([CH2:55][C:56](O)=[O:57])([CH2:51][N+:52]([O-:54])=[O:53])[CH2:47][CH2:46]1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:1]([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:15][C:56](=[O:57])[CH2:55][C:48]2([CH2:51][N+:52]([O-:54])=[O:53])[CH2:47][CH2:46][CH:45]([CH2:44][NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])[CH2:50][CH2:49]2)[B:20]2[O:28][CH:27]3[C:22]([CH3:32])([CH:23]4[CH2:29][CH:25]([CH2:26]3)[C:24]4([CH3:31])[CH3:30])[O:21]2)[C:8]=1[O:33][CH3:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCC(CC(=O)O)(C[N+](=O)[O-])CC1
Reactant: COc1c(CC(N[Si](C)(C)C)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Product: COc1c(CC(NC(=O)CC2(C[N+](=O)[O-])CCC(CNC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C

Procedure:
Prepared from 2-Methoxy-3-[2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(trimethylsilanyl-amino)-ethyl]-benzoic acid tert-butyl ester and [4-(tert-Butoxycarbonylamino-methyl)-1-nitromethyl-cyclohexyl]-acetic acid following the procedure described in Step 1 of Example 1. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc/hexane). ESI-MS m/z 742 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[F:8][C:9]([F:22])([F:21])[C:10](=O)[CH2:11][C:12]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=O>C(O)(=O)C>[CH3:7][C:5]1[N:6]=[C:2]2[N:1]=[C:10]([C:9]([F:22])([F:8])[F:21])[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:3]2[N:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccnc1
Reactant: Cc1nc(N)n[nH]1
Solvent: CC(=O)O
Product: Cc1nc2nc(C(F)(F)F)cc(-c3cccnc3)n2n1
Yield: 47.5 %

Procedure:
A reaction mixture of 0.986 g of 3-amino-5-methyl-1,2,4-triazole and 2.178 g of 4,4,4-trifluoro-1-(3-pyridyl)-1,3-butanedione in 25 ml of glacial acetic acid was refluxed for 4 hours. The mixture was then evaporated to dryness in vacuo and gave a crystalline residue. This residue was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane and the procedure of Example 1 was continued to give 1.33 g of the desired product as colorless crystals, mp 195°-197° C.
Reaction SMILES: [C:1]1([CH2:6][C@H:7]([NH:14][C:15](=[O:34])[C@@H:16]([NH:26]C(=O)OC(C)(C)C)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:8]([C@@:10]2([CH3:13])[CH2:12][O:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@@H:16]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[C:15]([NH:14][C@@H:7]([CH2:6][C:1]1[CH2:5][CH2:4][CH2:3][CH:2]=1)[C:8]([C@@:10]1([CH3:13])[CH2:12][O:11]1)=[O:9])=[O:34]
Reactant: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C[C@H](N)C(=O)N[C@@H](CC2=CCCC2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.5 h

Procedure:
To tert-butyl ((S)-1-(((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)amino)-3-(4-methoxyphenyl)-1-oxopropan-2-yl)carbamate (0.99 g, 2.1 mmol) was added DCM (5 mL) and TFA (5 mL). The mixture was allowed to stand at ambient temperature for 30 min then it was concentrated to provide crude (S)-2-amino-N-((S)-3-(cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-(4-methoxyphenyl)propanamide (quant.) and carried forward without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][OH:18])[O:10]2)=[CH:5][CH:4]=1.O[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:25]3[CH:26]=[N:27][C:28]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:29]=4)[O:10]2)=[CH:5][CH:4]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: COc1ccc2c(c1)OC(CNCCCO)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(CNCCCOc1cnc3ccccc3c1)CC2
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of 3-(7-methoxy-chroman-2-ylmethyl-amino)-propanol (3.07 g, 13 mmol), 7-hydroxy quinoline (1.88 g, 13 mmol), triphenylphosphine (3.67 g, 14 mmol) in anhydrous tetrahydrofuran (50 mL) was slowly added a solution of diethylazodicarboxylate (2.44 g, 14 mmol) in tetrahydrofuran (10 ml). The reaction was allowed to stir for 3 hours and was then quenched with water, extracted with methylene chloride (150 mL) dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. Chromatography (2.5% MeOH -methylene chloride) afforded 2.72 g of the title compound (55% yield) which was converted to the monohydrate, dimaleate salt in tetrahydrofuran, mp 132°-134° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[O:11]=[C:12]1[C:17]2[S:18][CH:19]=[C:20]([S:21](Cl)(=[O:23])=[O:22])[C:16]=2[CH2:15][CH2:14][CH2:13]1>>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[S:21]([C:20]1[C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:11])[C:17]=2[S:18][CH:19]=1)(=[O:22])=[O:23]
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Reactant: CNCCc1ccncc1
Product: CN(CCc1ccncc1)S(=O)(=O)c1csc2c1CCCC2=O

Procedure:
From methyl-(2-pyridine-4-yl-ethyl)-amine (the compound of Preparation Example 16) (82 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (150 mg), the title compound (100 mg) was obtained as a colorless oily matter, in the same way as Preparation Example 41.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([NH:9][C:10](=[O:22])[CH2:11][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)[CH:8]=1.B(Br)(Br)Br.C(OCC)C>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:23])=[C:7]([NH:9][C:10](=[O:22])[CH2:11][C:12]23[CH2:21][CH:16]4[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]4)[CH2:19]2)[CH2:13]3)[CH:8]=1
Reactant: COc1ccc(C)c(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(O)cc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(5-methoxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide prepared as described in Example 5 (1.00 g) in dichloromethane (20 ml), was added boron tribromide (4 ml of a 1.0M solution in dichloromethane) at −78° C. under an inert atmosphere. The reaction mixture was stirred for 24 hours and then warmed to ambient temperature and washed with brine. The organic layer was dried over magnesium sulphate (MgSO4) and concentrated under reduced pressure to yield a residue. Trituration with diethyl ether gave a solid (0.335 g). A portion of this material (0.050 g) was further purified by Supercritical Fluid chromatography using a Cyano column, eluting with a gradient of methanol in supercritical carbon dioxide to give the title compound as a white solid (0.030 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([OH:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CS(C)=O>[CH2:29]([O:20][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: Oc1ccc(F)cc1-c1ccccc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCOc1ccc(F)cc1-c1ccccc1-c1ccccc1
Yield: 81.8 %

Procedure:
Treatment of 5-fluoro-2′-phenylbiphenyl-2-ol (6.8 g, 25.7 mmol) with potassium carbonate (5.3 g, 38.6 mmol) and allyl bromide (3.3 mL, 38.6 mmol) in DMSO (150 mL) according to the procedure described for Example 69, Step 3 provided 6.4 g (82%) of 2-allyloxy-5-fluoro-2′-phenylbiphenyl as a white solid. MS (EI) m/z 304.1264 ([M]+); mp 48–49° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[C@@H:10]([C:22]([O:24]C)=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[C@H:9]1[C@@H:10]([NH:11][C:12](=[O:13])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:22](=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]1
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Sc1ccccc1N)c1cc(F)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1cc(F)ccc1F)OCc1ccccc1
Yield: 59.9 %

Procedure:
A suspension of methyl β-[(2-aminophenyl)thio]-N-[(benzyloxy)carbonyl]-2,5-difluorophenylalaninate (4:1, Z:E) (4.3 g) and p-toluenesulfonic acid (catalytic) in xylenes (100 mL) was heated to reflux for 2 h, using a Dean-Stark apparatus to remove water. The mixture was then cooled, resulting in precipitation of the crude product as a white solid (3.3 g, 4:1, cis:trans). This was recrystallized from ethyl acetate/ether to afford the title compound (2.4 g, 60%). 1H NMR (300 MHz, d6-DMSO) δ 4.63 (t, 1H), 4.96 (s, 2H), 5.47 (d, 1H), 7.00 (d, 1H), 7.23-7.34 (m, 9H), 7.49-7.53 (m, 2H), 7.70 (d, 1H), 10.57 (s, 1H). MS APCI, m/z=441 (M+1). LC/MS: 2.74 min.