Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]1[C:18](O)=[O:19])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]1[C:18](=[O:19])[NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Reactant: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)NC1CC1

Procedure:
Cyclopropylamine was coupled with (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (8 g), EDC, HOBt, TEA in DMF to give 5 g of (2R,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a white semi-solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[CH:27][C:24]=1[CH:25]=O.C(OC(N1CCC[C@H](NCC2C=C(C(F)(F)C)C=CC=2OC(F)(F)F)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:2]([NH:1][CH2:25][C:24]2[CH:27]=[C:28]([C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:30][C:23]=2[O:22][CH3:21])[C@@H:3]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1C=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(C)(F)F)ccc2OC(F)(F)F)[C@@H]1c1ccccc1
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This Compound was prepared from Compound 12 and Compound 40 in the same manner of Compound 26. This was employed in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][OH:13].C[O-].[Na+].O>CO>[CH3:12][O:13][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CO
Reactant: ClCc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 18.7 %

Procedure:
2-Chloromethylbenzimidazole (1.67 g, 10 mmol) was suspended in methanol (34 mL), 28% sodium methoxide methanol solution (9.6 mL, 50 mmol) and water (50 mL) were added, and the mixture was stirred at room temperature for 20 min. The precipitated solid was collected by filtration, and purified by silica gel column chromatography (chloroform/methanol=100/0 to 93/7) to give the title compound (303 mg, 19%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]Br)[C:5]([I:8])=[N:6][CH:7]=1.C([O-])([O-])=[O:12].[Ca+2]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:12])[C:5]([I:8])=[N:6][CH:7]=1
Reactant: BrCc1cc(Br)cnc1I
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(Br)cnc1I
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a stirred solution of 5-bromo-3-bromomethyl-2-iodo-pyridine (25.0 g, crude, 66.313 mmol, 1 eq) in 1,4-dioxane (200 mL) was added suspension of CaCO3 (34.5 mL, 345 mmol, 5.2 eq) in water (200 mL) at room temperature. Resulting reaction mixture was refluxed for 10 hours. After complete consumption of starting material, reaction mixture was cooled to room temperature and filtered through celite bed over Buchner funnel, celite bed was washed with DCM (2×300 mL). Combined filtrate was washed with water (300 mL) and aqueous sodium bicarbonate (120 mL), dried over sodium sulfate and concentrated under reduced pressure to afford off white solid (15.3 g, crude). Crude compound was purified by washing with n-pentane (2×150 mL) to get desired compound as white solid (9.5 g, impure). Impure title compound was used as such for the next reaction. 1H NMR (400 MHz, CDCl3) δ: 2.14 (t, J=5.8 Hz, 1H), 4.62 (d, J=5.8, 2H), 7.86 (d, J=1.32 Hz, 1H), 8.33 (d, J=3.32, 1H). LC-MS (m/z): 313.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[NH2:4].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:3]=1[N:4]1[C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=2[C:15]1=[O:20]
Reactant: COC(=O)Oc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 79.1 %

Procedure:
A solution of 2-fluoro-4-chloro-5-methoxycarbonyloxyaniline (20.0 g, 91.1 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (14.0 g, 92.0 mmol) in acetic acid (200 ml) was reacted for 5 hours while heating under refluxing. After completion of the reaction, the mixture was-cooled to room temperature, water (200 ml) was added thereto, and extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with an aqueous solution of sodium carbonate and water, dried, and the solvent was distilled off under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent: ethyl acetate/hexane=1/5) to obtain N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)-3,4,5,6-tetrahydrophthalimide as a white solid (26.2 g, 72.1 mmol, 79.2% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)[CH2:6][C:7]1[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2].[OH2:38]>CO.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:37])[N:5]([CH2:22][C:23]1[CH:24]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:26]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:28]=1)[CH2:6][C:7]1[C:8]([S:18]([CH2:19][CH2:20][CH3:21])=[O:38])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH3:2]
Reactant: O
Reactant: CCCSc1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: CCCS(=O)c1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
(3,5-bis-trifluoromethyl-benzyl)-(8-methyl-2-propylsulfanyl-quinolin-3-ylmethyl)-carbamic acid ethyl ester (Example 135) (116 mg, 0.18 mmol) was dissolved in methanol (2 mL) and water (2 mL) followed by the addition of magnesium bis(mono peroxy phthalate hexahydrate) (MMPP) (267.1 mg, 0.54 mmol). The resulting mixture was stirred at room temperature overnight. The sample was diluted with methylene chloride and washed one time with water andone time with brine. The organic phase was dried, filtered and concentrated by rotary evaporation. The resulting sample was dried overnight under vacuum. (Biotage Horizon HPFC chromatography system, SiO2, 70:80 hexanes: ethyl acetate) gave a whit solid (80 mg, 72%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>O1CCCC1>[CH3:32][S:33]([N:3]1[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([C:26]#[N:27])=[CH:28][CH:29]=2)[C:5]2[C:20](=[O:21])[CH2:19][CH2:18][C:6]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:2]1=[O:1])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2,5-Dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)benzonitrile (example 1, 255 mg, 0.64 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 72 mg, 1.8 mmol) in dry tetrahydrofuran (15 mL) and the mixture is stirred at room temperature for 10 min. Methanesulfonyl chloride (104 μL, 1.35 mmol) is added and the mixture is stirred at 50° C. for 2 h. Water (1 mL) is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 230 mg; ESI mass spectrum [M+H]+=476; Retention time HPLC: 0.91 min (Z018_S04).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[CH2:12]([N+:19](C)(C)C)[C:13]1C=CC=C[CH:14]=1.C(#N)C=C>C(O)(C)(C)C>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:13][C:12]#[N:19]
Reactant: Sc1nc2ccccc2s1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C=CC#N
Product: N#CCCSc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
2-Mercaptobenzothiazole (25.0 g; 0.15 moles) was mixed with t-butanol (125 ml) and benzyltrimethylammonium hydroxide (40% in methanol; 3 ml). Acrylonitrile (15.9 g; 0.30 moles) was added dropwise and the mixture stirred at room temperature for 7 days. The product was removed by filtration and recrystallized from benzene.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([Cl:10])=[N:8][CH:7]=[CH:6][N:5]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24][CH2:23]1>ClCCl>[Cl:10][C:9]1[C:4]([CH2:3][NH:2][C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:29])=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: NCc1nccnc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C(=O)NCc2nccnc2Cl)CC1
Yield: 83 %

Procedure:
To a solution of 2-aminomethyl-3-chloropyrazine hydrochloride (content 70%; 7.85 mmol, 1.7 g) in N,N-diisopropylethylamine (39.3 mmol, 6.84 ml) and dichloromethane (30 ml) at 0° C. was added carefully 1-methylpiperidine-4-carbonyl chloride hydrochloride (9.42 mmol, 2.2 g). Then the cooling bath was removed. After two hours saturated aqueous sodium hydrogencarbonate solution (40 mL) was added and extracted five times with dichloromethane (30 mL). The organic extracts were combined, dried and concentrated and co-evaporated twice with toluene to give N-((3-chloropyrazin-2-yl)methyl)-1-methylpiperidine-4-carboxamide (1.75 g)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[C:26]1([C:32]2[N:33]=[CH:34][C:35]([NH:38][C:39](=O)[O:40]C3C=CC=CC=3)=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[C:26]1([C:32]2[N:33]=[CH:34][C:35]([NH:38][C:39]([N:2]3[CH2:7][CH2:6][C:5](=[CH:8][C:9]4[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=5)[CH:10]=4)[CH2:4][CH2:3]3)=[O:40])=[N:36][CH:37]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cnc(-c2ccccc2)cn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 5-phenylpyrazin-2-ylcarbamate (0.291 g, 1.00 mmol) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and heated to 60° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (200 mg, 37%) as white crystals after trituration in diethyl ether. MS (APCI 10V) AP+ 532.25; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.46 (t, J=5.46 Hz, 2H) 3.50 (t, J=5.46 Hz, 2H) 6.37 (s, 1H) 6.69 (d, J=8.77 Hz, 1H) 7.01-7.03 (m, 2H) 7.10 (d, J=7.81 Hz, 1H) 7.19 (d, J=8.59, Hz, 1H) 7.35-7.39 (m, 2H) 7.43-7.47 (m, 2H) 8.02 (dd, J=7.03 Hz, 1.95 Hz, 2H) 8.17 (dd, J=8.78 Hz, 2.15 Hz, 1H) 8.53 (d, J=2.5 Hz, 1H) 8.85 (s, 1H) 9.04 (s, 1H) 9.63 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[N:20]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[O:12]([C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:19])[NH2:20])=[CH:7][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CNc1ccc(Oc2ccccc2)cc1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1ccc(Oc2ccccc2)cc1
Reaction time: 2 h

Procedure:
N-(4-Phenoxyphenyl)glycine methylester (Intermediate 75, 13.5 g, 0.0525 mol) was dissolved in a mixture of acetic acid (90 ml) and water (5 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (3,8 g, 0.55 mol) in water (10 ml) over 15 minutes. Stirring was continued for 2 hours and the reaction was cooled to ~0° C. Zinc dust (13.4 g, 0.2048 mol) was added over 30 minutes and the reaction stirred at 0°-5° C. for 2 hours before being poured into water (200 ml) and extracted with ethyl acetate (2×150 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased, dried (MgSO4) and evaporated to give a brown semi-solid. This was triturated with ether/hexane (1:1) to recover starting material (6.5 g, 48%). The liquors were evaporated and purified by flash column chromatography on silica (Merck 9385; 250 g) eluting with ether-hexane (1:1) to give the title compound (Intermediate 76) as an off white solid (1.25 g, 9%) m.p 71°-73° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:35][C:36]1[CH:41]=[C:40]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)C=C(c1cccc(Cl)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Yield: 95.4 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.0 mmol), 3-chloro-phenylboronic acid (2.35 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated in a microwave at 100° C. for 2 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a saturated sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, 5% ethyl acetate/petroleum ether) afforded 2-(1-(3-chloro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.5 g, 95.4%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.51 (dd, 1H, J1=4.8 Hz, J2=1.8 Hz), 7.89 (dd, 1H, J1=7.8 Hz, J2=1.8 Hz), 7.68 (dd, 2H, J1=8.7 Hz, J2=1.5 Hz), 7.44 (m, 1H), 7.28-7.06 (m, 5H), 6.53 (s, 1H), 6.13 (d, 1H, J=10.2 Hz), 2.65 (m, 1H), 1.15-1.08 (m, 6H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)#[N:22]>C(#N)C>[C:21]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:20]=[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:25][CH:24]=1)#[N:22]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(CN=C(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.1 %

Procedure:
270 g (2.0 mol) of anhydrous K2CO3 were added to a solution of 150 g (0.8 mol) of 97% pure benzophenone imine and 144.8 g (0.74 mol) of p-cyanobenzyl bromide in 450 ml of acetonitrile, and the mixture was left to stir at room temperature for 6 h. The inorganic salts were filtered off with suction and then most of the solvent was removed by distillation, 300 ml of water were added to the residue, and the mixture was extracted several times with ethyl acetate. The organic phase was washed 2× with water, dried over Na2SO4 and evaporated to dryness. Digestion with ether resulted in 180 g of white crystals, melting point 101-102° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C@@H:14]([O:19][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:15]([F:18])([F:16])[F:17])[CH2:11][O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](O)C(F)(F)F)COC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](Oc2ccc([N+](=O)[O-])cc2)C(F)(F)F)COC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a cooled, stirred solution of (S)-2,2-dimethyl-4-((R)-3,3,3-trifluoro-2-hydroxy-propyl)-oxazolidine-3-carboxylic acid tert-butyl ester (1.99 g) and 1-fluoro-4-nitrobenzene (0.69 ml) in THF (20 ml) at 0° C. was added dropwise potassium bis(trimethylsilyl)amide solution (7.7 ml, 1 M solution in THF). The reaction mixture was stirred for 30 min at 0° C., then allowed to warm to room temperature and stirred for a further 1 h. The mixture was then diluted with dichloromethane and washed with sat. aq. ammonium chloride solution. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-2,2-dimethyl-4-[(R)-3,3,3-trifluoro-2-(4-nitro-phenoxy)-propyl]-oxazolidine-3-carboxylic acid tert-butyl ester as a yellow viscous oil (2.7 g, 97%). MS (ISP): 435.3 ([M+H]+), 379.3 ([M+H—C4H8]+), 335.4 ([M+H—C4H8—CO2]+).
Reaction SMILES: NC1C([O:12][C:13]([F:16])([F:15])[F:14])=CC=CC=1C(OC)=O.[CH:17]([O:20][C:21]([N:23]1[CH2:29][CH2:28][CH2:27][CH:26]([N:30]([C:46](=[O:48])[CH3:47])[CH2:31][C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)[C:25]2[CH:49]=[CH:50][CH:51]=[CH:52][C:24]1=2)=[O:22])([CH3:19])[CH3:18]>>[C:46]([N:30]([CH2:31][C:32]1[CH:37]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:35]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:33]=1)[CH:26]1[CH2:27][CH2:28][CH2:29][N:23]([C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[O:22])[C:24]2[C:52]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:51][CH:50]=[CH:49][C:25]1=2)(=[O:48])[CH3:47]
Reactant: COC(=O)c1cccc(OC(F)(F)F)c1N
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(OC(F)(F)F)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-trifluoromethoxybenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 601 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][O:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39]>>[CH3:36][O:37][C:38]([C:40]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:41][CH2:42][N:43]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:44][CH2:45]1)=[O:39]
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)CC1

Procedure:
The method of example 3.3 was used with 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (5 mmol) and 4-phenyl-piperidine-4-carboxylic acid methyl-ester hydrochloride (6 mmol, 1.2 eq.) to obtain a residue. The residue was chromatographed on silica gel eluting sequentially with 1% methanol in dichloromethane and then 2% methanol in dichloromethane to give the title compound:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.[CH:10]1[C:23]2[CH:22]([C:24](Cl)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>>[CH:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:24]([CH:22]2[C:23]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[O:15][C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:25])=[N:6]1)([CH3:9])[CH3:8]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CC(C)n1nnc(N)n1
Product: CC(C)n1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, MS: (neg. ions): m/e=334.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-isopropyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.[CH3:23][O:24][CH2:25][CH:26](O)[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH:26]([CH3:27])[CH2:25][O:24][CH3:23])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: COCC(C)O
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COCC(C)OC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Yield: 97 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid and 1.8 g of 1-methoxy-2-propanol were dissolved in 50 ml of benzene, followed by addition of 0.5 g of p-toluene sulfonic acid. Then, the mixture was heated under reflux for 6 hours. After completion of the reation, 50 ml of ether was added to the reaction mixture. The resulting mixture was washed with water by the customary method and dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.9 g of 1-methyl-2-methoxyethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetate.