Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11](O)=[O:12])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[Cl:14]C1C=CC(OS([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=O)=CC=1.CN(C)C=O>N1C=CC=CC=1>[ClH:14].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[O:12])[CH2:7][CH2:6]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(C(=O)O)CC1
Reactant: O=S(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)N1CCC(C(=O)Oc2ccc(Cl)cc2)CC1
Yield: 70.5 %

Procedure:
A mixture of 1.5 g of 1-amidino-4-piperidinecarboxylic acid hydrochloride and 8.8 g of bis-(p-chlorophenyl)sulfite was stirred at room temperature for 1 hour in a solution of 14 ml of dry dimethylformamide and 7 ml of dry pyridine. The solvent was removed under reduced pressure, and the residue was washed twice with dry ether. Acetone was added to the residue to give crystals. The crystals were washed with ether and then with ethyl acetate and recrystallized from methanol-ether to obtain 1.62 g (yield: 70.4%) of p-chlorophenyl 1-amidino-4-piperidinecarboxylate hydrochloride as colorless crystals having a melting point of 196° to 198° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[N:8](C(C)(C)C)[CH:7](O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)=O>[Br:1][C:2]1[C:10]2[S:9](=[O:12])(=[O:11])[NH:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)N1C(O)c2cccc(Br)c2S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Product: O=S1(=O)NCc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
7-bromo-2-(1,1-dimethylethyl)-2,3-dihydro-1,2-benzisothiazol-3-ol 1,1-dioxide (1.4 g, 4.4 mmol) was treated with formic acid (10 mL). The reaction was stirred at ambient temperature over 18 h, concentrated in vacuo and dissolved in methanol (10 mL). The mixture was cooled to 0° C. and treated with sodium borohydride (0.17 g, 4.4 mmol) in small portions over 20 min. The cooling bath was removed and the resulting reaction mixture stirred at ambient temperature over 18 h. The work-up consisted of slowly quenching the reaction mixture with ice, dilution with water and extraction with ethyl acetate. Drying over sodium sulfate and concentrating under reduced pressure provided the crude product that was purified by a plug of silica gel (ethyl acetate/hexane, 1:4) to afford the desired 7-bromo-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (0.6 g, 60% over 2 steps). 1H NMR (CD3OD): δ4.40 (s, 2H), 7.53 (m, 2H), 7.70 (m, 1H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C(C1C=C(N[C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)ON=1)(C)C>>[F:1][C:2]([C:5]1[CH:9]=[C:8]([NH:10][C:20](=[O:28])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:7][N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: CC(C)(F)c1cc(N)on1
Product: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Yield: 68 %

Procedure:
Prepared from 3-(2-fluoropropan-2-yl)isoxazol-5-amine (4.83 g, 33.54 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate as a colorless solid (6.04 g, 68%). 1H NMR (300 MHz, CDCl3) δ 7.80 (brs, 1H), 7.39-7.45 (m, 2H), 7.18-7.32 (m, 3H), 6.27 (s, 1H), 1.74 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 265 (M+H)+.
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@:16]4([CH2:37][C:38]([O:40]CC)=[O:39])[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17]4)[CH2:11]1)(=O)C1C=CC=CC=1>COCCOCCOC.[OH-].[Li+]>[C:38]([CH2:37][C@:16]12[C:15]3[CH2:14][CH2:13][C@@H:12]4[C@:32]([CH3:35])([CH2:33][CH2:34][C@H:10]([OH:9])[CH2:11]4)[C:31]=3[CH2:30][CH2:29][C@:28]1([CH3:36])[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17]2)([OH:40])=[O:39]
Reactant: CCOC(=O)C[C@@]12C=C[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CCC1=C2CC[C@H]2C[C@@H](OC(=O)c3ccccc3)CC[C@]12C
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CC(C)CCC[C@@H](C)[C@H]1C=C[C@@]2(CC(=O)O)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1CC3

Procedure:
A mixture of 3β-benzoyloxy-14α-carbethoxymethyl-5α-cholest-8,15-diene (209 mg, 0.36 mmole) in diglyme (5 mL) and 1N lithium hydroxide (5 mL) was heated at 125° C. to 135° C. for 4 hours, and worked up according to the procedure described in Example 2(iii) to provide 122 mg (77%) of white, crystalline 14α-carboxymethyl-5α-cholest-8,15-dien-3β-ol; mp 221°-222° C. (from CH3CN).
Reaction SMILES: C[O:2][C:3]([C@@H:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[ClH:13]>>[CH:9]1[CH:8]=[CH:7][C:6]([C@H:5]([NH2:12])[C:3]([OH:4])=[O:2])=[CH:11][CH:10]=1.[ClH:13]
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: Cl
Product: N[C@H](C(=O)O)c1ccccc1

Procedure:
A solution of methyl L-phenylglycinate (-)-hemitartrate mono-ethanol solvate ([α]D + 62.4°, 36.888 g., 0.102 mole) in 6N-hydrochloric acid (68 ml., 0.408 mole, 4 equiv.) was refluxed for 1 hour 10 minutes and then distilled for 15 minutes. Water (68 ml.) was added and the pH of the warm solution adjusted to 7.0 with ammonium hydroxide solution (0.880, 35 ml.). The mixture was cooled in ice, filtered, and the solid was washed with water (2 × 25 ml.) and ethanol (25 ml.) and dried over phosphorus pentoxide to give L-phenylglycine as white plates (13.406 g., 87%), [α]D21 + 152.1° (c 1.007, 1N-HCl).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:25])[NH:9][C:10](=[O:24])[C:11]=2[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:57][C:58]([F:62])([F:61])[CH2:59]O>C1COCC1>[C:1]1([C:7]2[C:8](=[O:25])[N:9]([CH2:59][C:58]([F:62])([F:61])[F:57])[C:10](=[O:24])[C:11]=2[NH:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=O)C(c2ccccc2)=C1Nc1ccc(OC(F)(F)F)cc1
Reactant: OCC(F)(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C(Nc2ccc(OC(F)(F)F)cc2)=C(c2ccccc2)C(=O)N1CC(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 2.6 %

Procedure:
A mixture of 3-phenyl-4-{[4-(trifluoromethoxy)phenyl]amino}-1H-pyrrole-2,5-dione (0.63 mmol, 220 mg), diethyl azodicarboxylate (0.70 mmol, 121 mg) and triphenylphosphine (0.70 mmol, 182 mg) in dry THF (4 mL) was prepared in sealed reaction vessel. 2,2,2-Trifluoroethanol (0.70 mmol, 70 mg) was added. The mixture was first stirred at rt. for three days, then at 40° C. for two hours and finally at 100° C. for 30 min. in a microwave reactor. The reaction mixture was filtered and purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN) to give 7 mg (3%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.45 (s, br, 1H), 7.22-7.09 (m, 3H), 7.02-6.97 (m, 2H), 6.92-6.84 (m, 2H), 6.70-6.65 (m, 2H), 4.24 (q, J=8.6 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:21][CH2:20]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][S-:29].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:19]1([CH2:18][N:15]2[CH2:16][CH2:17][N:12]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([S:29][CH3:28])=[N:7][C:6]=4[CH:8]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: C[S-]
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(CC4CC4)CC3)cc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCN(CC4CC4)CC3)cc2n1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
2-Chloro-6-(4-(cyclopropylmethyl)piperazin-1-ylmethyl)-4-morpholin-4-ylthieno[3,2-d]pyrimidine (0.2 g, 0.49 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100° C. with stirring. After 2 hours the contents of the tube were diluted with EtOAc then washed with saturated aqueous NaHCO3 (×2) followed by brine and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford 6-(4-(cyclopropylmethyl)piperazin-1-ylmethyl)-2-methylsulfanyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a pale yellow solid (0.2 g, 97%). LCMS (Method D): RT=2.04 min, [M+H]+ 419
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:4]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1cccc(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
Chloroacetyl chloride (4 g, 35.4 mmol) was added to a stirred mixture of 3-aminobenzamide (4.0 g 25.9 mmol), K2CO3 (22 g, 159 mmol), water (40 ml), and dioxane (40 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and 25° C. for 16 hours, resulting in a solid precipitate. The precipitate was collected, washed, and dried to yield 4.1 g (75%) of the desired 3-chloroacetamidobenzamide, mp: 210 (D).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:13](=[O:14])[CH2:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[S:9][C:8]=2[CH:19]=1)=[O:3].[Na].[OH:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>O1CCCC1>[O:14]=[C:13]1[CH2:12][C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[S:9][C:8]2[CH:19]=[C:4]([C:2]([O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:3])[CH:5]=[CH:6][C:7]1=2
Reactant: O=C(O)CCO
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(O)CCOC(=O)c1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve 1.0 gm. of 3-chlorocarbonyl-10,11-dihydro-11-oxodibenzo[b,f]thiepin in 20 cc. of tetrahydrofuran and add 1.0 gm. of the sodium salt of β-hydroxypropionic acid. Stir the mixture at room temperature for 18 hours. Filter and evaporate the filtrate to dryness. Recrystallize the solid residue from ethanol to obtain the title product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][N:20]([S:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33]>C(Cl)Cl>[ClH:33].[ClH:33].[C:27]1([S:24]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:15]=3[C:22]([CH3:23])=[CH:21]2)(=[O:25])=[O:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: ClCCl
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCNCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of 4-(7-Benzenesulfonyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (4.0 g, 13 mmol) in DCM (100 mL) was treated with anhydrous HCl (4M in dioxane, 100 mL) and stirred at room temperature overnight. The suspension was concentrated in vacuo to give 7-Benzenesulfonyl-5-methyl-4-piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (5.4 g, 100%.) LCMS (APCI+) m/z 358 [M+H]+; Rt: 1.79.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=N[CH2:24][CH2:25][CH2:26][N:27]([CH3:29])C.C1C=CC2N(O)N=NC=2C=1.N1CCCC1>CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[CH2:4]([O:3][C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@@H:12]1[C:13]([N:27]1[CH2:26][CH2:25][CH2:24][CH2:29]1)=[O:15])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C([C@H]1CCCN1C(=O)OCc1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (+)-carbobenzyloxy-D-proline (1.5 g, 6 mmol), EDAC (2.3 g, 12 mmol), HOBt (800 mg, 6 mmol), TEA (1.5 mL) and pyrrolidine (853 mg, 12 mmol) in DMF (20 mL) was stirred at rt for 18 hours. The reaction was diluted with water and sodium bicarbonate, extracted with DCM (3×). The combined DCM was concentrated and purified on a silica gel column to give (R)-2-(pyrrolidine-1-carbonyl)-pyrrolidine-1-carboxylic acid benzyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].O>CS(C)=O>[C:26]1(=[O:35])[N:25]([CH2:24][CH2:23][CH2:22][N:4]([C:5]2[CH:18]=[CH:17][C:8]([C:9]([CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:7][CH:6]=2)[C:1](=[O:3])[CH3:2])[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(=O)Nc1ccc(C(=O)C(C)CC(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(C(=O)C(C)CC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
30.0 g (120 mmol) of 3-(4-acetamidobenzoyl)-butyric acid are added to a suspension of 7.6 g (253 mmol) of sodium hydride (80%) in 150 ml of dimethyl sulphoxide and the mixture is stirred for 30 minutes at 60° C. After the addition of 33.2 g (120 mmol) of N-(3-bromopropyl)-phthalimide, stirring is continued at 80° C. for 6 hours. After cooling, the reaction mixture is poured out on 200 ml of iced water and extracted with 3×100 ml of dichloromethane. The extracts are discarded. The aqueous phase is then adjusted to pH 6.5 with 2N hydrochloric acid and again extracted with 3×100 ml of dichloromethane. The combined organic phases are dried and concentrated by evaporation under vacuum. The oil obtained as residue crystallizes when triturated with 20 ml of ethanol.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:8]=[C:9]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:16]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[F:30][C:31]([F:36])([F:35])[CH:32]1[O:34][CH2:33]1>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:16]=3)[CH2:33][CH:32]([OH:34])[C:31]([F:36])([F:35])[F:30])[CH:10]=[CH:11][CH:12]=2)=[CH:28][CH:29]=1
Reactant: FC(F)(F)C1CO1
Reactant: Fc1ccc(Oc2cccc(NCc3cccc(OC(F)(F)C(F)F)c3)c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccc(F)cc2)c1)C(F)(F)F
Temperature: 40 °C
Yield: 80.9 %

Procedure:
The N-[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amine (612 mg, 1.5 mmol) product from EX-634C and 1,1,1-trifluoro-2,3-epoxypropane (268 mg, 2.4 mmol) were dissolved in 1.0 mL of acetonitrile. Ytterbium (III) trifluoromethanesulfonate (43 mg, 0.07 mmol) was added, and the stirred solution was warmed to 40° C. for 2.5 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that no secondary amine starting material remained. The reaction was quenched with water and extracted with ether. The ether layer was washed with brine and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:11) to give 633 mg (81%) of the desired 3-[[3-(4-fluorophenoxy)phenyl][[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl] amino]-1,1,1-trifluoro-2-propanol product as a yellow oil, 99% pure by HPLC analysis. 1H NMR (CDCl3) δ 7.35 (t, 1H), 7.15 (m, 3H), 6.98 (m, 5H), 6.49 (dd, 1H), 6.38 (dd, 1H), 6.33 (m, 1H), 5.92 (tt, 1H), 4.67 (ABq, 2H), 4.37 (m, 1H), 3.91 (dd, 1H), 3.59 (dd, 1H), 2.48 (d, 1H). 19F NMR (CDCl3) δ −79.2 (d, 3F), −88.5 (m, 2F), −120.33 (m, 1F), −137.2 (dt, 2F). HRMS calcd. for C24H19F8NO3: 522.1315 [M+H]+, found: 522.1297.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.65 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.20 mmol) according to the general procedure IVb. Obtained as a white solid (0.66 g, 73%). MS (EI) 446.0 [(M)+]; mp 134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: Nc1ccc(F)c(C(=O)O)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)ccc1F
Yield: 81.8 %

Procedure:
To a solution of 5-amino-2-fluorobenzoic acid (89.6 g, 577 mmol) in MeOH (1000 mL) was added sulfurous dichloride (82.4 g, 692 mmol) dropwise at 0° C. Then the mixture was heated to reflux for overnight. The solvent was removed. The residue was diluted with EtOAc (1 L). Then the pH was adjusted to around 9 by progressively adding saturated NaHCO3. The organic layer was separated. The aqueous layer was extracted with EtOAc (500 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound of step A (79.8 g, 81.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.16-7.20 (m, 1H), 6.90-6.98 (m, 1H), 6.75-6.82 (m, 1H), 3.89 (s, 3H), 3.51-3.70 (br, 2H).
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O>C(OCC)C>[OH:4][C:5]1([C:15]([F:18])([F:17])[F:16])[NH:3][N:2]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:6]1
Reactant: NN
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccn1
Solvent: CCOCC
Solvent: O
Product: OC1(C(F)(F)F)CC(c2ccccn2)=NN1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 104.9 %

Procedure:
2-(2′,4′-difluorophenyl)pyrazole (3.6 g, 20 mmol) and K3IrBr6 (6.3 g, 8 mmol) were added to a flask containing 90 ml 2-ethoxyethanol and 30 ml water. The reaction mixture was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the pale yellow precipitate was vacuum filtered and washed first with ethanol followed by heptanes. The product [2-(4′,6′-diflouorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-diflouorophenyl)pyrazole]2 was dried in vacuum oven (4.2 g, 81%). Step 2 To a 60 ml THF suspension of potassium t-butoxide (7.9 g, 59 mmol) and 2-acetylpyridine(7.1 g, 59 mmol) was added dropwise ethyl trifluoroacetate (10 g, 70 mmol) at 10° C., and the mixture was stirred at room temperature for 15 h. After the PH value of the mixture had been adjusted to 6-7 with 10% H2SO4, the solution was extracted with Et2O. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 followed by recrystallization from ethanol to give 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (10.2 g, 81%). Step 3 Hydrazine hydrate (1.44 g, 27.7 mmol) was added dropwise to 2-(3-oxo-4,4,4-trifluorobutanoyl)pyridine (5 g, 23 mmol) in 250 ml diethyl ether, and the mixture was stirred at ambient temperature for 3.5 h. Most of the solvent was evaporated and the mixture was extracted with water. The organic layer was dried (MgSO4) and evaporated to give 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 78%). Step 4 Compound 5-hydroxy-3-(pyridine-2-yl)-5-trifluoromethyl-4,5-dihydropyrazole (5.58 g, 24 mmol) was boiled under reflux in 300 ml ethanol in the presence of conc. sulfuric acid (1.85 ml) for 30 min. The reaction mixture was then extracted with water. Evaporation and chromatography (ethyl acetate/heptanes 1:5) gave 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (4.2 g, 85%). Step 5 [2-(4′,6′-difluorophenyl)pyrazole]2Ir2(μ-Br)2[2-(4′,6′-difluorophenyl)pyrazole]2 (0.15 g, 0.12 mmol), 3-(pyridine-2-yl)-5-trifluoromethylpyrazole (70 mg, 0.3 mmol) and 0.2 g of K2CO3 were refluxed under an nitrogen atmosphere in 2-ethoxyethanol for 18 h. After cooling to room temperature, water was added and a white precipitate was filtered and washed with water. The crude product was chromatographed on a silicon column with dichloromethane/methanol (9:1 v/v) as the mobile phase (110 mg, 60%).
Reaction SMILES: P(Cl)(Cl)Cl.[N:5]1[CH:6]=[CH:7][N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[C:19]3[CH2:24][CH2:23][N+:22]([O-])([C:25]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:26])[CH2:21][CH2:20]3)[C:9]=12.O.N>ClCCl>[N:5]1[CH:6]=[CH:7][N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10](=[C:19]3[CH2:24][CH2:23][N:22]([C:25]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)=[O:26])[CH2:21][CH2:20]3)[C:9]=12
Reactant: O=C(c1ccncc1)[N+]1([O-])CCC(=C2c3ccccc3CCn3ccnc32)CC1
Agent: N
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccncc1)N1CCC(=C2c3ccccc3CCn3ccnc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of phosphorous trichloride (0.25 ml)in dichloromethane (3 ml) was added to a solution of 4-(5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-(4-pyridinylcarbonyl)-piperidine N1 -oxide (B, 0.4 g) and dichloromethane (5 ml). The reaction mixture was allowed to stir overnight at 25° C. in an atmosphere of nitrogen, and was then poured onto a mixture of ice and water. The resulting mixture was basified with concentrated aqueous ammonia, and the aqueous layer was extracted with dichloromethane. The dried (magnesium sulfate), filtered extracts were concentrated to give 4-(5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene )-1-(4-pyridinylcarbonyl)piperidine (A, 0.34 g), m.p. 207°-209° C. from carbon tetrachloride. ##STR25##
Reaction SMILES: [C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:30][C:31](OC(C)(C)C)=[O:32])[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:40][C:41]1[CH:51]=[CH:50][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][CH:42]=1>>[C:1]1([CH3:39])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:29])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:13][CH:12]([NH:30][C:31]([NH:40][C:41]3[CH:42]=[CH:43][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:50][CH:51]=3)=[O:32])[C:11]2=[O:38])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)NC2CN(C(=O)c3ccccc3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)cc1

Procedure:
Step 2 of Example 10 was repeated except that 1-(2-toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzoyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine was used instead of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine. Subsequently, Step 3 of Example 10 was repeated except that ethyl 4-aminobenzoate was used instead of ethyl 3-aminobenzoate, to thereby obtain the title compound.