Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:11][N:10]1C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CC(C)=O.Cl>CC(C)=O.O>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:11][NH:10]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3)cc2)C(=O)O1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)NC3)cc2)C(=O)O1
Yield: 91.9 %

Procedure:
The N-trityl compound (Example 30, 0.528 g, 0.79 mM) in acetone (8 ml) at 0° C. was treated with freshly prepared HCl/acetone (4 ml) and stirred. The mixture was periodically treated with 10% HCl in water until TLC indicated consumption of starting material. The reaction mixture was then diluted with EtOAc (30 ml) and taken to pH 11 with NH4OH solution. The aqueous layer was extracted with EtOAc and the combined organics dried (MgSO4) and evaporated to a residue which was triturated with diethyl ether to give the title amine (0.309 g, 92%) which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([S:5][C:6]1[CH:15]=[CH:14][C:9](OC(=O)C)=[C:8]([OH:16])[C:7]=1[CH2:17][CH2:18][CH3:19])=[O:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:37][C:38](C)=[O:39]>>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:16][C:8]1[C:7]([CH2:17][CH2:18][CH3:19])=[C:6]([S:5][C:3](=[O:4])[N:2]([CH3:1])[CH3:20])[CH:15]=[CH:14][C:9]=1[C:38](=[O:39])[CH3:37]
Reactant: CC(C)=O
Reactant: BrCCCCCCBr
Reactant: CCCc1c(SC(=O)N(C)C)ccc(OC(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCc1c(SC(=O)N(C)C)ccc(C(C)=O)c1OCCCCCCBr
Reaction time: 9.5 h
Yield: 79.7 %

Procedure:
A mixture of (4-(N,N-dimethylcarbamoylthio)-2-hydroxy-3 -propylphenoxy)ethanone (5.8 g), 1,6-dibromohexane (25 g), potassium iodide (1 g) and potassium carbonate (5.7 g) in acetone (40 ml) was heated with refluxing and stirring. Each of potassium carbonate (2.9 g) was added thereto after 9.5 hours, 20 hours and 30.5 hours, and the mixture was subjected to refluxing for total 41 hours. After cooled, inorganic materials were filtered off and the filtrate was concentrated under a reduced pressure. The resultant residue was purified through silica-gel column chromatography (eluting with benzene:hexane=1:1, then benzene:ethyl acetate=9: 1) to give (2-(6-bromohexyloxy)-4-(N,N-dimethylcarbamoylthio) -3-propylphenyl)ethanone (7.3 g, 79.7%) as brown oil. 1H-NMR (CDCl3) δ: 0.99 (3H, t, J=7 Hz, —CH2CH2CH3), 1.2-1.8 (10H, m, —CH2CH2CH3 and —OCH2CH2CH2CH2CH2CH2Br), 2.59 (3H, s, COCH3), 2.70 (2H, m, —CH2CH2CH3), 3.08 (6H, s, —N(CH3)2), 3.35 (2H, t, J=6 Hz, —CH2Br), 3.77 (2H, m, t, J=6 Hz, —OCH2(CH2)5Br), 7.30 (2H,
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=1[F:38]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:29][C:30]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[CH:32][C:31]=3[F:38])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc(C)cc1
Reactant: Fc1cc(F)c(CBr)c(F)c1
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)c(C)nc3c2ccn3Cc2c(F)cc(F)cc2F)cc1

Procedure:
The title compound was prepared from methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-(bromomethyl)-1,3,5-trifluorobenzene in a manner similar to that described in Example 25 as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.63 (d, J=7.6 Hz, 1 H), 7.40-7.30 (m, 3 H), 7.07 (d, J=3.5 Hz, 1 H), 6.78-6.69 (m, 2 H), 6.25 (d, J=3.5 Hz, 1 H), 5.71-5.56 (m, 2 H), 5.53 (s, 1 H), 2.84 (s, 3 H), 2.47 (s, 3 H), 0.95 (s, 9 H); LCMS (m/z) ES+=497 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Product: O=C(O)c1cc(NCc2ccc(C(F)(F)F)cc2)ccc1O
Yield: 50.3 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-(trifluoromethyl)benzyl chloride (760 mg, 3.92 mmole), 510 mg (50% yield) of 5-(4-(trifluoromethyl)benzyl)aminosalicylic acid was obtained as a white solid.: mp>188° C. (decompose).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:14])=[O:15])=[CH:9][CH:8]=2)[C:3]1=[O:22]
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(N3CC[C@@H](O)C3=O)cc2)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Synthesized according to General Procedure 8. To a stirred suspension of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (41 g, 0.121 mol) in DCM (205 mL) under N2 at 0° C. was added DIEA (15.6 g, 21 mL, 0.121 mol). To this suspension at 0° C. was added 4-methoxybenzenesulfonyl chloride (25 g, 0.121 mol) portionwise over 15 minutes. The cooling bath was removed and the suspension was allowed to warm to RT over 1 hour during which time the reaction mixture became a homogeneous solution. The solution was cooled to 0° C. and MeOH (2.05 L) was added. Stirring was continued at 0° C. After 10 minutes a precipitate formed. The resulting suspension was stirred at 0° C. for 30 minutes and then filtered. The filter cake was washed with MeOH (2×250 mL) and then dried under vacuum to constant weight to provide (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(4-methoxyphenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide as a white solid (55.49 g, 0.109 mol, 90% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.70 (d, J=5.1 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.03-6.98 (m, 3H), 5.88 (d, J=5.9 Hz, 1H), 4.38-4.32 (m, 1H), 3.85-3.77 (m, 1H), 3.81 (s, 3H), 3.70 (td, J=9.4, 5.4 Hz, 1H), 2.48-2.41 (m, 1H) and 1.92-1.82 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=510.0; tR=1.22 min.
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[CH2:1]([NH:7][C:12](=[O:13])[CH2:11][Cl:10])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C(CCl)NCc1ccco1
Yield: 85 %

Procedure:
N-Furfurylchloroacetamide was prepared by adding 20.0 g. (0.206 mole) furfuryl amine in sufficient toluene to make a 15% solution to a 500 ml. three neck round bottom flask equipped with magnetic stir bar, addition funnel, and cooling bath and then adding 36 ml. of 20% sodium hydroxide. The mixture was cooled to 0°-5° C. and chloroacetyl chloride was added dropwiseso that the reaction temperature was maintained at 5°-10° C. After the addition, a solid deposited on the walls of the flask. It was recrystallized from ether as a light tan solid. Yield was 85%.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C@@H:16]([CH3:35])[C@H:17]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=1.[N+:36]([C:39]1[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=1)([O-:38])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N+:36]([C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:15][C@H:16]([CH3:35])[C@H:17]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[O:44])=[CH:46][CH:47]=1)([O-:38])=[O:37]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
Diisopropyl azodicarboxylate (6 ml) was added dropwise to a solution of tert-butyl [(1R,2S)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamate (5.88 g), 4-nitrobenzoic acid (4.84 g), and triphenylphosphine (7.59 g) in THF (100 ml) under ice-cooling in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for two hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (toluene:ethyl acetate=97:3). Then, the resulting powder was triturated with toluene-hexane to obtain 6.69 g of the title compound.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br[CH2:30][CH2:31][CH2:32][OH:33]>O1CCOCC1.O>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:30][CH2:31][CH2:32][OH:33])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 17 h

Procedure:
To 1-benzhydrylpiperazine (64 mmol) and diisopropylethylamine (77 mmol) in dioxane/H2O (9:1, 100 mL) is added 3-bromo-1-propanol (64 mmol) while stirring. After about 17 hours, the solution is concentrated in vacuo, and the residue is taken up in EtOAc (250 mL) and washed with 1N NaOH (2×100 mL), and brine (2×). The organic phase is dried over Na2SO4 (s), concentrated in vacuo and recrystallized from hot EtOAc to afford white crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[C:32]([O:36][C:37]([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42](O)=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:41]2[CH:40]=[C:39]([CH:47]=[CH:46][CH:45]=2)[C:37]([O:36][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:38])=[O:43])=[C:3]([C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][C@@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21][CH2:20]3)[CH:29]=[CH:30][N:31]=2)[CH:4]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CC(C)(C)OC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a mixture of (S)-2-(2-amino-5-(diethylamino)phenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide (7.1 mmol, 2.94 g), 3-(tert-butoxycarbonyl)benzoic acid (8.52 mmol, 1.89 g) and DIEA (35.5 mmol, 4.59 g) in DMF (16 mL) was added HATU (8.52 mmol, 3.24 g). The mixture was stirred at 60° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried and concentrated. The residue was purified by column to give a yellow solid (4.31 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:24]([O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[CH2:24]([O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][CH:29]=1)[CH3:25]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1

Procedure:
In analogy to Example 1, step 7, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19, Step 5) was reacted with ethyl-4-(bromomethyl)benzoate and potassium carbonate to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=528.3 [M−H−].
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[F:13][C:14]([F:22])([C:18]([F:21])([F:20])[F:19])C([O-])=O.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.[Cu]I>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:14]([F:22])([F:13])[C:18]([F:21])([F:20])[F:19]
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1C(F)(F)C(F)(F)F
Temperature: 150 °C

Procedure:
To a 250 mL round-bottom flask was added 2-bromo-1-methoxy-4-nitrobenzene (3.5 g, 15.08 mmol), copper(I) iodide (5.75 g, 30.2 mmol), and sodium 2,2,3,3,3-pentafluoropropanoate (5.25 g, 28.2 mmol) in DMF (75 ml) and toluene (25 ml) to give a tan suspension. The mixture was heated at 150° C. and toluene was removed by a Dean-Stark trap. The mixture was heated at 155° C. for 6 h under nitrogen, cooled and poured into 100 mL of water and 100 mL of ether, filtered through a 1-inch plug of Celite and the plug was rinsed with ether. The filtrate layers were separated. The organic layer was washed with brine, dried (Na2SO4) filtered and concentrated. The dark oil was flash chromatographed on an Isco 40 g silica cartridge eluting with 4:1 hexane/EtOAc to give a yellow oil that was a (3:1) mix of desired material and starting material (1.5 g, 37%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=O)[CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:6](=[S:21])[CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1[nH]c(C(F)(F)F)cc1=O
Solvent: Cc1ccccc1
Product: Cn1[nH]c(C(F)(F)F)cc1=S
Yield: 105.7 %

Procedure:
5.25 g of 1-methyl-3-(trifluoromethyl)pyrazol-5-one (8-4) and 10.23 g of Lawesson's reagent were suspended in 300 ml of anhydrous toluene. The suspension was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to produce 4.87 g of 1-methyl-3-(trifluoromethyl)pyrazol-5-thione (8-5).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.O[C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=1[O:31][CH3:32].[C:33](=[O:36])([O-])[O-:34].[K+].[K+]>CN(C=O)C>[C:13]([O:34][C:33]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][O:11][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][C:21]=2[O:31][CH3:32])[CH2:18][CH2:17]1)=[O:36])([CH3:18])([CH3:14])[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCNCC2)cc1
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 161.7 %

Procedure:
1-tert-Butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (40 g, 0.11 mol), (prepared as described for the starting material in Example 1), was added to a suspension of ethyl 4-hydroxy-3-methoxybenzoate (19.6 g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) in dry DMF (200 ml). After stirring at 95° C. for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The resulting oil was crystallised from petroleum ether and the suspension was stored overnight at 5° C. The solid was collected by filtration, washed with petroleum ether and dried under vacuum to give ethyl 4(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-3-methoxybenzoate (35 g, 89%).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:49][N:50]([CH3:59])[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C)C=O>[CH3:49][N:50]([CH3:59])[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][N:56]([C:8]([NH:9][C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]4([C:38]([NH:39][C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[O:47])[CH2:37][CH2:36]4)=[O:34])=[CH:30][CH:31]=3)[CH:22]=[CH:21][N:20]=2)=[O:7])[CH2:55][CH2:54]1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1
Reactant: CN(C)CCN1CCNCC1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccn2)CC1
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To [4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (50 mg) was added a solution of 1-[2-(dimethylamino)ethyl]piperazine (48.6 mg) in N,N-dimethylformamide (1.0 ml) at room temperature, followed by stirring for 5 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solvent was removed under reduced pressure. The solid residue was dried under reduced pressure to provide the titled compound as white powder (34.7 mg, 76%).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][C:26](O)=[O:27])[N:22]=[CH:21]1)([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:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.C(CN)O.CCOC(C)=O>[C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: B
Solvent: NCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(1-Trityl-1H-imidazol-4-yl)acetic acid (65 g, 0.17 mol) is suspended in THF (400 mL) and cooled to 0° C. To this is added BH3.THF solution (350 mL, 1.0 M). The clear solution obtained is stirred at 0° C. for 30 min before warming to room temperature until LCMS indicated completion of the reaction. The solution is cooled again to 0° C. and quenched carefully with water (250 mL). The resulting solution is diluted with EtOAc (300 mL) and transferred to a separatory funnel and the aqueous layer is extracted with EtOAc. The organic phase is dried over anhydrous Na2SO4 and evaporated to give a sticky residue which is taken up in ethanolamine (800 mL) and heated to 90° C. for 2 h. The reaction is transferred to a separatory funnel, diluted with EtOAc (1 L) and washed with water (3×600 mL). The organic phase is dried over anhydrous Na2SO4 and evaporated to give 2-(1-trityl-1H-imidazol-4-yl)-ethanol as a white solid that is used as is without further purification. MS (ESI) m/z 354.8 (M+H) (prepared by alternate method in J. Med. Chem. 1996, 39(19), 3806)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=O)[CH:3]=1.[NH2:11][OH:12].Cl.C([O-])(=O)C.C(O)(=O)C.[Na+]>C(O)C.O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH:9]=[N:11][OH:12])[CH:3]=1
Reactant: Cc1nc(Br)cc(C=O)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(Br)cc(C=NO)n1
Temperature: 90 °C
Yield: 33.8 %

Procedure:
To a stirred solution of 6-bromo-2-methylpyrimidine-4-carbaldehyde (11 g, 54.7 mmol, Preparation #17 step 1) and NH2OH.HCl (7.61 g, 109 mmol, Sisco Research Labs) in ethanol (75 mL) and water (25 mL) was added sodium acetate acetate (13.47 g, 164 mmol). The reaction mixture was heated to reflux at about 90° C. for about 1 h. The mixture was cooled to RT and diluted with water (200 mL). The separated product (solid) was collected by filtration, washed with water and dried under vacuum to afford 6-bromo-2-methylpyrimidine-4-carbaldehyde oxime 4.0 g (33.8%), 1H NMR (400 MHz, DMSO) δ: 12.43 (s, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 2.61 (s, 3H), MS m/z: 216 (negative mode).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[C:10]([C:15](=O)[CH3:16])[C:11]([O:13][CH3:14])=[O:12].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27]>CN(C)C=O.C(OCC)(=O)C>[CH3:16][C:15]1[NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:19])([F:18])[F:1])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: Nc1ccccc1S
Reactant: COC(=O)C(=Cc1ccccc1C(F)(F)F)C(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)Nc2ccccc2SC1c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 2-[[2-(trifluoromethyl)phenyl]methylene]-3-oxobutanoic acid, methyl ester (1.8 g., 6.61 mmole) in dimethylformamide (5 ml.) is treated with 2-aminothiophenol (919 mg., 6.61 mmole) at room temperature. The reaction is stirred at room temperature for about 72 hours. The reaction is then heated at 65°-70° (oil bath temperature) for 10 hours. It is cooled to room temperature and diluted with ethyl acetate (50 ml.). The solution is thoroughly washed with water, sodium bicarbonate, and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped off to give a yellow solid. Recrystallization from isopropyl ether-dichloromethane gives 783 mg. of product as fluffy needles. The mother liquor is purified by flash chromatography (20% ethyl acetate in hexane) and the resulting solid is recrystallized from isopropyl ether-dichloromethane to give 153 g. of additional product. Recrystallization from isopropyl ether-dichloromethane gives an analytically pure sample of 2,5-dihydro-4-methyl-2-[2-(trifluoromethyl)phenyl]-1,5-benzothiazepine-3-carboxylic acid, methyl ester; m.p. 165°-166.5°. TLC (silica gel, hexane: ethyl acetate, 60:40) Rf =0.36.