Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[N:17]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:14][N:13]=1)=O)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[NH2:11][C:12]1[N:17]=[C:16]([CH:18]([OH:23])[C:19]([F:22])([F:20])[F:21])[CH:15]=[CH:14][N:13]=1
Reactant: O=C(Nc1nccc(C(O)C(F)(F)F)n1)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nccc(C(O)C(F)(F)F)n1
Temperature: 25 °C

Procedure:
To a solution of 1-[2-(N-benzyloxycarbonylamino)pyrimidin-4-yl]-2,2,2-trifluoroethanol (9a) in ethanol-tetrahydrofuran (1:1) (500 mL) under nitrogen-atmosphere was added palladium on carbon (785 mg). The mixture was put under a hydrogen atmosphere (balloon) and stirred at room temperature. After 45 minutes the reaction mixture was filtered through celite and concentrated under vacuum and purified by flash chromatography (dichloromethane/methanol 99:1 to 95:5) to give the title compound (1.52 g).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:21][C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: NC1CCCCC1
Product: c1ccc2c(c1)nc(NC1CCCCC1)c1nccn12

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with cyclohexylamine, according to a procedure that is similar to that followed in example 3, there is obtained 4-cyclohexylaminoimidazo[1,2-a]quinoxaline. m.p. (DSC)=94.0° C. (onset); IR (KBr): 3227, 2924, 1560 cm-1 ; 1H-NMR (CDCl3): δ7.85 (1H,d, J=2 Hz), 7.8÷7.4 (3H,m), 7.4÷7.1 (2H,m), 6.0 (1H,d), 4.2 (1H,m), 2.3÷1.95 (3H,m), 1.95÷0.9 (6H,m); UV (EtOH): λmax =225, 242, 283, 294, 316, 330 nm. Elementary analysis for C16H18N4 (m.w.266.35): calcd. C 72.15, H 6.81, N 21.03%; found C 72.25, H 7.04, N 21.19%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:4][CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[C:26]([Sn](CCCC)(CCCC)CCCC)=[N:25]1>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=2)[C:26]([C:2]2[N:7]=[C:6]3[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]3=[N:4][CH:3]=2)=[N:25]1
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(F)(F)F)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(C(F)(F)F)cc34)nc12
Temperature: 80 °C
Yield: 70.6 %

Procedure:
To a solution of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (300 mg, 0.81 mmol) and 1-methyl-3-(tributylstannyl)-5-(trifluoromethyl)-1H-indazole (396 mg, 0.89 mmol) in DMF (10 mL) were added CuI (30 mg, 0.16 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol), the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling, water (50 mL) was added to the mixture and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was triturated with petroleum ether (2 mL) then decanted and dried to give methyl 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (280 mg, 70.7%) as an orange solid. LCMS: (M+H)+=490.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH:12]1[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[NH2:18][C:17]1[CH:12]=[CH:13][C:14]([O:19][C:5]2[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:15][CH:16]=1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1ccc(Oc2ncc(Cl)cn2)cc1

Procedure:
A mixture of 5-chloro-2-methylsulfonylpyrimidine* (94 g), p-aminophenol (53 g), potassium carbonate (50 g) and methyl ethyl ketone (350 ml) was heated under reflux for a period of 3 hours. The mixture was filtered and the residue was washed with 2×200 ml of boiling acetone. Evaporation of the combined organic liquors left an orange oil. This readily dissolved in benzene and on standing the product crystallised and was collected by filtration and dried. Yield 80 g (74%), m.p. 125° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10]O.P(Br)(Br)[Br:13].O>C(OCC)C>[Br:13][CH2:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: OCCCc1ccccc1F
Reactant: BrP(Br)Br
Solvent: CCOCC
Solvent: O
Product: Fc1ccccc1CCCBr

Procedure:
Compound 22-1 (8.68 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (6.35 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3 hr. To the reaction mixture was slowly added water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (5.00 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].[C:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:24])[CH3:23]>C(Cl)Cl.CN(C=O)C>[C:22]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:11])=[CH:30][CH:29]=1)(=[O:24])[CH3:23]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: CC(=O)OCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCCc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
To a solution of commercially available 5-bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) in 30 mL of anhydrous DCM was added a catalytic amount of DMF followed by oxalyl chloride (1.95 mL, 22.3 mmol) and stirred for 2 h at room temperature. A mixture of aluminum trichloride (3.68 g, 27.6 mmol) and phenethyl acetate (3.38 mL, 21.23 mmol) in 15 mL DCM was cooled in an ice-bath and the acid chloride was transferred to it using a canula. The mixture was stirred at room temperature for 4 h. The mixture was poured into 100 mL of ice-cold water and the organic layer was isolated. The aqueous solution was extracted with 25 mL DCM. The combined organic solution was washed with brine (25 mL) and dried (Na2SO4), filtered and evaporated. Purification on silica gel using an ISCO column with 5:1 hexane:EtOAc followed by 10:1 hexane:EtOAc gave intermediate BF (2.1 g, yield 26%). 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J=2.4 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.59 (d, J=2.7 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 4.31 (t, J=6.9, 6.6 Hz, 2H), 3.01 (t, J=6.9, 6.6 Hz, 2H), 2.04 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[C:14](ON1C(=O)CCC1=O)([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15].Cl>O.O1CCOCC1>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@@H:2]([C:6]([OH:8])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: C[C@@H](O)[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H](O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
All Fmoc amino acids were synthesized from the corresponding free amino acids by the following general procedure. To a solution of D-allo-Thr (25) (1.62 g, 13.6 mmol) and NaHCO3 (3.4 g, 41 mmol) in H2O (60 mL) was added a solution of Fmoc-OSu (4.58 g, 13.6 mmol) in dioxane (60 mL) and the turbid reaction mixture stirred at RT overnight. The mixture was then diluted with H2O, acidified to pH≤4 by addition of 37% HCl and extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with saturated NaCl (2×100 mL), dried (MgSO4) and taken to dryness by rotary evaporation to give a colorless oil which was crystallized from ethyl acetate/hexane, yielding Fmoc-D-allo-Thr (26) as white crystals (3.7 g, 80%), mp 152°-153° C. Anal. (C19H19NO5) C, H, N.
Reaction SMILES: [CH3:1][C:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH2:3].[PH2:9]([OH:11])=[O:10]>>[CH3:3][CH:2]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:1][PH:9](=[O:10])[OH:11]
Reactant: C=C(C)CC(C)(C)C
Reactant: O=[PH2]O
Product: CC(C[PH](=O)O)CC(C)(C)C

Procedure:
A mixture of diisobutylene (112 g, 1 mol) and hypophosphorous acid (30%, 230 mL) are reacted in the presence of t-butyfperbenzoate. After aqueous work up, 45 g of oily product are obtained. It is characterized by 1H NMR and 31P NMR which shows formation of product (64% pure).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C(N(CC)CC)C.[OH:17][CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C(O)C>[F:9][C:2]([F:1])([F:8])[C:3]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([OH:17])[CH2:19]1)=[O:5]
Reactant: OC1CCCNC1
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(N1CCCC(O)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Ethyl trifluoroacetate (1.31 mL, 11.0 mmol) and triethylamine (1.68 mL, 12.0 mmol) were added to 3-hydroxypiperidine (1.01 g, 10.0 mmol) in ethanol (10 mL). The mixture was stirred at room temperature for 8 hours. Subsequently, the reaction mixture was concentrated and water was added. The mixture was then extracted with ethyl acetate and the extract washed with brine and dried over magnesium sulfate. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 1.68 g (85%) of the desired compound as a colorless oil.
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.ClC1[S:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:29][N:30]=1>>[CH3:22][C:14]1([CH3:21])[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:12]([C@H:10]2[CH2:11][C@H:8]([NH:7][C:6]3[S:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][N:30]=3)[CH2:9]2)[C:13]1=[O:23]
Reactant: Clc1ncc(-c2ccccc2)s1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cccnc32)C1
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3ncc(-c4ccccc4)s3)C2)c2ncccc21

Procedure:
3,3-Dimethyl-1-(trans-3-((5-phenylthiazol-2-yl)amino)cyclobutyl)-1H-pyrrolo[2,3-b]pyridin-2(3h)-one was prepared by Method B7 using starting materials 1-(trans-3-aminocyclobutyl)-3,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one hydrochloride (intermediate 26, 0.100 g, 0.329 mmol) and 2-chloro-5-phenylthiazole (0.0643 g, 0.329 mmol) at 120° C. for 96 h. M+1: 391.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 6 H) 2.31-2.40 (m, 2 H) 3.21-3.31 (m, 2 H) 4.34-4.43 (m, 1 H) 5.17 (quin, J=8.46 Hz, 1 H) 7.08 (dd, J=7.24, 5.09 Hz, 1 H) 7.17-7.22 (m, 1 H) 7.35 (br. t, J=7.70, 7.70 Hz, 2 H) 7.45 (br. d, J=7.20 Hz, 2 H) 7.52 (s, 1 H) 7.76 (dd, J=7.24, 1.56 Hz, 1 H) 8.21 (dd, J=5.28, 1.56 Hz, 1 H) 8.30 (d, J=6.20 Hz, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.Cl>>[N:24]1([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2/[CH:13]=[CH:14]/[C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Agent: Cl
Product: C(=C/c1ccccc1OCCCCn1ccnc1)\c1nc2ccccc2o1
Yield: 40 %

Procedure:
The title compound was prepared in accordance with Example 18 starting with (D) of Example 18 (2.5 g, 7.6 mmol) and using imidazole in place of dibutylamine to produce 1.1 g (40% yield) of the title compound as the HCl salt, mp 204°-205° C. IR(KBr): 3400, 1600 cm-1. MS: 360(MH+). 1H NMR (CD3OD): δ 9.02 (s, 1H), 7.89-6.89 (m, 12H), 4.38 (t, J=5.3 Hz, 2H), 4.08 (t, J=5.4 Hz, 2H), 1.97 (m, 4H).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:9]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)=O.Cl>CO>[OH:4][CH2:5][CH2:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:9]=1[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(-c2noc(CCO)c2-c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
Sodium borohydride (5.9 g) was added to a suspension of 5 g of 5-methoxycarbonylmethyl-3,4-bis(4-methoxyphenyl)isoxazole in 20 ml of methanol, and the resulting mixture was stirred for 1 hour with ice cooling. The reaction mixture was made acidic by portionwise addition of 1N hydrochloric acid and then extracted with 80 ml of ethyl acetate. The extract was washed with 20 ml of 1N hydrochloric acid and 20 ml of water in that order, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4.5 g (yield 98%) of 5-(2-hydroxyethyl)-3,4-bis(4-methoxyphenyl)isoxazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1>>[CH3:16][O:17][CH2:18][C@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:15]
Reactant: COC[C@H]1CCCN1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: COC[C@H]1CCCN1C(=O)c1cnoc1-c1ccc(C)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and (R)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (5.9 mg). Calcd for C17H20N2O3: 300.1474, found 300.1478.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8](F)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16].[Br:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:23]2[CH:24]=[C:20]([Br:19])[N:21]=[CH:22]2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: Brc1c[nH]cn1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-n2cnc(Br)c2)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 95.2 %

Procedure:
In a similar way as in the previous example a solution of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1 g, 3.73 mmol), 4-bromo-imidazole (0.68 g, 4.5 mmol) and N-ethyl-diisopropyl-amine (2.62 ml, 14.9 mmol) in 10 ml of dioxane is heated to reflux for 16 hours. After a similar workup procedure 1.4 g (3.55 mmol, 95%) of 5-(4-bromo-imidazol-1-yl)-2-nitro-4-trifluoromethyl-benzoic acid methyl ester are obtained, m.p. 90° C., ES-MS: m/z 395 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.CN1CCOCC1.ClC(OCC)=O.Cl.[CH3:25][O:26][NH2:27]>O1CCCC1>[CH3:25][O:26][NH:27][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CON
Reactant: O=C(O)Cn1nnnc1S
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CONC(=O)Cn1nnnc1S
Reaction time: 1 h

Procedure:
To a solution cooled at -28° C. to -35° C. of 5-mercapto-1H-tetrazole-1-acetic acid (0.8 g) in tetrahydrofuran (40 ml) are added N-methylmorpholine (1.26 ml) and ethyl chloroformate (0.62 ml). After stirring for 1 hour, a solution of methoxyamine hydrochloride (0.34 g) and N-methylmorpholine (0.71 ml) in tetrahydrofuran (11 ml) is added to the mixture at -50° C. After 2 hours' stirring at about -30° C., the mixture is concentrated under reduced pressure, and the resultant mixture is diluted with water (50 ml) and ethyl acetate (50 ml). The mixture is acidified to pH 2 with hydrochloric acid and extracted with ethyl acetate. The extract solution is dried over magnesium sulfate and concentrated to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester. mp. 165°-167° C. (decomp.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH2:26][SH:27])[CH:23]=[CH:24][CH:25]=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:27][CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)=[CH:11][CH:12]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Reactant: FC(F)(F)c1cccc(CS)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and (3-trifluoromethyl-phenyl)-methanethiol.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].[CH3:13][S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]1[CH:31]=[C:30]([O:32][CH:33]3CCNC[CH2:34]3)[N:29]=[CH:28][N:27]=1)[CH2:21][CH2:20]2)(=[O:16])=[O:15]>C1COCC1>[N:8]1([C:1]([N:3]2[CH2:4][CH2:34][CH:33]([O:32][C:30]3[N:29]=[CH:28][N:27]=[C:26]([N:22]4[C:23]5[C:19](=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:25][CH:24]=5)[CH2:20][CH2:21]4)[CH:31]=3)[CH2:6][CH2:7]2)=[O:2])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
1,1′-carbonyldiimidazole (67.0 mg, 0.413 mmol) was added to a THF (2.06 mL) solution of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline (103 mg, 0.275 mmol) produced in Reference Example 28, and the mixture was stirred at room temperature for 1 hour. From the reaction solution, the solvent was distilled off under reduced pressure. To the residue, water was added, and the mixture was stirred. The deposit was collected by filtration and washed with water to obtain the title compound as white powder (105 mg, yield: 82%).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:11]=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[F:1][C:2]1[C:3]([CH2:11][OH:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc2c(cc1F)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1cc2c(cc1F)OCO2
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of 6-fluoro-benzo[1,3]dioxole-5-carbaldehyde (700 mg, 4.2 mmol) in MeOH (50 mL) was added NaBH4 (320 mg, 8.4 mmol) in portions at 0° C. The mixture was stirred at this temperature for 30 min and was then concentrated in vacuo to give a residue. The residue was dissolved in EtOAc and the organic layer was washed with water, dried over Na2SO4, and concentrated in vacuo to afford (6-fluoro-benzo[1,3]dioxol-5-yl)-methanol (650 mg, 92%), which was directly used in the next step.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10]([Br:28])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c(-c2cccc3c2c(=O)ccn3Cc2ccccc2)c(C)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-c2cccc3c2c(=O)c(Br)cn3Cc2ccccc2)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
1-Benzyl-5-mesitylquinolin-4(1H)-one (0.52 g, 1.5 mmol) was dissolved in N,N-dimethylformamide (10 mL) and cooled to 0° C. N-bromosuccinimide (0.27 g, 1.5 mmol) was added and the reaction stirred for 1 hr. The reaction was quenched with water (100 mL) and the precipitate was collected by vacuum filtration. 0.57 g (90%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[Br:19]N1C(C)(C)C(=O)N(Br)C1=O>O>[Br:19][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 184 %

Procedure:
A 5000 mL, three neck round bottom flask (RBF) equipped with an overhead stirrer was charged with 2-methyl-3-nitro benzoic acid (150.0 g, 0.82 mol) and concentrated H2SO4 (600 mL). To this solution was added 1,3-dibromo-5,5 dimethylhydantoin (130.7 g, 0.455 mol) over ten minutes with vigorous stirring. The reaction was vigorously stirred at ambient temperature for 5 hours. The reaction mixture was then added to water (4000 mL), and the mixture was cooled in an ice bath over 30 minutes. This mixture was then filtered, and the solids were washed twice with water and further dried under vacuum to yield 217.7 g (99.8%) of an off-white solid. 1H NMR (CDCl3) δ 8.18 (s, 1H), 7.95 (s, 1H), 2.59 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.Br[CH2:37][CH2:38]F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([CH2:37][CH3:38])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: FCCBr
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1[C@H](C)CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@@H]1C
Temperature: 120 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
A mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol), 1-Bromo-2-fluoro-ethane (65 mg, 0.45 mmol) and Cesium carbonate (200 mg, 0.6 mmol) in N,N-Dimethyl-formamide (2 mL) was stirred at 120° C. for 1 h under the irradiation of microwave. The reaction mixture was filtered over celite and purified by pre-TLC (Hexanes/EtOAc=1:1) to afford 314 Yield=56%. 1H NMR (CDCl3, 400 MHz): δ8.02 (s, 1H), 7.49-7.46 (m, 1H), 7.11-6.97 (m, 4H), 6.45 (d, J=8.8 Hz, 1H), 4.18 (t, J=4.8 Hz, 2H), 3.86 (d, J=11.6 Hz, 2H), 3.07 (t, J=4.8 Hz, 2H), 2.96 (q, J1=7.2 Hz, J2=5.2 Hz, 2H), 2.64-2.51 (m, 4H), 1.13 (d, J=6.0 Hz, 6H), 0.88-0.81 (m, 3H). ESI− MS: m/z=523 [M+H+]