Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].O>CS(C)=O>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=Cc1ccc(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)N1CCN(c2ccc(C=O)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 4-fluoro-2-nitrobenzaldehyde (0.20 g, 1.2 mmol) in DMSO (3.5 mL) was added with 1-methanesulfonylpiperazine (0.71 g, 3.5 mmol), followed by stirring at 100° C. for 1 hour. The reaction mixture was added with water and the organic layer was extracted with hexane/ethyl acetate (4/1) to remove impurities. The aqueous layer was extracted with ethyl acetate and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain 4-(4-methanesulfonylpiperazin-1-yl)-2-nitrobenzaldehyde (0.36 g,
Reaction SMILES: Br[C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8](C(C(OCC)=O)=O)[CH:7]([CH:19]([C:21](OC)=O)C)[CH2:6][CH2:5]2.F[B-](F)(F)F.[O:30]=[N+]=O.[N+]([O-])([O-])=O.[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.C(Cl)(Cl)Cl>[C:19]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=1)(=[O:30])[CH3:21]
Reactant: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1C(C)C(=O)OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc2ccccc2n1

Procedure:
The title compound was prepared by the route outlined in Example 22-6 to 7 starting with 6-bromo-N-ethoxalyl-2-(1-methoxycarbonylethyl)tetrahydroquinoline (less polar). In nitration step of Example 22-6, conditions of nitronium tetrafluoroborate in dichloromethane at room temperature were employed instead of those of refluxing ammonium nitrate-trifluoroacetic anhydride in chloroform: mp 242° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (s, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 4.93 (bd, 1H, J=10 Hz), 3.40 (s, 3H), 2.89 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.80 (dm, 1H, J=17.1 Hz), 2.60 (qd, 1H, J=7, 10 Hz), 2.23 (dm, 1H, J=13.5 Hz), 1.72~1.91 (m, 1H), 1.11 (d, 3H, J=7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:22]([O-])=O)=[C:6]([CH:21]=1)/[CH:7]=[N:8]/[C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=1[F:20].P(OCC)(OCC)(OCC)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:7][N:8]([C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]=3[F:20])[N:22]=2)[CH:21]=1
Reactant: CCOC(=O)c1ccc(/N=C/c2cc(Br)ccc2[N+](=O)[O-])c(F)c1
Solvent: CCOP(=O)(OCC)OCC
Product: CCOC(=O)c1ccc(-n2cc3cc(Br)ccc3n2)c(F)c1

Procedure:
A mixture of (E)-ethyl 4-(5-bromo-2-nitrobenzylideneamino)-3-fluorobenzoate (432 mg, 1.09 mmol) and triethyl phosphate (1.5 mL, 9.0 mmol) was irradiated in a microwave instrument at 150° C. for 1.5 h. The cooled reaction mixture was purified by silica gel column chromatography (hexane/ethyl acetate) to give ethyl 4-(5-bromo-2H-indazol-2-yl)-3-fluorobenzoate as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=2.0 Hz, 1H), 8.25 (t, J=7.8 Hz, 1H), 8.02-7.90 (m, 2H), 7.89 (d, J=0.8 Hz, 1H), 7.66 (d, J=9.2 Hz, 1H), 7.40 (dd, J=1.6, 9.2 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −123.4. MS (ESI) m/z: Calculated: 363.18; Observed: 363.2 (M++1).
Reaction SMILES: [F:1][C:2]([F:17])([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)[C:3]([NH:5][NH2:6])=O.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>Cl.CO>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]2[N:5]([C:3]([C:2]([F:17])([F:1])[C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[N:13]=[CH:12][CH:11]=[CH:10]4)=[N:20][N:21]=2)[N:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Agent: Cl
Solvent: CO
Product: FC(F)(c1ccc2ncccc2c1)c1nnc2ccc(Cl)nn12
Temperature: 90 °C

Procedure:
A suspension of 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide (2000 mg, 8432 μmol) and 3,6-dichloropyridazine (3768 mg, 25295 μmol) in 1.25 M HCl in MeOH (20 mL) was heated to 90° C. with microwaves for 50 min. The solvents were then removed under reduced pressure and residue partitioned between 9:1 CHCl3/IPA (60 mL) and 1 M NaOH (20 mL). The organic phase then dried over MgSO4, concentrated, then purified on silica (120 g) eluting with 1>2.5% of 2 M NH3 in MeOH/DCM to provide product isolated as a dark tan solid. MS (ESI pos. ion) m/z: 332 (MH+). Calc'd exact mass for C15H8ClF2N5: 331.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=1>C(OCCO)C>[C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[O:31])=[CH:28][CH:27]=1)=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2)#[N:17]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc(C(N)=O)cc3)c2cc1OC
Yield: 73.4 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 163.4 mg (1.2 mmol) of 4-amino-benzamide to give 255.7 mg (73.4%) of the product as a light yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 348.9.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[OH:13][C@H:14]([CH2:20][CH2:21][CH3:22])[CH2:15][C:16]([O:18][CH3:19])=[O:17].Br[CH2:24][C:25]([CH3:27])=[CH2:26]>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:26][C:25](=[CH2:24])[CH2:27][C@H:15]([C@H:14]([OH:13])[CH2:20][CH2:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17]
Reactant: C=C(C)CBr
Reactant: CCC[C@@H](O)CC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=C(C)C[C@@H](C(=O)OC)[C@H](O)CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a stirred solution of diisopropylamine (19.4 mL, 139 mmol) in 70 mL of THF at −78° C. is added dropwise 86.6 mL (139 mmol) of 1.6 M n-butyllithium in hexanes over 15 min. After 1 h, a solution of methyl (3R)-3-hydroxyhexanoate (9.2 g, 63 mmol) in 10 mL of THF is added dropwise over several minutes. The reaction mixture is stirred 1 h, then treated with a solution of 3-bromo-2-methyl-1-propene (7.6 mL, 75.6 mmol) in 10 mL of HMPA and is allowed to stand at −20° C. overnight. The reaction mixture is poured into ice-cold 1 N hydrochloric acid (300 mL) and extracted with two 200-mL portions of EtOAc. The combined organic layers are washed with two 100-mL portions of saturated aqueous sodium chloride, dried over sodium sulfate, and filtered. The solvents are removed under reduced pressure. Purification by flash chromatography on silica gel eluting with 10% EtOAc-hexanes affords 7 g (55%) of methyl (2R,3R)-2-(2-methyl-2-propene-1-yl)-3-hydroxyhexanoate as an oil.
Reaction SMILES: [C:1]([F:8])([F:7])([F:6])[C:2](Cl)([Cl:4])[F:3].Cl.[CH2:10]([O:12]CC)C>>[C:1]([C:2]([CH2:10][OH:12])([F:3])[Cl:4])([F:8])([F:7])[F:6]
Reactant: CCOCC
Reactant: FC(F)(F)C(F)(Cl)Cl
Agent: Cl
Product: OCC(F)(Cl)C(F)(F)F

Procedure:
The reaction product of CFC-114a, an aldehyde and a reactive metal may be neutralized by diluting the reaction product mixture with a mixture of a solvent, ice, and an aqueous solution of an acid. The solvent can be any commonly used organic solvent, such as diethyl ether. The aqueous solution of an acid may be an aqueous solution of a common mineral acid, such as hydrochloric acid. After stirring the resulting mixture for a period of time, the layer comprising the organic solvent is separated. The organic solvent layer can be subsequently washed with a dilute aqueous solution of an acid, followed by a brine solution. The organic layer is then dried. The drying is accomplished by stirring the organic layer over an anhydrous salt, such as anhydrous magnesium sulfate or anhydrous sodium sulfate. The organic solvent may then be evaporated to afford CF3CClFCH2OH.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27](O)=[O:28]>>[CH3:24][C:25]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1ccc(C)c(C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cc(C)ccc2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2,5-Dimethyl-benzoic acid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6](Br)[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[CH:6][C:5]3[NH:14][CH2:15][CH2:16][CH2:17][C:4]=3[C:3]1=2
Reactant: CC1CC(=O)Nc2nc(Br)c3ncccc3c21
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CC(=O)Nc2ncc3c(c21)CCCN3
Yield: 64.4 %

Procedure:
1.5 g (0.005 mol) of 1-methyl-6-bromo-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one are hydrogenated for 24 hours at room temperature and atmospheric pressure in a mixture of 100 ml of ethanol and 100 ml of glacial acetic acid with Pd/C (0.3 g/10%) with addition of 0.4 g (0.005 mol) of Na-acetate. The catalyst is removed by filtration under suction, the filtrate is concentrated, and the residue is recrystallized from ethanol. 0.7 g (64.4% of theory) of 1-methyl-1,2,7,8,9,10-hexahydropyrido[2,3-c][1,8]naphthyridin-3(4H)one is obtained.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:16]=[C:15]1[CH2:27]Cl)[CH:11]([CH3:13])[CH3:12])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].CC(C)([O-])C.[K+]>O1CCCC1.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CO>[CH:11]([C@@H:10]1[N:14]2[C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:16]=[C:15]2[CH2:27][O:8][CH2:9]1)([CH3:13])[CH3:12]
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)n1c(CCl)nc2cnc3ccccc3c21
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H]1COCc2nc3cnc4ccccc4c3n21
Temperature: -78 °C
Yield: 68.7 %

Procedure:
1-[(1S)-1-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-methylpropyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline (4.85 g, 11.6 mmol) was dissolved in 110 mL of tetrahydrofuran (THF) and the solution was cooled to −78° C. under N2. A 1.0 M solution of tetrabutylammonium fluoride in THF (12.8 mL) was added and the reaction mixture was allowed to warm to 0° C. overnight. The reaction mixture was then treated with 50 mL of saturated sodium bicarbonate solution and 100 mL of CHCl3. The layers were separated and the organic portion was washed with H2O (50 mL) and brine (4×25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow syrup. The syrup was concentrated from toluene (3×) to give a pale yellow foam. This material was dissolved in 100 mL of anhydrous THF and the solution was cooled 0° C. and stirred under N2. Solid potassium tert-butoxide was then added and the reaction mixture was allowed to warm to ambient overnight. The THF was then removed under reduced pressure and the resulting material was partitioned between 100 mL of CHCl3 and 100 mL of saturated sodium bicarbonate solution. The layers were separated and the organic portion was washed with H2O and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced to give brown foam. Chromatography (SiO2, 0%-50% 80:18:2 CHCl3/methanol/concentrated NH4OH(CMA) in CHCl3) gave (11S)-11-isopropyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (2.13 g) as a light yellow solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[C:27](B(O)O)[C:26]([F:32])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[Br:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]([CH3:20])([CH3:19])[O:10][C:9]3=[O:21])=[CH:4][CH:3]=2)[C:26]([F:32])=[CH:25][N:24]=1
Reactant: CC1(C)OC(=O)N(c2ccc(I)cc2)[C@H]1c1ccccc1
Reactant: OB(O)c1cc(Br)ncc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(-c3cc(Br)ncc3F)cc2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A microwave vial was charged with (S)-3-(4-iodophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (Intermediate C)(0.200 g, 0.509 mmol), 2-bromo-5-fluoropyridine-4-boronic acid (commercially available from Combi Blocks, San Diego, Calif.) (0.224 g, 1.017 mmol), sodium carbonate (0.162 g, 1.526 mmol), dioxane (3.0 mL), and water (0.60 mL). Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (DCM adduct)(0.042 g, 0.051 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture was then stirred at 100° C. in the microwave for 1 hour. Additional 2-bromo-5-fluoropyridine-4-boronic acid (0.224 g, 1.017 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) DCM adduct (0.042 g, 0.051 mmol) were added, the system was purged with argon, and the tube was sealed. The resulting mixture was then stirred at 100° C. in a microwave for 1 hour. Additional 2-bromo-5-fluoropyridine-4-boronic acid (0.224 g, 1.017 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) DCM adduct (0.042 g, 0.051 mmol) were added, the system was purged with argon, and the tube was sealed. The resulting mixture was stirred at 100° C. in a microwave for 1 hour. The reaction mixture was then filtered through Celite® brand filter aid and the filtrate was concentrated to afford a dark brown oil. The oil thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% EtOAc-hexane) to afford (S)-3-(4-(2-bromo-5-fluoropyridin-4-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.062 g, 0.140 mmol, 28% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (s, 3H), 1.65 (s, 3H), 5.53 (s, 1H), 7.17-7.49 (m, 5H), 7.59-7.73 (m, 4H), 7.83 (d, J=5.97 Hz, 1H), 8.48 (d, J=2.35 Hz, 1H). m/z (ESI) 441 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:11])[C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO.O>[F:1][CH:2]([F:11])[C@@H:3]1[CH2:6][CH2:5][C@H:4]1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)[C@@H]1CC[C@H]1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CC[C@H]1C(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.6 %

Procedure:
To a solution of Intermediate 238B (200 mg, 1.218 mmol) in THF (1 mL), MeOH (0.3 mL) and water (1 mL) was added NaOH (97 mg, 2.437 mmol) and the resulting solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the residue was added water and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to 4 using an aqueous solution of 1.5 N HCl and the compounds were extracted with EtOAc (3×10 mL). The combined organic layer was dried on Na2SO4, filtered and filtrate evaporated under reduced pressure to afford Intermediate 238C as a viscous liquid (120 mg, 65.6% yield). The crude product was taken further without any purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.24 (bs, 1H), 5.87-6.21 (m, 1H), 3.03 (q, J=8.85 Hz, 1H), 2.89 (dd, J=8.82, 4.05 Hz, 1H) 1.94-2.14 (m, 2H) 1.79-1.94 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]([NH2:10])[CH2:8][S:7][C:6]=2[CH:11]=1.[C:12]([O:16][C:17]([NH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:18])[NH:19][C:20]1([C:23](=[O:24])[NH:10][CH:9]2[CH2:8][S:7][C:6]3[CH:11]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:22]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Reactant: NC1CSc2cc(Br)ccc21
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2CSc3cc(Br)ccc32)CC1

Procedure:
In analogy to the procedures described for the preparation of intermediates A-1 [B] and A-1 [C], and for the preparation of example 5, (rac)-6-bromo-2,3-dihydro-benzo[b]thiophen-3-ylamine (intermediate A-9 [A]) has been coupled with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid to give [1-((rac)-6-bromo-2,3-dihydro-benzo[b]thiophen-3-ylcarbamoyl)-cyclopropyl]-carbamic acid tert-butyl ester, which was then reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) and (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) to give {1-[(rac)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzo[b]thiophen-3-ylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester, which was then treated again with (1,1′-bis-diphenylphosphino)-ferrocene)palladium-(II)dichloride (1:1 complex with CH2Cl2) and 5-(2-bromo-4-chloro-6-fluoro-phenyl)-2-methyl-2H-tetrazole (intermediate B-3) to give the title compound as light yellow amorphous solid. MS: 545.2 (MH+, 1Cl).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:8](=[O:23])[CH:7]=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][C:7]1[C:8](=[O:23])[N:9]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=[O:17])[C:10]([CH3:12])=[CH:11][C:6]=1[O:5][CH2:4][C:3]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reaction time: 14 h
Yield: 74 %

Procedure:
3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (5.9 g, 15.2 mmol) (from step 3 above) was taken up in dichloromethane (25 ml). N-Bromosuccinimide was added and the reaction stirred for 14 hours. The dichloromethane was removed in vacuo and the residue was taken up in acetonitrile. The precipitate was collected on a filter pad and rinsed with acetonitrile to yield the desired product as a white solid (5.2 g, 74%). 1H NMR (300 MHz, CD3OD) δ 7.87 (dd, J=7.85, 1.61,Hz, 1H), 7.82 (d, J=1.81 Hz, 1H), 7.69 (app q, J=8.06 Hz 1H), 7.57 (d, J=8.06 Hz, 1H), 7.09 (dt, J=8.66, 2.22 Hz, 1H), 6.70 (s, 1H), 5.40 (s, 2H), 2.14 (s, 3H), 2.02 (s, 3H); ES MS m/z 464 (M+H). ES-HRMS m/z 464.0275 (M+H calcd for C21H17BrF2NO4 requires 464.0304).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:2]([N:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:11]1[CH:13]=[CH:14][C:8]([Br:7])=[C:9]([Cl:15])[CH:10]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCN(CCCCC)c1ccc(Br)c(Cl)c1
Yield: 106.4 %

Procedure:
1-Bromopentane (0.42 mL, 3.4 mmol) was added to a mixture of 4-bromo-3-chloroaniline (200 mg, 0.9 mmol) and potassium carbonate (199 mg, 1.4 mmol) in DMF (20 mL) and the reaction was heated to 13 0˜˜C overnight. The mixture was cooled, diluted with water (20 mL) and extracted with petroleum ether (3×25mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash column chromatography using 9:1 petroleum ether:ethyl acetate as eluent to give N,N-Dipentyl-4-bromo-3-chloroaniline (1) (332 mg, 68%). 1HNMR (CDCI3) 67.02 (d, IH, ArH); 3.12 (t, 4H, 2×NCH2); 0.95 (t, 6H, 2×CH3). MS; 347 (M+H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[Br:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>C(O)C>[Br:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][C:5]([NH:4][C:1](=[O:3])[CH3:2])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: BrCCCc1ccccc1CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(Cc1ccccc1CCCBr)(NC(C)=O)C(=O)OCC

Procedure:
To a stirred solution of 0.61 g (27 mmol) Na in 40 mL of dry ethanol was added portionwise 5.86 g (27 mmol) of solid diethyl acetamidomalonate. This mixture was stirred at reflux under nitrogen for 2 h, then cooled to 0°-10° C. on an ice bath. Then, 8.0 g (27 mmol) of 2-(3-bromopropyl)benzyl bromide in 40 mL of dry ethanol was rapidly added. The reaction mixture was stirred for 2 h at 0°-10° C., then 24 h at room temperature. The precipitated inorganic salt was removed by filtration, and was washed with 20 mL of ethanol and discarded. The combined solvents were removed under reduced pressure yielding an orange colored oil. This oil was chromatographed on a column of silica gel with hexane-ethyl acetate (3:1) as eluant. The combined fractions were concentrated under reduced pressure to yield an oil which solidified upon standing, yield 9.5 g (82%), mp 73°-74.5° C. IR(nujol): 1745, 1648 cm-1 (C=O). 1H NMR(D2O) δ 1.3 (t, 6H); 1.9-2.4 (m, 5H); 2.7 (t, 2H); 3.4 (t, 2H); 3.75 (5, 2); 4.3 (q, 4); 6.6 (s, 1H); 7.0-7.3 (m, 4H). Anal Calcd. for C19H26NO3Br: C, 53.28; H, 6.12; N, 3.27; Br, 18.66. Found: C, 53.33; H, 6.13; N, 3.23; Br, 18.67.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][N:6]2[CH2:9][CH2:10][NH:11][C:5]=12)([O-])=O.[S:12](=[O:16])(=[O:15])([OH:14])[OH:13]>[Pd].O>[S:12](=[O:14])(=[O:13])([OH:16])[OH:15].[NH2:1][C:4]1[CH:8]=[N:7][N:6]2[CH2:9][CH2:10][NH:11][C:5]=12
Reactant: O=[N+]([O-])c1cnn2c1NCC2
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cnn2c1NCC2

Procedure:
A suspension of 7-nitro-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (97 g) in a mixed solvent of sulfuric acid (34 ml) and water (2000 ml) was treated with 10% palladium on carbon (10 g) under a hydrogen atmosphere at room temperature for 4 days. After the catalyst was filtered off, the filtrate was concentrated in vacuo. The residue was triturated with methanol and dried in vacuo to give 7-amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole sulfuric acid salt (90.2 g) as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[NH:26][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: COc1cccc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (100 mg, 0.385 mmol) and m-anisidine (43 μl, 0.385 mmol) similar to Example 13 and isolated as a pale yellow solid (38 mg, 29%). 1H NMR (Acetone-d6): 9.61 (d, J=2.4 Hz, 1H), 9.42 (s, 1H), 8.76-8.70 (m, 2H), 7.57-7.53 (m, 2H), 7.39 (s, 1H), 7.36 (s, 1H), 7.15 (s, 1H), 6.79-6.75 (m, 1H), 3.87 (s, 3H).