Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@H:9]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])C1C=CC=CC=1>CO.[C].[Pd]>[NH2:8][C@H:9]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CCCC[C@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCC[C@@H](N)CC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 1.15 g of tert-butyl (3R)-3-{benzyl[(1R)-1-phenylethyl]amino}heptanoate in 30 ml of methanol was added 450 mg of 10% palladium-carbon, followed by stirring overnight under a hydrogen atmosphere at 4 atm. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 460 mg of tert-butyl (3R)-3-aminoheptanoate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18](=S)[CH3:19])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([NH:27][NH2:28])=O.C(O)CCC>ClCCl.[Hg]=O>[Cl:1][C:2]1[C:3]([N:17]2[C:18]([CH3:19])=[N:28][N:27]=[C:25]2[C:24]2[CH:29]=[CH:30][CH:31]=[C:22]([Cl:21])[CH:23]=2)=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([O:15][CH3:16])=[N:5]2
Reactant: NNC(=O)c1cccc(Cl)c1
Reactant: COc1nc2cc(Cl)c(Cl)c(NC(C)=S)c2nc1OC
Agent: O=[Hg]
Solvent: ClCCl
Solvent: CCCCO
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(C)nnc3-c3cccc(Cl)c3)c2nc1OC
Yield: 35.4 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-thioacetamidoquinoxaline (250 mg, 0.753 mmol), 3-chlorobenzhydrazide (167 mg, 0.978 mmol), mercury(II) oxide (163 mg, 0.753 mmol), powdered 4 Å molecular sieves (175 mg) and n-butanol (7 mL) was heated under reflux for 18 hours. After being cooled, the mixture was filtered through ARBOCEL (trade mark) filter aid and the residue washed with dichloromethane. The filtrate was concentrated under reduced pressure to afford a green solid which was dissolved in dichloromethane, washed twice with 2M aqueous hydrochloric acid solution followed by brine, then dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane:methanol (98:2, by volume) to give the title compound (120 mg, 35%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:48]([O:55][CH2:56][C:57]([C:60]1[N:64]=[C:63]([CH3:65])[O:62][N:61]=1)([NH2:59])[CH3:58])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:59][C:57]([C:60]3[N:64]=[C:63]([CH3:65])[O:62][N:61]=3)([CH3:58])[CH2:56][O:55][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)COCc2ccccc2)no1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(C(C)(COCc2ccccc2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c, 0.58 g, 2.22 mmol) in dry DMF (10 ml) was added triethylamine (270 mg, 371 μl, 2.66 mmol) and TBTU (713 mg, 2.22 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by addition of 1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine (example 112d, 577 mg, 2.33 mmole) and the reaction was then stirred at room temperature overnight. DMF was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate and the organic phase was collected. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (805 mg, 74%) as a light yellow oil. MS (ESI, m/z): 491.5 (M+H+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([CH:21]=O)[CH:15]=[CH:14]2.[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([N:8]=[CH:21][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc2cc(C=NCc3ccccc3)ccc2c1
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A solution of benzylamine (0.57 mL, 5.37 mmol) in 5 mL of methylene chloride was added dropwise under nitrogen over 5 minutes to a mixture of 6-methoxy-naphthalene-2-carbaldehyde (1.0 g, 5.37 mmol) and anhydrous MgSO4 (3 g) in 20 mL of methylene chloride. The reaction stirred under nitrogen for 24 h (overnight). The MgSO4 was removed by filtration and the solvent removed under reduced pressure to give benzyl-(6-methoxy-naphthalen-2-ylmethylene)-amine (1.455 g, 98%) as an off-white solid, mp 115-117° C.
Reaction SMILES: [Si](O[CH2:9][CH:10]1[CH2:12][CH:11]1[CH:13]([CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)CC)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:43]1CC[CH2:45][CH2:44]1>>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[O:18][CH2:17][C:16]#[C:13][CH2:11][CH2:12][CH:10]1[CH2:9][CH:45]1[CH2:44][OH:43]
Reactant: CCC(CCOC1CCCCO1)C1CC1CO[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCC1CC1CCC#CCOC1CCCCO1
Reaction time: 0.5 h

Procedure:
The 2-(5-tetrahydropyranyloxy-3-pentyl)cyclopropylmethyl t-butyldimethylsilyl ether (3 g, 10 mmol) was dissolved in tetrahydrofuran (10 ml), and tetrabutyl ammonium fluoride (factor=1.0, 12 ml, 12 mmol) was added at 0° C. The mixture was stirred for 30 minutes. The solvent was distilled off, and the product was purified by silica gel column chromatography to obtain 2-(5-tetrahydropyranyloxy-3-pentynyl)cyclopropanemethanol (1.2 g)
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.O(CC([NH:17][C@@H:18]1[C:37](=[O:38])[N:20]2[C:21]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[C:22]([CH:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[CH2:23][S:24][C@H:19]12)=O)C1C=CC=CC=1.CN1CCOCC1.CO>ClCCl.O>[NH2:17][C@@H:18]1[C:37](=[O:38])[N:20]2[C:21]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[C:22]([CH:25]3[CH2:29][CH2:28][CH2:27][O:26]3)[CH2:23][S:24][C@H:19]12
Reactant: CC(C)(C)OC(=O)C1=C(C2CCCO2)CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)C1=C(C2CCCO2)CS[C@@H]2[C@H](N)C(=O)N12
Reaction time: 1 h
Yield: 26.9 %

Procedure:
Phosphorus pentachloride (1.538g, 7.5mmol) in dichloromethane (39ml) was added to t-butyl(6R,7R)-7-phenoxyacetamido-3-[(RS)-tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (2.267g, 4.9mmol) and N-methylmorpholine (1.1ml, 10mmol) in dichloromethane (20ml) at -25° C. The reaction was stirred at -10±5° C. for 0.75h then methanol (10ml) added all at once, stirred 0.75h then water (20ml) added and stirred vigorously for 1h. The dichloromethane was evaporated in vacuo, the aqueous residue washed with ether then adjusted to pH7 with ammonium hydroxide in the presence of ethyl acetate. The mixture was extracted twice with ethyl acetate, the extracts dried, concentrated and flash chromatographed on silica gel eluting with 30,40,50% ethyl acetate in hexane to give the more mobile (S)-diastereoisomer of the title compound (0.431g, 27%); (Found: M+, 326.1299. C15H22N2O4S requires M, 326.1300); vmax (CH2Cl2) 1777, 1716, 1158 and 1052cm-1 ; δH (CDCl3, 250MHz) 1.52 (9H,s), 1.55-1.8 (1H, m), 1.85-2.05 (4H, m), 2.3-2.45 (1H, m), 3.30 and 3.59 (2H, ABq, J18.4Hz), 3.8-4.0(2H,m), 4.75 (1H, d, J5.0Hz) and 4.9-5.0 (2H, m). Further elution with 60% ethyl acetate in hexane gave the more polar (R)-diastereoisomer (0.533g, 33%); (Found: M+ 326.1299. C15H22N2O4S requires M, 326.1300) vmax (CH2Cl2) 1776, 1721, 1158 and 1052cm-1 ; δH (CDCl3, 250MHz) 1.41 (2H, bs), 1.54 (9H, s), 1.6-1.85 (1H, m), 1.9-2.05 (2H, m), 2.05-2.2 (1H, m), 3.40 and 3.55 (2H, ABq, J17.8Hz) 3.8-4.0 (2H, m), 4.67 (1H, d, J5.0Hz), 4.93 (1H, d, J5.0Hz), 5.0-5.15 (1H, m).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[CH3:7][Si:8]([C:11]#[CH:12])([CH3:10])[CH3:9]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH3:7][Si:8]([CH3:10])([CH3:9])[C:11]#[C:12][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.4 %

Procedure:
Under a nitrogen atmosphere a solution of 12.0 grams (0.074 mole) of 2-bromothiophene, 9.0 grams (0.092 mole) of trimethylsilylacetylene, and 120 ml of triethylamine was stirred, and 0.52 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride and 0.28 gram (catalyst) of copper(I) iodide were added. Upon completion of addition, the reaction mixture was stirred at ambient temperature during an 18 hour period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether, and the solution was washed with two portions of an aqueous 10% ammonium chloride solution, one portion of water, and one portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10% methylene chloride in hexane. The appropriate fractions were combined and concentrated under reduced pressure yielding 11.0 grams of 2-trimethylsilylethynylthiophene. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH2:24]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH2:27][CH3:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:33][C:32]4[CH:34]=[CH:35][C:29]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:30][CH:31]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CCCCCc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCCCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 21.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-pentylaniline (55.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-pentylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.7 mg).
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])[CH3:3].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)(C)C>[CH3:10][C:9]1[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[CH:2]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)[CH3:3]
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)Br
Solvent: CC(C)O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)N1CCN(C)CC1
Yield: 32.4 %

Procedure:
A mixture of 5-(1-bromoethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.5 g) and N-methylpiperazine (1.13 g) in isopropylalcohol (15 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. The residue was chromatographed on allumina eluting with a mixture of ethyl acetate and n-hexane (1:20). The fractions containing the desired product were combined and concentrated in vacuo. The residue was crystallized from a mixture of n-hexane and diethyl ether to give 6-methyl-5-[1-(4-methylpiperazin-1-yl)ethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine (0.51 g).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]([CH:8]=O)=[CH:2]1.C([NH:13][CH:14](P(OC)(OC)=O)[C:15]([O:17][CH3:18])=[O:16])(=O)C.C1CCN2C(=NCCC2)CC1.S1C=CC=C1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:5]1[S:1][CH:2]=[C:3]2[C:4]=1[CH:6]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[N:13]=[CH:8]2
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Reactant: O=Cc1cscc1C=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccsc1
Product: COC(=O)c1cc2cscc2cn1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
3,4-Thiophene dicarboxaldehyde (1.0 g, 7.13 mmol) is dissolved in CH2Cl2 (40 ml) and chilled to 0° C. Methyl (acetylamino)(dimethoxyphosphoryl)acetate (1.88 g, 7.85 mmol) is dissolved in CH2Cl2 (30 ml) and combined with DBU (1.1 ml, 7.85 mmol). This solution is added dropwise to the chilled thiophene solution after stirring for 5 min. The reaction mixture is stirred at 0° C. for 1 h and then overnight at rt. The volatiles are removed in vacuo and the crude material is chromatographed over 68 g slurry-packed silica eluting with 70% EtOAc/hexane. The appropriate fractions are combined and concentrated to yield 2.09 g of the carbinol intermediate as a white foam. The intermediate is dissolved in CHCl3 (50 ml) and treated with DBU (1.32 ml, 8.8 mmol) and trifluoracetic anhydride (1.24 ml, 8.8 mmol) in a drop-wise fashion. The reaction is stirred overnight at rt and is then quenched with saturated NaHCO3 solution (50 ml). The layers are separated, and the aqueous layer is extracted with CHCl3 (2×50 ml). The combined organics are dried over MgSO4, filtered, and concentrated to a yellow oil. This oil is chromatographed over 50 g slurry-packed silica, eluting with 90% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 1.2 g (88%) of methyl thieno[3,4-c]pyridine-6-carboxylate as a yellow solid. MS (EI) m/z: 193 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[F:21][C:22]([F:31])([F:30])[C:23](I)([F:28])[C:24]([F:27])([F:26])[F:25]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.COC(C)(C)C>[F:28][C:23]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:24]([F:27])([F:26])[F:25])[C:22]([F:31])([F:30])[F:21]
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Reactant: Nc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: O
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.6 %

Procedure:
100 g (1.02 mol) of aniline, 230 g (1.12 mol) of 85% sodium hydrosulfite, and 35.1 g (0.100 mol) of tetrabutylammonium hydrogen sulfate were charged to a mixed solution of 1500 ml of t-butyl methyl ether and 1500 ml of water, and 94.7 g (1.12 mol) of sodium hydrogen carbonate was added thereto. 350 g (1.12 mol) of heptafluoroisopropyl iodide was added dropwise thereto at room temperature, followed by stirring at room temperature for 6 hours. After the liquid separation, the organic layer was washed with 1 M hydrochloric acid, water, and a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and 500 ml of ethyl acetate was charged thereto. 255 g (1.02 mol) of a 4 M hydrogen chloride/ethyl acetate solution was added dropwise thereto, followed by stirring at room temperature for 30 minutes and at 5° C. for 1 hour. The precipitated solid was separated by filtration, and the solid was charged to 1000 ml of ethyl acetate, adjusted to pH 8 to 9 by the addition of 1000 ml of a saturated aqueous sodium hydrogen carbonate solution at 20° C. or lower, and subjected to liquid separation. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to prepare 188 g (yield 71%) of a target compound.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH3:13].CN(C)C(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([Br:1])[N:3]=2)=[CH:18][CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(Nc2nc(Br)cn3ccnc23)cc1
Temperature: 160 °C

Procedure:
A mixture of 6,8-dibromoimidazo[1,2-a]pyrazine (0.18 mol), 4-aminobenzoic acid ethyl ester (2) (0.18 mol), and N,N-dimethylacetamide (30 mL) is heated at 160° C. for 30 min. The mixture is cooled to room temperature, treated with ethyl acetate (150 mL), stirred, and filtered to afford an orange/brown solid. This solid is slurried with ethyl acetate and saturated sodium bicarbonate solution to give 4-(6-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid ethyl ester (18) freebase.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]\[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(=C\C(C)c1ccccc1C)CO
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1[C@H](C)[C@@H]1C[C@@]1(C)CO
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −20° C. Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −5 to −15° C. for 10 minutes, and then cooled to −25° C. (E)-2-Methyl-4-(2-methylphenyl)pent-2-en-1-ol (0.80 g, 4.2 mmol) was added dropwise at −20 to −25° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (3.1 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(2-methylphenyl)ethyl)cyclopropyl]methanol (0.32 g, 1.6 mmol, 37% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(2-methylphenyl)ethyl)cyclopropyl]methanol (0.025 g, 0.12 mmol, 3% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][CH2:14][C:15]1[CH:16]=[C:17]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([NH2:34])[C:24]2=[O:35])[C:18]([F:22])=[CH:19][C:20]=1[Cl:21].[CH2:36]([O:38][C:39]([NH:41]O)=[O:40])[CH3:37]>O1CCCC1>[CH2:36]([O:38][C:39]([NH:41][O:13][CH2:14][C:15]1[CH:16]=[C:17]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([NH2:34])[C:24]2=[O:35])[C:18]([F:22])=[CH:19][C:20]=1[Cl:21])=[O:40])[CH3:37]
Reactant: CCOC(=O)NO
Reactant: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(CO)c(Cl)cc2F)c1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)NOCc1cc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
0.9 g of carbonyldiimidazole was added to a solution of 1.8 g of 3-(3-hydroxymethyl-4-chloro-6-fluorophenyl)-1-amino-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione in 100 ml of tetrahydrofuran. After the reaction mixture had been stirred for 1 hour, 0.58 g of N-ethoxycarbonylhydroxylamine was added. The mixture was subsequently stirred for a further 14 hours at 20° C. whereupon the solvent was removed by distillation. The residue was taken up in 100 ml of methylene chloride. The resulting organic phase was washed with water, dried over sodium sulfate and finally concentrated. The crude product was purified by means of chromatography on silica gel (eluent: methylene chloride). Yield: 0.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[C:14]([CH:20]([CH3:22])[CH3:21])[CH:13]=1)C(O)=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:33])=[O:32]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:8]=[C:9]([Br:23])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH:20]([CH3:21])[CH3:22])[CH:13]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH2:34])(=[O:32])=[O:33]
Reactant: COc1ccc(Oc2c(Br)cc(C(=O)O)cc2Br)cc1C(C)C
Agent: Nc1ccccc1S(N)(=O)=O
Product: CC(C)c1cc(Oc2c(Br)cccc2Br)ccc1O
Yield: 56.3 %

Procedure:
3,5-Dibromo-4-(4-methoxy-3-isopropylphenoxy)benzoic acid (0.035 mmol) was coupled with 2-aminobenzenesulphonamide (0.175 mmol) using the method described in Example 58. Purification on HPLC of the residue gave 11 mg (54%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[NH:15][C:14]3[CH:16]=[C:17]([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])[C:18]([C:20](=[O:31])[NH:21][C:22]4[CH:30]=[C:29]5[C:25]([CH:26]=[N:27][NH:28]5)=[CH:24][CH:23]=4)=[CH:19][C:13]=3[N:12]=2)[CH:5]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C1COCC1>[CH2:35]([N:32]([CH2:33][CH3:34])[C:17]1[C:18]([C:20](=[O:31])[NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)=[CH:19][C:13]2[N:12]=[C:11]([NH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])[NH:15][C:14]=2[CH:16]=1)[CH3:36]
Reactant: CCN(CC)c1cc2[nH]c(Nc3cccc(C(=O)OC)c3)nc2cc1C(=O)Nc1ccc2cn[nH]c2c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CC)c1cc2[nH]c(Nc3cccc(C(=O)O)c3)nc2cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
To a solution of 3-[6-diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoic acid methyl ester (0.2 mmol; see Example 115) in methanol (2 mL) and THF (2 mL) was added 1M aqueous LiOH solution (2 mL). The resulting solution was then stirred at RT until the reaction was complete. The pH of the reaction mixture was adjusted with 5% aqueous citric acid solution to bring its pH to 4-5. The solid obtained was filtered, washed with ice-cold water, and dried under vacuum to afford 3-[6-diethylamino-5-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-benzoic acid as a white solid. MS: m/z 484 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH3:9])[CH:3]=1.[CH3:10][S:11]([OH:13])=[O:12].[Na]>[Cu]I.CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:11]([CH3:10])(=[O:13])=[O:12])=[C:4]([CH3:9])[CH:3]=1
Reactant: CS(=O)O
Reactant: Cc1cc(Br)ccc1I
Agent: [Cu]I
Agent: [Na]
Solvent: CS(C)=O
Product: Cc1cc(Br)ccc1S(C)(=O)=O
Temperature: 125 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-1-iodo-2-methylbenzene (240 μL, 1.68 mmol, Aldrich), Copper(I) iodide (353 mg, 1.85 mmol, Alfa Aesar), Methanesulfinic acid, sodium salt (688 mg, 6.74 mmol, Alfa Aesar) and DMSO (7.2 mL) was purged with Argon and then heated under microwave condition at 125° C. for 20 min. The resulting mixture was stirred at 100° C. for 3 h and then cooled to room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0-50% EtOAc in hexanes) to yield 270 mg of desired product as a white solid. MS (ESI) 249 (M+H).