Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:35][C:36]1([CH3:47])[CH2:41][O:40][C:39]([CH:45]=[CH2:46])([C:42]([OH:44])=[O:43])[CH2:38][O:37]1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:46]=[CH:45]/[C:39]4([C:42]([OH:44])=[O:43])[CH2:38][O:37][C:36]([CH3:35])([CH3:47])[CH2:41][O:40]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)COC(C)(C)CO1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COC(C)(C)CO4)cc3n2)N1
Temperature: 50 °C
Yield: 100 %

Procedure:
A mixture of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (198 mg, 0.371 mmol), 5,5-dimethyl-2-vinyl-[1,4]dioxane-2-carboxylic acid (69 mg, 0.371 mmol), triethylamine (112 mg, 155 μL, 1.11 mmol) and tri(o-tolyl)phosphine (23 mg, 0.074 mmol) in 1,4-dioxane (7.5 mL) was degassed with nitrogen for 5 min and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.037 mmol) was added and the mixture was heated to 80° C. for 40 min and then allowed to cool to room temperature. The suspension was filtered and evaporated to give crude title compound (0.371 mmol) which was used directly in the next stage. LCMS (m/z) 640.3 [M+H], Tr=1.94 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[NH:22][C:28]2=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g), CDI (668 mg), and DBU (1.2 ml) in THF (25 mL) was heated at 60° C. overnight. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=97/3 to 9/1) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (993 mg) as a pale brown solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.[CH3:25][Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8]([CH3:25])([OH:10])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H]1C[C@H]2NC(=O)C=C[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)(C)O)CC[C@H]3[C@H]12
Temperature: 25 °C
Yield: 76.7 %

Procedure:
To a solution of 20 mg (0.06 mmol) 7β-methyl-5α-4-azapregn-1-ene-3,20-dione in 4 ml dry tetrahydrofuran at -40° C. under N2 was added 10 eq methylmagnesium bromide (0.6 mmol) in ether. The reaction was stirred and allowed to warm to RT over 18 hours. Aqueous ammonium chloride (5 ml) was added and the solvents were evaporated. The residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using 5% isopropanol/hexane at 20 ml/min to yield 16 mg (0.046 mmol, 77% yield) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(OC(=O)C)(=O)C>>[C:11]1([C:9](=[N:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:10])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(NCc1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=NCc1ccccc1)c1ccccc1

Procedure:
Benzyl-(1-phenylethyl)amine, conversion>99%, ee 82% (GC, sample derivatised by treatment with acetic anhydride pyridine, Chirasil DEX CB, 25 m×0.25 mm, injector/detector 200° C., helium 20 psi, 170° C. for 40 minutes then ramp at 15° C./min to 200° C., retention times 29.71 minutes and 30.73 minutes).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-])=O)=[C:12]([CH:17]=2)[C:13]([O:15][CH3:16])=[O:14])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:18][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(CN2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(CN2CCOCC2)ccc1N

Procedure:
Methyl 5-(morpholin-4-ylmethyl)-2-nitrobenzoate was allowed to undergo a reaction with iron and ammonium chloride in an ethanol-water mixed solvent to obtain methyl 2-amino-5-(morpholin-4-ylmethyl)benzoate.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N:4]1([CH:9](Cl)[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][CH3:12])[CH:8]=[N:7][CH:6]=[N:5]1.O>CO.[I-].[K+]>[N:4]1([CH:9]([O:2][CH3:1])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][CH3:12])[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: C[O-]
Reactant: CCC(c1ccc(Cl)cc1Cl)C(Cl)n1cncn1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(c1ccc(Cl)cc1Cl)C(OC)n1cncn1
Yield: 23.7 %

Procedure:
9.4 g of sodium methylate and 0.2 g of potassium iodide are added to a solution of 26.6 g of 1-(1,2,4-triazol-1-yl)-1-chloro-2-(2,4-dichlorophenyl)-butane in 200 ml of methanol. The reaction mixture is refluxed for 48 hours, after which 100 ml of water are added to the solution and the mixture is extracted several times with methyl tert-butyl ether. The organic phase isolated is washed twice with water, then dried over sodium sulfate and evaporated down and the remaining residue is purified by chromatography over silica gel (9:1 ethyl acetate/n-hexane). 6.2 g (24%) of 1-(1,2,4-triazol-1-yl)-1-methoxy-2-(2,4-dichlorophenyl)-butane are obtained as a 1:1 diastereomer mixture [compound No. 1).
Reaction SMILES: [NH2:1][C:2]1([C:11](OCC)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>O.C(O)C>[NH2:1][C:2]1([CH2:11][OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(N)CCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC1(CO)CCc2ccccc21
Yield: 85 %

Procedure:
The product of Example 434A (0.292 g, 1.423 mmol) and sodium borohydride (0.275 g, 7.113 mmol) were reacted in 1:3 v/v water/ethanol (7 mL), at reflux for 4 hours. The reaction was concentrated by rotary evaporation the partitioned between water (5 mL), ethyl ether (20 mL), 1N aqueous sodium hydroxide (0.712 mL). Solid sodium chloride was added to saturate the aqueous phase and separate the phases. The aqueous phase was extracted with ethyl ether (2×25 mL). The combined ethereal extracts were washed with brine (25 mL), dried over potassium carbonate, filtered, and concentrated by rotary evaporation to afford the title compound (0.197 g, 1.209 mmol, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.64-1.80 (m, 1 H) 1.85 (s, 2 H) 2.16-2.31 (m, 1 H) 2.63-2.91 (m, 2 H) 3.30 (d, J=5.52 Hz, 2 H) 4.74 (t, J=5.52 Hz, 1 H) 6.80-7.63 (m, 4 H). MS (DCI) m/z 164 (M+H)+, 181 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:29]#[N:30])[C:16]([CH2:31][CH3:32])=[C:15]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].CC([N-]C(C)C)C.[Cl:49]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[C:23]([Cl:49])=[C:22]3[C:29]#[N:30])[C:16]([CH2:31][CH3:32])=[C:15]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc3c(c2)c(C#N)c(Cl)n3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Yield: 82.3 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-6-(3-cyano-1-methyl-1H-indol-5-yl)-5-ethylnicotinate (1.80 g, 3.39 mmol), prepared in Example 359 step 2, in THF (24 mL) was added LDA solution (1.5M in cyclohexane, 3.40 mL, 5.10 mmol, 1.5 eq) dropwise at −78° C. The reaction mixture was stirred for 15 min before a solution of hexachloroethane (1.21 g, 5.1 mmol, 1.5 eq) in THF (6 mL) was added dropwise at −78° C. The reaction progress was monitored by LC-MS. Upon completion, the reaction was quenched with sat. NH4Cl solution then extracted with Et2O (4×30 mL). The combined organic layers were dried over Na2SO4 then concentrated to give a crude product which was purified by flash column chromatography (0-10% EtOAc in 1/1 CH2Cl2/hexanes) to afford the title compound (1.58 g, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[OH:13])([O-:3])=[O:2]>C(OCC)(=O)C.[Pd]>[NH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc([N+](=O)[O-])c1O
Reaction time: 5 h

Procedure:
A solution of 2,6-dinitrophenol (6.31 g, 27.4 mmol) in ethyl acetate (50 mL) was cooled to 0° C., 10% palladium activated carbon (250 mg) was added thereto, and the mixture was stirred under a hydrogen atmosphere for 5 hr. The reaction mixture was filtered through Celite (registered trademark) and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with chloroform, anhydrous sodium sulfate was added thereto, and the mixture was stirred for 15 min. Anhydrous sodium sulfate was filtered off, followed by concentration under reduced pressure. The resulting residue was powdered with hexane and collected by filtration to afford 2-amino-6-nitrophenol as a brown amorphous substance (2.41 g).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:22][C:23]([C@@H:25]3[CH:40]=[C:39]4[C@@H:28]([CH2:29][C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][C:37]=64)[NH:32][CH:31]=5)[N:27]([CH3:41])[CH2:26]3)=[O:24])([CH:19]([CH3:21])[CH3:20])[O:18][C@@:13]2([OH:42])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:3].OP(O)(O)=O.C[Si](C)(C)[Br:50]>ClCCl>[CH3:3][CH:2]([CH2:4][C@@H:5]1[N:14]2[C:15]([C@@:17]([NH:22][C:23]([C@@H:25]3[CH:40]=[C:39]4[C@@H:28]([CH2:29][C:30]5[C:38]6[C:33](=[CH:34][CH:35]=[CH:36][C:37]=64)[NH:32][C:31]=5[Br:50])[N:27]([CH3:41])[CH2:26]3)=[O:24])([CH:19]([CH3:20])[CH3:21])[O:18][C@@:13]2([OH:42])[C@H:12]2[N:8]([CH2:9][CH2:10][CH2:11]2)[C:6]1=[O:7])=[O:16])[CH3:1]
Reactant: C[Si](C)(C)Br
Reactant: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]cc(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: CC(C)C[C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@](NC(=O)[C@@H]3C=C4c5cccc6[nH]c(Br)c(c56)C[C@H]4N(C)C3)(C(C)C)C(=O)N12

Procedure:
Following the process of Example 30, 1 g of α-ergocryptine phosphate is brominated with 2.0 ml of trimethylbromosilane. After isolating, the title base is obtained in a yield of 0.9 g (0.001359 mole, 91.5%), m.p.: 218° C., [α]D20 =-195° (c=1, dichloromethane).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[C:23]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccc2ncccc2c1)c1cnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc2ncccc2c1)c1cnc2ccc(-c3ccccc3)nn12

Procedure:
A 48 mL sealed tube was charged with (6-chloroimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone (0.530 g, 1.72 mmol), phenylboronic acid (0.314 g, 2.58 mmol), cesium carbonate (1.68 g, 5.15 mmol), PdCl2(dppt)-CH2Cl2 adduct (0.0701 g, 0.0858 mmol), 1,4-dioxane (6.31 ml, 73.8 mmol), and water (1.11 ml, 61.8 mmol), flushed with argon, sealed, then placed in an 80° C. oil bath for 8 hours. The mixture was concentrated then triturated with water, followed by MeOH/DCM to give (6-phenylimidazo[1,2-b]pyridazin-3-yl)(quinolin-6-yl)methanone as a reddish brown solid.
Reaction SMILES: II.[CH2:3]([O:5][C:6](=[O:20])[CH2:7][CH2:8][CH2:9][N:10]1[C:14]([NH2:15])=[C:13]([C:16](=[S:18])[NH2:17])[S:12][C:11]1=[S:19])[CH3:4].[O-]S([O-])(=S)=O.[Na+].[Na+].[CH2:28](O)[CH3:29]>>[CH2:3]([O:5][C:6](=[O:20])[CH:7]([CH2:28][CH3:29])[CH2:8][CH2:9][N:10]1[C:14]2=[N:15][S:18][C:16]([NH2:17])=[C:13]2[S:12][C:11]1=[S:19])[CH3:4]
Reactant: CCO
Reactant: CCOC(=O)CCCn1c(N)c(C(N)=S)sc1=S
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Product: CCOC(=O)C(CC)CCn1c(=S)sc2c(N)snc21
Yield: 95 %

Procedure:
An excess of iodine (I2) in ethanol was added dropwise to a stirred solution of 4-(4-amino-5-thiocarbamoyl-2-thioxo-thiazol-3-yl)-butyric acid ethyl ester (360 mg, 1.18 mmol) in ethanol (25 ml), at 25° C., while monitoring the reaction progress by TLC. Once the reaction was completed, (upon stirring overnight at 25° C.), a solution of Na2S2O3 was added, so as to remove excess of I2, and the resulting solution was neutralized with a 5% solution of NaHCO3. A mixture of water and ethyl acetate was added thereafter, phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4 and the solvents were evaporated under reduced pressure to give yellow oil. Precipitation in acetonitrile gave 342 mg of Compound 43 (95% yield).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:5])[CH:3]=[O:4].[C:26]1(C)C=CC=CC=1.C[Mg]Br.C1COCC1.S(NN)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[OH:4][CH:3]([CH3:26])[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:25])[C:13]([CH3:24])([S:15]([CH:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)(=[O:17])=[O:16])[CH3:14])[O:8][N:7]=1)([CH3:1])[CH3:5]
Reactant: Cc1ccccc1
Reactant: CC(C)(C=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Agent: C[Mg]Br
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)C(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 3 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a cooled (−20° C.) solution of N-[3-(1,1-Dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (792 mg, 2.13 mmol) in DCM (16 mL) is added dropwise 1.4 M methylmagnesium bromide toluene/THF solution (75:25) over 10 minutes. DCM (7 mL) is added after ⅓ of the addition of 1.4 M methylmagnesium bromide toluene/THF solution. After the addition, the reaction mixture is stirred in a cold bath and slowly warmed up to 3° C. after 30 minutes. After this time, the reaction mixture is quenched with saturated aqueous NH4Cl solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The solids are dissolved in DCM (30 mL) and PS-TsNHNH2 (200 mg, 0.55 mmol) is added and the mixture is placed on a shaker for 1 h. After this time, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Purification by preparative HPLC affords the title compound. Yield: 80%; m/z 389 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[C:33]([O:34][CH3:35])=[CH:32][C:20]([CH2:21][O:22][C:23]([NH:25][CH:26]([CH3:31])[CH2:27][C:28](O)=[O:29])=[O:24])=[C:19]([N+:36]([O-:38])=[O:37])[CH:18]=1.CC(C)N=C=NC(C)C>C1COCC1>[O:13]=[C:12]1[CH:11]=[CH:10][C:9](=[O:14])[N:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][C:28](=[O:29])[CH2:27][CH:26]([NH:25][C:23]([O:22][CH2:21][C:20]2[CH:32]=[C:33]([O:34][CH3:35])[C:17]([O:16][CH3:15])=[CH:18][C:19]=2[N+:36]([O-:38])=[O:37])=[O:24])[CH3:31])=[CH:7][CH:6]=1
Reactant: COc1cc(COC(=O)NC(C)CC(=O)O)c([N+](=O)[O-])cc1OC
Reactant: O=C1C=CC(=O)N1c1ccc(O)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NC(C)CC(=O)Oc2ccc(N3C(=O)C=CC3=O)cc2)c([N+](=O)[O-])cc1OC
Temperature: 0 °C

Procedure:
1-(4-Hydroxy-phenyl)-pyrrole-2,5-dione (1 mmol), NHS (1.0 mmol) and 3-(4,5-dimethoxy-2-nitro-benzyloxycarbonylamino)-butyric acid (1 mmol) is dissolved in THF (3 mL). The solution is cooled to 0° C. and treated dropwise with DIC (1.2 mmol). The cooling bath is removed after 1 hour and the reaction mixture is left at room temperature o/n. The solvent is evaporated in vacuo and the pure product (3-(4,5-dimethoxy-2-nitro benzyloxycarbonyl-amino)-butyric acid 4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester) is isolated by silica column purification using EtOAc-heptane (1:4 then 1:2 then 1:1) as eluent.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:34]1([C:39]2[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=2)[CH:38]=[CH:37][CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.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.CCCCCC>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:43]3[CH:42]=[CH:41][CH:40]=[C:39]([N:34]4[CH:38]=[CH:37][CH:36]=[N:35]4)[CH:44]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1cccc(-n2cccn2)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cccc(-n2cccn2)c1

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)-benzyl]-4-methyl-1,3-oxazolidin-2-one (0.05 g, 0.084 mmol), 3-(1H-pyrazol-1-yl)phenyl boronic acid (0.031 g, 0.167 mmol), tetrakis(triphenylphosphine)palladium (5% mol) and sodium carbonate (0.019 g, 0.18 mmol) in 7 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (EtOAc:hexane/1:1) showed that the reaction was over. The solvents were removed. Water (10 ml) was added. The organic was extracted with methylene chloride (3×10 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/1:1 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=2.5 Hz, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.76 (s, 1H), 7.75 (s, 2H), 7.73 (m, 1H), 7.71 (m, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.53 (d, J=7.5 Hz, 1H), 7.26 (m, 1H), 6.54 (t, J=2 Hz, 1H), 5.55 (d, J=7.5 Hz, 1H), 5.02 (d, J=16 Hz, 1H), 4.21 (d, J=16 Hz, 1H), 3.82 (m, 1H), 0.54 (d, J=6.5 Hz, 3H). LC-MS (M+1): 614.3.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[N:9]=[C:4]2[CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCCl>[CH:20]1([NH:26][C:27]([NH:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([CH3:1])[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]3=[N:6][CH:7]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NC1CCCCC1
Reactant: Cc1cc2nc(N)cnc2n1COCC[Si](C)(C)C
Solvent: ClCCCl
Product: Cc1cc2nc(NC(=O)NC3CCCCC3)cnc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Yield: 95.3 %

Procedure:
6-Methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (58 mg, 0.208 mmol) was dissolved in 1,2-dichloroethane (2.1 mL). Cyclohexylisocyanate (0.54 mL, 4.16 mmol) was added and the reaction mixture was heated to reflux overnight, cooled to RT, concentrated, purified by SiO2 chromatography (12 g SiO2, hexanes/EtOAc 0-50% EtOAc) to give 80 mg of 1-cyclohexyl-3-[6-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a yellow solid (95% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8]C)=O)[N:3]=[CH:2]1.[F:10][C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[C:15]([F:17])[CH:16]=1>O1CCCC1>[F:10][C:11]1[CH:12]=[C:13]([C:6]([C:13]2[CH:12]=[C:11]([F:10])[CH:16]=[C:15]([F:17])[CH:14]=2)([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)[OH:8])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: COC(=O)c1c[nH]cn1
Reactant: Fc1cc(F)cc([Mg]Br)c1
Solvent: C1CCOC1
Product: OC(c1cc(F)cc(F)c1)(c1cc(F)cc(F)c1)c1c[nH]cn1
Yield: 73 %

Procedure:
Methyl 4-imidazolecarboxylate 0.80 g (6.34 mmol) was placed in a flask and under argon 50 ml (25 mmol) of a 0.5M 3,5-difluorophenylmagnesium bromide solution in tetrahydrofuran were added. The mixture was refluxed for 2 hours and then most of the solvent was evaporated. Water was added with cooling, and the mixture was extracted twice with ethyl acetate. The combined organic extracts were concentrated and the residue was purified by flash chromatography (silica gel, heptane/ethyl acetate 8:2) to yield 1.5 g (73%) of bis-(3,5-difluoro-phenyl)-(1H-imidazol-4-yl)-methanol as a white solid; MS (ISP): 305.1 ((M-OH)+); 323.4 ((M+H)+.).
Reaction SMILES: [N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:2].[CH3:14][S:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:14][S:15]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])=[O:2]
Reactant: CSc1sccc1[N+](=O)[O-]
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)c1sccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 2 h

Procedure:
There was added 0.95 g of p-nitroperbenzoic acid to a solution of 0.88 g of 2-methylthio-3-nitrothiophene in 15 ml of chloroform at a temperature from 0° to 10° C. After stirring for 2 hours at 5° C., a solution of 2 g of sodium bicarbonate in approximately 50 ml of water was added; the reaction mixture was then stirred for 15 minutes. The chloroform layer was separated, washed with water, and filtered. After distilling the solvent, the desired product was obtained in a yield of 0.95 g; melting-point 155° C.