Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)(=[O:3])[CH3:2]>C(O)C.[Pt].[H][H]>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CCCC1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pt]
Solvent: CCO
Product: CC(=O)N1CCCC1Cc1ccc(N)cc1

Procedure:
Hydrogenate 3.3 g of 1-acetyl-2-(4-nitrobenzyl)pyrrolidine with platinum/hydrogen in ethanol. Filter the catalyst from the hydrogenated product and concentrate the filtrate to obtain the title compound as a yellowish liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[C@@H:11]([N:20]1[C:24](=[O:25])[C@@H:23]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][OH:35])=[CH:28][CH:27]=2)[NH:22][C:21]1=[O:36])[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]>CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:37])[C@@H:11]([N:20]1[C:24](=[O:25])[C@H:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][OH:35])=[CH:30][CH:31]=2)[NH:22][C:21]1=[O:36])[C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13]
Reactant: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OCCO)cc2)C1=O
Solvent: CO
Product: C[C@@H](c1ccccc1)[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@@H](c2ccc(OCCO)cc2)C1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.2 %

Procedure:
A solution of (2S,3S)—N-(2-fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (prepared as described in example 48) (50 mg, 0.081 mmol) was dissolved in methanol (3 mL) and stirred at ambient temperature for 4 days. The resulting mixture of isomers was concentrated in vacuo and then purified by super-critical fluid chromatography using a Chiracel OJ column eluted with carbon dioxide at 100 bar and 30° C. modified with 35% v/v ethanol in acetonitrile eluted at 2 mL/minute. The first eluted compound was collected and concentrated in vacuo to obtain (2S,3S)—N-(2-fluoro-4-iodo-phenyl)-2-{(S)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (9.1 mg, 18%) The compound eluted second was identical with (2S,3S)—N-(2-fluoro-4-iodo-phenyl)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (19.9 mg, 40%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#[N:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=O)C.CN(C)C=O.[BH4-].[Na+].BrC1[CH:30]=[CH:29][CH:28]=[CH:27]N=1>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:30]=[CH:29][CH:28]=[CH:27][N:13]=2)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: Brc1ccccn1
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccn2)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 5.85 g. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 20 ml. dimethylformamide is cooled, under nitrogen, to about 0° C. and 1.14 g. of sodium borohydride is added. The exothermic reaction is controlled to less than about 30° C., then the mixture is stirred for one hour at 20°-30° C. 6 Ml. of 2-bromopyridine is added and the mixture warmed slowly to about 110° C. and kept at that temperature for 1 hour. The mixture is cooled, diluted with water, and filtered. The crude product is recrystallized from aqueous methanol, yielding 1-amino-2-nitro-4-(pyrid-2-ylthio)benzene.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>C(O)C>[C:18]([O:17][C:15](=[O:16])[CH2:14][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC1CCCCC1
Yield: 97.1 %

Procedure:
To a mixture of cyclohexylamine (61.0 g, 0.615 mol) and sodium bicarbonate (12.9 g, 0.154 mol) in 200 ml of ethanol was added dropwise t-butyl bromoacetate (30.0 g, 0.154 mol). After 72 hours the ethanol was evaporated and the residue partitioned between water and chloroform. The chloroform layer was washed with water, dried, filtered and concentrated under vacuum to give 31.9 g (97%) of N-cyclohexylglycine t-butyl ester as an oil, Rf =0.59 (25% acetone/25% ethyl acetate/50% hexane).
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:15])=[C:7]2[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:15][C:6]1[CH2:5][S:4][CH:3]2[N:8]([C:9](=[O:10])[CH:2]2[NH:1][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C1=C(C)CSC2C(N)C(=O)N12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(C)CSC2C(NC(=O)Cc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1126) (801 mg, 3.51 mmol) was dissolved in dry dichloromethane (DCM) (20 mL), cooled to ˜0° C. in an ice bath before adding triethylamine (0.587 mL, 4.21 mmol) followed by phenylacetyl chloride (0.514 mL, 3.86 mmol) in Dichloromethane (DCM) (5 mL) slowly over 5-10 mins. The reaction was then allowed to warm up to RT and stirred for 4 hours then left to stand overnight. LCMS run, desired material seen. Diluted with DCM (40 ml), washed with saturated sodium bicarbonate solution (45 ml). Aqueous layer extracted with DCM (2×30 ml). Combined extracts were washed with brine (45 ml), dried over Na2SO4, filtered and evaporated to afford a red gum of crude material. Purified on a SNAP 100 cartridge, eluting with DCM (3CV) to 100% 10% MeOH in DCM (12CV). Compound identified and solvent removed to afford an orange gum of desired product in 972 mg.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:13]1)=O)C1C=CC=CC=1.[BrH:33]>C(O)(=O)C>[BrH:33].[NH2:11][C@H:12]1[CH2:16][N:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14](/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH2:13]1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NC(=O)OCc2ccccc2)CN1Cc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](N)CN1Cc1ccccc1

Procedure:
A solution of (2S,4R)-4-benzyloxycarbonylamino-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)pyrrolidine (700 mg) and 30% hydrogen bromide in acetic acid (2 ml) was stirred at room temperature for 2 hours and the solvent was evaporated in vacuo to give (2S,4R)-4-amino-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1(phenylmethyl)pyrrolidine hydrobromide 800 mg) as an oil.
Reaction SMILES: [N+](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[NH:5][C:4]1=[O:13])=[N-].[I:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]([CH3:25])[CH3:24])=[CH2:22])=[CH:17][CH:16]=1>C1C=CC=CC=1.C1COCC1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C@:3]12[CH2:22][C@:21]1([C:18]1[CH:17]=[CH:16][C:15]([I:14])=[CH:20][CH:19]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: [N-]=[N+]=C1C(=O)Nc2ccc(F)cc21
Reactant: C=C(c1ccc(I)cc1)C(C)C
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)[C@@]1(c2ccc(I)cc2)C[C@@]12C(=O)Nc1ccc(F)cc12
Temperature: 80 °C
Yield: 105.9 %

Procedure:
The 3-diazo-5-fluoroindolin-2-one (0.177 g, 1 mmol) and Rh(OAc)2 dimer (2.2 mg) were placed into a Schlenk tube under Argon atmosphere, then dissolved in dry benzene (3 mL). The mixture was heated to 80° C. for 10 minutes. The 1-iodo-4-(3-methylbut-1-en-2-yl)benzene (0.544 g) was dissolved in dry THF (2 mL) and added into the mixture in one portion. The mixture was concentrated in vacuo, the residue was purified by flash column chromatography (Petroleum ether: AcOEt=5:1) to give the title compound as white powder (0.446 g, 53%). LC/MS m/e calcd. for C19H17FINO: 421, observed (M+H)+: 422.1.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[O:8]([CH2:15][C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[CH:22]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C:23](=[CH2:27])[CH2:24][S:25](=O)[C@H:20]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(=O)C.C(OCC)(=O)C>[O:8]([CH2:15][C:16]([NH:18][CH:19]1[C:41](=[O:42])[N:21]2[CH:22]([C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=3)=[O:29])[C:23]([CH2:27][O:4][C:1](=[O:3])[CH3:2])=[CH:24][S:25][C@H:20]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C1CS(=O)[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)OCC1=CS[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 5 ml. of fresh acetic anhydride were added 500 mg. (1 millimole) of p-nitrobenzyl 7-phenoxyacetamido-3-methylenecepham-4-carboxylate-1-oxide. To the resulting mixture was added one drop of acetyl chloride. The mixture was refluxed at 130°--140° C. for 2.75 hours and then was cooled. Ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate and then with water. The resulting organic layer was separated and evaporated to obtain p-nitrobenzyl 7-phenoxyacetamido-3-acetoxymethyl-2-cephem-4-carboxylate as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10].[OH:19]O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:19])=[N:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: OO
Reactant: COC(=O)CSCc1ccc(OC)c([N+](=O)[O-])n1
Solvent: CC(=O)O
Product: COC(=O)CS(=O)Cc1ccc(OC)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
Methyl 2-((5-methoxy-6-nitropyridin-2-yl)methylthio)acetate (1.0 mmol, 0.27 g) and hydrogen peroxide 30% (1.0 mmol, 0.12 mL) were dissolved in acetic acid (10 mL). The mixture stirred at r.t. for 6 hrs and the solvent was evaporated in vacuo. The mixture was purified by column chromatography using 1:1 PE/EtOAc to give the titled compound. Yield 95%; 1H-NMR (DMSO-D6) δ: 3.74 (s, 3H, OCH3), 3.76 (d, 1H, J=14.2 Hz), 4.02 (d, 1H, J=14.2 Hz,), 4.07 (s, 3H, OCH3), 4.27 (d, 1H J=12.9 Hz, CH), 4.42 (d, 1H J=12.9 Hz, CH), 7.76 (d, 1H, J=8.6 Hz, Py-H), 7.94 (d, 1H, J=8.6 Hz, Py-H); 13C-NMR (DMSO-D6) δ: 51.90, 55.1756.52, 57.31, 124.13, 130.82, 141.18, 146.90, 166.11, 205.26. HR-MS (ESI+) m/z 289.0428 [M+H]+ C10H12N2O6S, requires 288.0416.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:6]#[N:7].[NH3:16]>CO>[CH3:1][S:2][CH2:3][CH2:4][CH:5]([O:8][CH2:9][CH2:10][O:11][Si:12]([CH3:13])([CH3:15])[CH3:14])[C:6]([NH2:16])=[NH:7]
Reactant: N
Reactant: CSCCC(C#N)OCCO[Si](C)(C)C
Solvent: CO
Product: CSCCC(OCCO[Si](C)(C)C)C(=N)N

Procedure:
A solution of intermediate 18, 4-(methylthio)-2-(2-(trimethylsilyloxy)ethoxy)butanenitrile, (4.9 g, 0.02 mol) in 30 mL of methanol was saturated with ammonia. The flask was then sealed and heated in an oil bath at 80–90° C. for 16 hrs. After cooling, the flask was opened and the mixture concentrated in vacuo to give the title compound in essentially quantitative yield as a very viscous oil. 1H NMR (300 MHz, CDCl3) δ ppm: 3.94–4.02 (1H, m) 3.76–3.94 (3H, m) 3.68–3.77 (2H, m) 3.52–3.62 (2H, M) 2.53–2.67 (2H, m) 2.07 (3H, s) 1.89–2.01 (2H, m); LC/MS 193 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([Cl:20])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]N1C(=O)CCC1=O.CCOC(C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:12]2=[C:13]([Cl:20])[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[C:17]([I:23])[CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2nc3c(I)cnn3c(Cl)c2CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 0.1 g (0.31 mmol) 10-chloro-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester (route 1, step a to d) in 2 mL DMF, under nitrogen, was added 0.104 g (0.46 mmol) N-iodosuccinimide, and the reaction was stirred at room temperature for 16 hours. 20 mL EtOAc was added and the mixture was washed with a 10% solution of Na2S2O3 (2×5 mL). The aqueous layers were combined and extracted with EtOAc (2×10 mL). The organic layers were combined, washed with 10 mL saturated brine, and dried with MgSO4. After filtration and evaporation of the solvent the product was purified by column chromatography (silica, heptane/EtOAc 9:1).
Reaction SMILES: [CH3:1][C:2]1[C:7](Br)=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][CH:5]=[C:6]([CH3:9])[C:7]=1[B:17]([OH:20])[OH:18]
Reactant: COc1ccc(C)c(Br)c1C
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C)c(B(O)O)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dimethyl-3-bromoanisole (3.3 g, 15 mmol) in THF (15 mL) is added dropwise at −78° C. to a solution of n-butyllithium (11 mL of 1.6M in hexane, 17 mmol) in THF (35 mL). After 30 minutes, trimethyl borate (2.3 mL, 20 mmol) is added and the mixture is allowed to warm to room temperature overnight. The mixture is poured onto 10% HCl and extracted with ethyl acetate. The organic fraction is washed with saturated brine, dried (Na2SO4), and concentrated to give the desired product as a brownish oil. 1H NMR (CDCl3) 6.98 (d, 1H), 6.75 (d, 1H), 4.64 br s), 3.80 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH:10]=[O:11].O.N>[Cu].C(OCC)(=O)C>[N:1]1([C:12]2[CH:13]=[C:14]([O:15][CH3:16])[CH:7]=[CH:8][C:9]=2[CH:10]=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(C=O)cc1Br
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)c(-n2ccnc2)c1
Temperature: 100 °C
Reaction time: 72 h
Yield: 11.4 %

Procedure:
To an aqueous solution (15 mL) of imidazole (5.69 g), 3-bromo-4-methoxybenzaldehyde (3.00 g) and copper powder (86 mg) were added, and the reaction solution was agitated for three days at 100° C. under nitrogen atmosphere. A concentrated ammonia water and ethyl acetate were added to the reaction mixture, and the organic layer was partitioned. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate), and 321 mg of the title compound was obtained.
Reaction SMILES: [Mg].II.Br[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH3:14][O:15][B:16](OC)[O:17][CH3:18]>C1COCC1.CCOCC>[CH3:14][O:15][B:16]([O:17][CH3:18])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13]
Reactant: COB(OC)OC
Reactant: Cc1cc(C)c(Br)c(C)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COB(OC)c1c(C)cc(C)cc1C
Temperature: -15 °C
Reaction time: 3 h

Procedure:
To a stirred solution of activated magnesium flakes (3.11 g, 0.128 mol) and a crystal of iodine, 2-bromomesitylene (23.40 g, 0.118 mol) in THF (80 cm3) was added dropwise at room temperature. The reaction was allowed to reflux for 3 hours. After the reaction mixture was cooled, it was added dropwise to an ether solution (80 cm3) of trimethoxyborane (26 cm3, 0.229 mol) at −15° C. The reaction stirred at −15° C. for 3 hours and then was warmed up to room temperature and left to stir overnight. The solution was then filtered under argon and the precipitated salts were washed with dry pentane (20 cm3). The filtrates were combined, concentrated and distilled under vacuum to give the desired dimethoxymesitylborane. 1H NMR (200 MHz, CDCl3) δ 2.28 (s, 6H), 2.30 (s, 3H), 3.58 (s, 6H), 6.84 (s, 2H).
Reaction SMILES: I[C:2]1[N:20]([S:21]([C:24]2[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([OH:19])[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[CH:36]=[C:35]2B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([CH3:41])[CH:36]=[C:35]2[C:2]1[N:20]([S:21]([C:24]2[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=2)(=[O:22])=[O:23])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([OH:19])[CH2:16][CH2:17][CH2:18]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2cc(F)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)ccnc32)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(F)cc34)cc3c(-c4cnc(C5(O)CCC5)s4)ccnc32)cc1
Temperature: 70 °C

Procedure:
To a stirred ambient solution of 1-(5-(2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thiazol-2-yl)cyclobutanol (Example 107C) (150 mg, 0.272 mmol) and 5-fluoro-1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Example 107A) (112 mg, 0.408 mmol) in N,N-dimethylformamide (2.04 mL) was added saturated aqueous bicarbonate solution (680 μL) followed by bis(triphenylphosphine) palladium dichloride (13.37 mg, 0.019 mmol). The mixture was heated to 70° C. for 3 hours and was quenched by the addition of water and dichloromethane. The layers were separated, and the aqueous layer was extracted with additional dichloromethane. The combined organics were dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 100% ethyl acetate in hexane, to give the title compound LCMS APCI(+) m/z 602.99 [M+H]+.
Reaction SMILES: C([CH:3]([C:26]([OH:28])=[O:27])[N:4]([C:16](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH2:12][CH:13]([CH3:15])[CH3:14])([CH2:8][CH:9]([CH3:11])[CH3:10])=[S:7])C.Br.[CH3:30]COCC>C(O)(=O)C>[CH2:16]([N:4]([CH2:5][P:6]([CH2:12][CH:13]([CH3:15])[CH3:14])([CH2:8][CH:9]([CH3:11])[CH3:10])=[S:7])[CH2:3][C:26]([OH:28])=[O:27])[CH3:30]
Reactant: CCOCC
Reactant: CCC(C(=O)O)N(CP(=S)(CC(C)C)CC(C)C)C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(=S)(CC(C)C)CC(C)C
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(diisobutylthiophosphinylmethyl)glycine (4 g., 0.009 mole) was dissolved in 10 ml. of 35% hydrogen bromide in glacial acetic acid at 0° C. The mixture was stirred for one hour. Ether was added and the oily precipitate isolated by decanting the ether layer. The oil was washed twice with diethyl ether and then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(diisobutylthiophosphinylmethyl)glycine (0.3 g., 0.001 mole) as an oil, ND25 =1.5121.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=1[F:12].[CH2:14]([NH2:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[F:12][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][NH:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:13]
Reactant: CCCCCCN
Reactant: COC(=O)c1cc(C=O)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCCCCNCc1ccc(F)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.7 %

Procedure:
To solution of 2-fluoro-5-formylbenzoic acid methyl ester (1.0 g; 5.49 mmol) in anhydrous DCE (50 mL) were added hexylamine (Aldrich, 0.87 mL; 6.59 mmol), triacetoxyborohydride (1.74 g; 8.24 mmol) and acetic acid (0.47 mL; 8.24 mmol). The resulting mixture was stirred at room temperature under N2 atmosphere for 5 hours. The mixture was poured into a saturated solution of NaHCO3 and extracted with DCM (2×200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtrated and the solvent was removed under reduced pressure. Purification by flash chromatography on silica gel (DCM/MeOH/NH4OH, 98:2:0.1) gave 920 mg (63%) of the title compound as a yellow cream. HPLC, Rt: 2.34 min (purity=94.9%), LC/MS: M+(ESI): 268.1, 1H NMR (CDCl3) δ: 7.8 (dd, J=2.2, 8.2 Hz, 1H), 7.42 (m, 1H), 7.00 (dd, J=8.2, 2.2 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 2H), 2.58 (t, J=7.1 Hz, 2H), 1.46 (qt, J=6.7 Hz, 2H), 1.22 (m, 6H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH:12]1[C:23](OCC)=[O:24].Cl>C(O)C>[OH:2][C:1]1[C:9]2[C:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][C:12]=3[C:23](=[O:24])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C1CC(c2ccccc2)CCC1=O
Agent: Cl
Solvent: CCO
Product: O=c1oc2cc(O)cc(O)c2c2c1CC(c1ccccc1)CC2

Procedure:
A solution of phloroglucinol (1.56 g) and ethyl 2-oxo-5-phenylcyclo-hexane-carboxylate (2.52 g) in ethanol (25 ml) was treated with dry HCl as described in example 1a. The precipitate was filtered and washed with water and ETOH. Yield 1.0 g (32%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21]1>>[O:20]1[CH:24]=[CH:23][C:22]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: O=Cc1ccoc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccoc4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with furan-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(furan-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].CN([CH:15]=[N:16][C:17](=[O:19])[CH3:18])C>C1COCC1.CC(O)=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10]/[N:11]=[CH:15]/[NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)N=CN(C)C
Reactant: NNc1cc(F)ccc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)N/C=N/Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
Alternatively, to a mixture of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (5.9 g, 28.8 mmol) and N-((dimethylamino)methylene)acetamide (3.30 g, 28.8 mmol) in THF (30 mL) was added 5 drops of HOAc, and the mixture stirred at room temperature under nitrogen for 15 min. The mixture was concentrated in vacuo, and the residue suspended in a mixture of ether (50 mL) and hexanes (50 mL) and the resulting precipitate collected and air-dried to provide 5.7 g of the title compound as an off-white powder. A second crop gave an additional 0.3 g.