Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+].CO.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cc(F)ccc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-bromo-5-fluorobenzoate (10, 21.30 g, 91.4 mmol) in dry THF (150 mL) was added NaBH4 (6.95 g, 183 mmol). Methanol (20 mL) was added dropwise at RT. After the addition, the mixture was stirred at RT for 1 h. Water (200 mL) was slowly added. The mixture was extracted with CH2Cl2 (100 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated to give (2-bromo-5-fluorophenyl)methanol (11).
Reaction SMILES: [CH:1]1C=CC(C(OC2C=CC(C(F)(F)F)=CC=2)CCN)=CC=1.[C:22]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([CH2:30][CH2:31][C:32]([O:34][CH3:1])=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: NCCC(Oc1ccc(C(F)(F)F)cc1)c1ccccc1
Product: COC(=O)CCCc1ccccc1

Procedure:
A preferred method of preparing enantiomerically pure enantiomers of norfluoxetine comprises the asymmetric synthesis of the compound from 3-benzoylpropionic acid. According to this method, 3-benzoylpropionic acid is methylated to provide methyl 3-benzylpropionate, which is then contacted with (+)-B-chlorodiisopinocamphenylborane chloride ((+)-DIP-Cl) to provide (R)-χ-phenyl-χ-butrolactone if R-norfluoxetine is being prepared, or with (−)-DIP-Cl to provide (S)-χ-phenyl-χ-butrolactone if S-norfluoxetine is being prepared. The lactone is subsequently contacted with ammonia to provide the corresponding chiral 4-hydroxy-4-phenylbutanamide (i.e., (R)- or (S)-4-hydroxy-4-phenylbutanamide). A cyclic carbamate is then prepared from the amide by contacting the chiral 4-hydroxy-4-phenylbutanamide with iodobenzene diacetate. The carbamate is then contacted with base to provide chiral 3-amino-(1R)-phenyl-propanol-1-ol, which is subsequently converted to the corresponding enantiomer of norfluoxetine free base by contacting it with sodium hydride and 4-chlorobenzotrifluoride. This free base can then be converted into a salt by known methods. For example, (D)-tartaric acid can be contacted with (R)-norfluoxetine free base to provide (R)-norfluoxetine.(D)-tartarate. Similarly, (L)-tartaric acid can be contacted with (S)-norfluoxetine free base to provide (S)-norfluoxetine.(L)-tartarate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH:14]3[CH2:16][CH2:15]3)([CH:12]=C)[C:6]=2[CH:17]=1.[O:18]=[O+][O-].[BH4-].[Na+].CC(C)=O>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH:14]3[CH2:16][CH2:15]3)([CH2:12][OH:18])[C:6]=2[CH:17]=1
Reactant: C=CC1(C2CC2)OC(=O)Nc2ccc(Cl)cc21
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: O=C1Nc2ccc(Cl)cc2C(CO)(C2CC2)O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
6-Chloro-4-cyclopropyl-4-vinyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (590 mg, 2.36 mmol) was dissolved in dichloromethane (2.5 mL) and methanol (2.5 mL), and the resulting solution was stirred at −78° C. in an ozone atmospher. After it was confirmed by thin-layer chromatography that the raw materials disappeared, the ozone atmospher was replaced by a nitrogen atmospher, and the solution was stirred for 5 minutes. The temperature of the reaction solution was raised to 0° C., and sodium borohydride (26.8 mg, 7.1 mmol) was added thereto. The reaction solution was stirred at 0° C. for 30 minutes, and then, acetone was added thereto to stop the reaction. After the solvent was evaporated under reduced pressure, water (50 mL) and 1 N hydrochloric acid were added to the residue and the pH thereof was adjusted to about 4, and then, the solution was stirred at room temperature. The resulting white solid was collected by filtration, washed with water and then dried under reduced pressure, whereby the objective compound (487 mg, 81%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]([F:31])([F:30])[C:14]1[C:15]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)=[CH:16][C:17]2[C:18]([CH:22]=1)=[N:19][S:20][N:21]=2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.ClCCl.O1CCCC1.CO.[OH-].[Li+]>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]2[C:14]([C:13]([F:31])([F:30])[F:12])=[CH:22][C:18]3=[N:19][S:20][N:21]=[C:17]3[CH:16]=2)=[CH:28][N:27]=1)=[O:5]
Reactant: Nc1ccc(-c2cc3nsnc3cc2C(F)(F)F)cn1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cc3nsnc3cc2C(F)(F)F)cn1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (27 mg, 152 μmol) was added to a stirred solution of 20 (30 mg, 101 μmol), Hünig's base (53 μL, 39 mg, 304 μmol), and DMAP (1 mg, 8 μmol) in dichloromethane (500 μL) at room temperature. The reaction was stirred for 10 min. The solution was diluted with tetrahydrofuran (1.5 mL), methanol (1 mL) and 1.2 M lithium hydroxide solution (500 μL). The mixture was stirred and heated to 60° C. for 10 min then cooled to room temperature and diluted with dichloromethane (5 mL) and dried with sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-30% ethyl acetate in hexane) provided 21 (33.6 mg, 76%) as a solid: LRESIMS ink 437.1 [M+H]+, calcd. for C19H10F5N4O1S1 437.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:13])[CH:6]=[C:7]([O:11]C)[C:8]=1[O:9][CH3:10].C1(C)C=CC(S(O)(=O)=[O:21])=CC=1.OO.[N+]([O-])(O)=O>C(O)(=O)C.O>[CH3:10][O:9][C:8]1[C:7](=[O:11])[CH:6]=[C:5]([CH3:13])[C:4](=[O:21])[C:3]=1[O:2][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(C)cc(OC)c1OC
Agent: OO
Solvent: CC(=O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: COC1=C(OC)C(=O)C(C)=CC1=O
Reaction time: 0.08 h

Procedure:
3,4,5-Trimethoxy toluene (18.2 g, MW 182.21, 0.1 mol), para-toluene sulphonic acid (1.7 g, MW 172.13, 0.01 mol) are dissolved in glacial acetic acid to give a total volume of 50 ml and the solution is connected to the pump 1. Hydrogen peroxide (0.2 mol, MW 34.02, 21.6 ml if H2O2 at 30% and 17.5 ml if H2O2 at 35%) diluted to 50 ml with glacial acetic acid is connected to the pump 1 (second tube). The nitric acid (90%, 0.05 mol, MW 63.02, d 1.49, 3.15 g, 3.5 g solution 90%, 2.35 ml solution 90%) dissolved in acetic acid (to 50 ml) is connected to the pump 2. The pump 1 is pumping approximately 3.8 ml/min for each of the two reagent solutions (total speed flow 7.6 ml/min, i.e. 38 ml reactor volume/5 min RT). Isoversinic tubes (ID 2 mm) was used on the peristaltic pump. The residence time of the reaction was about 5 min (38 ml volume reactor) and the reaction was performed at 75° C. pumping the solutions of the pumps 1. After 5 min the nitric acid solution was pumped at 3.8 ml/min into the second section of the reactor (11 ml, volume reactor) cooled by a cold water circuit.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[CH3:19][CH:20]([CH3:23])[CH:21]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:19][CH:20]([CH3:23])[CH2:21][NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C(N)C1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)CNC1CN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 4-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (840 mg) and 2-methylpropanal (256 mg) in dichloroethane (10 ml) were added acetic acid (203 mg) and sodium triacetoxyborohydride (931 mg). The mixture was stirred at room temperature for 1 hr. The mixture was neutralized with 6% aqueous sodium hydrogen carbonate. After partitioning, the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:1) was concentrated under reduced pressure to give the object compound (940 mg) as an oil.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:31][N:32](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[C:20]([O:19][C:17]([N:13]1[CH2:14][CH2:15][C:16]2[NH:8][CH:9]=[N:10][C:11]=2[CH:12]1[C:24]1[CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28][CH:29]=1)=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncn2C(=O)OC(C)(C)C)C1c1ccc(Br)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1c1ccc(C#N)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-(4-Bromo-phenyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-1,5-dicarboxylic acid di-tert-butyl ester (0.55 g, 1.14 mmol) and Zn(CN)2 (0.13 g, 1.14 mmol) were stirred in anh. DMF (10 mL) and degassed with Ar for 15 min. Tetrakis(triphenylphosphine)-palladium(0) was added to the solution and stirred at 80° C. under Ar overnight. The solution was concentrated in vacuo, partitioned between EtOAc and sat. NaHCO3 soln, washed with H2O, brine, and dried over MgSO4. Filtration, concentration, and silica gel chromatography (0-2% MeOH/CH2Cl2 with NH4OH) gave the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[CH2:17]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of N-tert-butoxycarbonylpiperidin-4-ol (25 g, 0.124 mol) in 100 ml anhydrous THF was added to a suspension of sodium hydride (5.96 g, 0.15 mol, pentane washed) in 100 ml anhydrous THF at 0° C. The reaction was stirred at 0° C. for 1 hour, then treated with a solution of benzyl bromide (25.65 g, 0.15 mol) in 20 ml anhydrous THF. The reaction was allowed to stand for 20 h at room temperature, cooled to 0° C., and 50 ml water was added cautiously. The product was extracted using ethyl acetate, the combined organic extracts were washed with water, dried (MgSO4) and concentrated. Chromatography using petroleum ether→20% ethyl acetate-petroleum ether gave 4-benzyloxy-1-tert-butoxycarbonyl-piperidine as a colourless solid. δH (250 MHz, CDCl3) 1.45 (9H, s), 1.51-1.65 (2H, m), 1.80-1.94 (2H, m), 3.04-3.15 (2H, m), 3.51-3.61 (1H, m), 3.70-3.84 (2H, m), 4.56 (2H, m), 7.26-7.35 (5H, m). m/e (ES) 292.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:28][C@H:29]1[C@H:32]([CH3:33])[N:31]([S:34]([O-:37])(=[O:36])=[O:35])[C:30]1=[O:38])=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH2:28][C@H:29]1[C@H:32]([CH3:33])[N:31]([S:34]([OH:37])(=[O:35])=[O:36])[C:30]1=[O:38]
Reactant: [H][H]
Reactant: C[C@H]1[C@H](NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)[O-]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCO
Product: C[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reaction time: 1 h

Procedure:
A mixture consisting of 5.52 g of potassium carbonate in 20 ml of water and 160 ml of 1,2-dichloroethane is brought to reflux and 15.5 mmole of N-sulfonyl benzyloxycarbonylthreonine amide, O-mesylate, tetrabutylammonium salt is added in 20 ml of 1,2-dichloroethane (20 ml used as a rinse). After refluxing for 30 minutes, the mixture is poured into a separatory funnel, diluted with 50 ml of water and 100 ml of methylene chloride and the phases split. The resulting organic phase is dried over sodium sulfate and concentrated to yield crude (3S-trans)-3-benzyloxycarbonylamino-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt. The crude azetidinone is treated in 250 ml of ethanol with 0.8 g of 5% palladium on charcoal catalyst and hydrogen is bubbled through the solution. After 90 minutes the mixture is filtered through Celite with 50 ml of ethanol used as a rinse. The addition of 1.2 ml of formic acid to this solution causes an immediate precipitation of the title zwitterion which is filtered after stirring for 1 hour to yield, after drying at 10-1 torr for 1 hour, 1.1 g of product. A second crop of product is obtained upon concentration of the filtrate and addition of more formic acid to give 1.3 g of the title zwitterion.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:30])[CH2:25][C:26]([CH3:29])([NH2:28])[CH3:27].O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:23][N:24]([CH3:30])[CH2:25][C:26]([NH:28][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:12]=2)[NH:17][CH:18]=1)=[O:22])([CH3:29])[CH3:27]
Reactant: CN(C)CC(C)(C)N
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CN(C)C)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), DCI (123 mg, 0.64 mmol) and DMAP (110 mg, 0.90 mmol) in 6 mL of DMF was added N1,N1,2-trimethylpropane-1,2-diamine (100 mg, 0.86 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of methanol and THF (1:3, v/v) to give N-(1-(dimethylamino)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (22 mg, 16.5%) as a yellow solid. MS: (M+H)+=392; 1H NMR (300 MHz, DMSO): δ 13.38 (s, 1H), 12.90 (brs, 1H), 9.15 (s, 1H), 8.47 (d, 1H, J=8.4 Hz), 8.37 (s, 1H), 7.97 (s, 1 h), 7.45 (s, 1H), 7.10 (d, 1H, J=8.4 Hz), 2.74 (s, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 2.01 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (112 mg, 0.459 mmol, Compound C of Example 22) in methylene chloride (4 mL) at 0° C. was added 96 μL (0.55 mmol) of diisopropylethylamine followed by 61 μL (0.48 mmol) of ethyl 3-chloro-3-oxopropanoate. The reaction was stirred at 0° C. for 1 h and was then quenched with 10 mL of saturate NaHCO3 solution. The aqueous layer was extracted with chloroform (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil that solidified on standing (180 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=1)(=[O:24])=[O:23].C1C(=O)N([I:42])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([I:42])=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=1)(=[O:24])=[O:23]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)ccc2n1
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a CH2Cl2 (20 mL) solution N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (315.0 mg, 619.0 μmol) was added n-iodosuccinimide (195.0 mg, 866.6 μmol, Alfa Aesar, Ward Hill, Mass.) as a solid in a single portion. The solution turned dark brown and was maintained at rt for 1 h. The solution was concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The crude residue was taken up in minimal CH2Cl2/MeOH and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (80 g) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (370.0 mg, 94.16% yield) as a brown solid. LCMS (ESI positive ionization) m/z: 635 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[F:1]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C(=O)OCC)c1ccc(N)c(F)c1

Procedure:
To a solution of 41.6 g diethyl 2-(4-nitro-3-fluorophenyl)-2-methylmalonate III in 210 ml ethyl acetate in a 500-ml Parr hydrogenation bottle is added 830 mg (2 wt %) of 5% palladium/carbon. The mixture is hydrogenated in a Parr apparatus at 25° C. under 10-12 psi hydrogen for 2.5 hours. The catalyst is removed by filtration through diatomaceous earth (Celite®) and is washed with a few ml of ethyl acetate. The solvent is removed in vacuo to give diethyl 2-(4-amino-3-fluorophenyl)-2-methylmalonate as a viscous oil, 37.6 g [100% wt. yield]. This material is used without purification.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:22][OH:23])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:35][CH3:36])CC)C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:22][OH:23])=[O:19])[NH:17][C:22](=[O:23])[CH:21]([C:36]1[CH:35]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: O=C(NCCC[C@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)N[C@@H](CO)c1ccccc1)OCc1ccccc1
Yield: 129.6 %

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(S)-N-(2-hydroxy-1-phenylethyl)ornithine amide hydrochloride (2.0 g, 4.74 mmol; from step (b) above), 2-nitrophenyl diphenyl acetate (1.67 g; 5.21 mmol; see Example 1(c) above) and triethylamine (0.726 mL; 5.21 mmol) in 150 mL of CH2Cl2. The reaction mixture was heated to reflux for 1 hour, followed by standard aqueous work up, yielding 1.78 g of the sub-title compound as a white solid.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.N#N.Br[C:10]1[C:11]([NH:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([NH:22][CH3:23])=[O:21])=[CH:12][C:13]([Cl:16])=[N:14][CH:15]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.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>[Cl:16][C:13]1[CH:12]=[C:11]([NH:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([NH:22][CH3:23])=[O:21])[C:10]([CH:1]2[CH2:3][CH2:2]2)=[CH:15][N:14]=1
Reactant: OB(O)C1CC1
Reactant: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C1CC1
Yield: 54.3 %

Procedure:
A solution of cyclopropylboronic acid (0.38 g, 4.40 mmole, 1.5 eq) in toluene (100 mL) was degassed with N2 at 50° C. for 15 min. To this was added Pd(PPh3)4 (0.17 g, 0.15 mmole, 0.05 eq) and 2-(5-bromo-2-chloro-pyridin-4-ylamino)-N-methyl-benzamide (1 g, 2.93 mmole, 1 eq) and the resulting reaction mixture was again degassed for 30 min. To this a degassed solution K3PO4 (2.49 g, 11.72 mmole, 4 eq) in H2O (4 mL) was added in one portion and the resulting reaction mixture was refluxed for overnight. Solvent was removed under reduced pressure and the residue was diluted with water (100 mL) and then extracted with DCM (3×75 mL). Combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield crude product. Crude compound was purified by column chromatography over silica gel (60-120 mesh) using 0.5% MeOH-DCM as the eluant to give the title compound as a pale yellow solid (0.480 g, 54%). 1H-NMR (400 MHz, DMSO-d6): δ 0.60-0.70 (m, 2H), 0.95-1.05 (m, 2H), 1.60-1.71 (m, 1H), 2.76 (d, 3H, J=4.48 Hz), 7.09 (s, 1H), 7.10-7.18 (m, 1H), 7.49-7.60 (m, 2H), 7.68-7.70 (d, 1H, J=7.64 Hz), 7.93 (s, 1H), 8.60-8.70 (m, 1H), 10.22 (s, 1H). LC-MS [M+H]+=302.0.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[N+:17]([O-])=O)[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:17][C:5]1[CH:6]=[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:15]=[CH:16][C:4]=1[NH:3][CH2:1][CH3:2])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCNc1ccc(NC(=O)C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)C(F)(F)F)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 4′-ethylamino-3′-nitro-2,2,2-trifluoroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 584 (MH+).