Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(O)(=O)C>[Br:1][C:10]1[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Bromine (27 ml) was added dropwise to a solution of 4-nitrophenol (50 g) in glacial acetic acid (400 ml) and the mixture stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure and the residue was crystallised from dichloromethane/hexane. The solid was collected and dried in vacuo to give the title compound as a colorless solid (67 g); δH (250MHz, CDCl3) 7.13 (1H, d, J 8.9 Hz, 6-H), 8.16 (1H, dd, J 2.6, 8.9 Hz, 5-H), 8.44 (1H, d, J 2.6 Hz, 3-H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)(=[O:17])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([O:38][CH2:39]C)(=[O:37])[CH3:36]>C(#N)C>[CH3:39][O:38][C:35](=[O:37])[CH2:36][N:23]1[C:24]2[C:20](=[CH:19][C:18]([S:15]([N:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:1])[F:28])=[CH:4][CH:5]=4)[CH2:14][CH2:13]3)(=[O:17])=[O:16])=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: O=S(=O)(c1ccc2[nH]ccc2c1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)Cn1ccc2cc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)ccc21
Yield: 99 %

Procedure:
5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-1H-indole (60 mg, 0.15 mmol), methyl bromo acetate (16 μL, 0.18 mmol) and cesium carbonate (95 mg, 0.29 mmol) were stirred in acetonitrile (10 ml) overnight at 70° C. The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated to provide {5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indol-1-yl}-acetic acid methyl ester (99%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.11 (d, 1H) 7.60 (dd, 1H), 7.43 (d, 2H), 7.36 (d, 1H), 7.24 (d, 1H), 6.83 (d, 2H), 6.90 (d, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.32-3.30 (m, 4H), 3.15-3.13 (m, 4H).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[N:15]([CH:16]2[CH2:19][O:18][CH2:17]2)[CH2:14][CH2:13][N:12]([C:20]2[C:21]([Cl:36])=[C:22]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:23]=[C:24]([C:26]#[N:27])[CH:25]=2)[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[Cl:36][C:21]1[C:20]([N:12]2[CH2:13][CH2:14][N:15]([CH:16]3[CH2:19][O:18][CH2:17]3)[CH:10]([CH2:9][OH:8])[CH2:11]2)=[CH:25][C:24]([C:26]#[N:27])=[CH:23][C:22]=1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CO[Si](C)(C)C(C)(C)C)C2)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCN(C3COC3)C(CO)C2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
(+/−) Tert-butyl (3-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(oxetan-3-yl)piperazin-1-yl)-2-chloro-5-cyanophenyl)carbamate (551 mg, 1.026 mmol) was taken up in THF (5 mL) and TBAF (1.539 mL, 1.539 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and washed with water, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-100% 20% (2N NH3/MeOH)/DCM). (+/−) Tert-butyl (2-chloro-5-cyano-3-(3-(hydroxymethyl)-4-(oxetan-3-yl)piperazin-1-yl)phenyl)carbamate (416 mg) was obtained as an orange glass.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[CH:6]=[CH:5][N:4]=1.C([O-])(O)=[O:23].[Na+]>>[O:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:11]2[N:10]=[C:9]([C:7]3[CH:6]=[CH:5][NH:4][C:3](=[O:23])[CH:8]=3)[CH:14]=[CH:13][N:12]=2)[CH2:17][CH2:18]1
Reactant: Fc1cc(-c2ccnc(NC3CCOCC3)n2)ccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Yield: 94 %

Procedure:
1M HCl (35 mL) was added to 4-(2-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.32 g, 1.2 mmol). The mixture was heated at reflux overnight. The cooled reaction mixture was neutralized with solid NaHCO3. The resulting solid was collected by vacuum filtration, washed into a flask with EtOAc/MeOH, evaporated and dried to afford 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.30 g, 1.1 mmol, 94% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.74 (br s, 1H), 8.40 (d, 1H), 7.48 (d, 1H), 7.33 (d, 1H), 7.11 (d, 1H), 6.99 (br s, 1H), 6.85-6.76 (m, 1H), 4.04-3.92 (m, 1H), 3.92-3.85 (m, 2H), 3.45-3.36 (m, 2H), 1.90-1.81 (m, 2H), 1.59-1.48 (m, 2H); m/z (APCI-pos) M+1=273.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([F:14])=[C:7]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=1.C(O)(=O)C.Cl>C(O)C.[Fe]>[CH3:21][CH:2]([CH3:1])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]([F:14])=[CH:9][C:10]=1[NH2:11]
Reactant: CCOC(=O)Nc1cc(NCC(C)C)c([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Nc1cc(NCC(C)C)c(N)cc1F
Yield: 82.5 %

Procedure:
A stirred mixture of 2.7 grams (0.009 mole) of N-(2-methylpropyl)-3-ethoxycarbonylamino-4-fluoro-6-nitroaniline, 2.0 grams (0.036 mole) of iron powder, 15 mL of acetic acid, and 0.5 mL (0.009 mole) of concentrated hydrochloric acid in 75 mL of ethanol was heated at reflux for about five hours. The reaction mixture was then concentrated under reduced pressure to a residue, which was taken up in ethyl acetate and washed with aqueous solutions saturated with sodium bicarbonate and sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. NMR analysis of the residue indicated the presence of product and acetic acid. The residue was washed with several portions of an aqueous solution saturated with sodium bicarbonate, and then was extracted thoroughly with ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 2.0 grams of 2-(2-methylpropylamino)-4-ethoxycarbonylamino-5-fluoroaniline.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:14][NH:15]OC(C)(C)C)=[S:11]=C=O)[CH:5]=1.C1(OC)C=CC=CC=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([NH:14][NH2:15])=[S:11])[CH:5]=1
Reactant: COC(=O)c1cccc(C(NNOC(C)(C)C)=S=C=O)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(C(=S)NN)c1

Procedure:
A solution of 3-(N′-tert-butoxy-carbonyl-hydrazinocarbothioyl)-benzoic acid methyl ester (0.93 g) in TFA (9 mL)/anisole (2 mL) was stirred at 0° C. for 1 h. The solvents were evaporated in vacuum to give crude 3-hydrazinothiocarbonyl-benzoic acid methyl ester trifluoroacetate (0.98 g) as a crystallizing oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH:15]([CH3:17])[CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]1[CH:15]([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CC(C)C1CN(Cc2ccccc2)CCC1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1CNCCC1O

Procedure:
A mixture of 1-benzyl-4-hydroxy-3-isopropylpiperidine (2.9 g, 12.44 mmole) and 20% palladium hydroxide (0.25 g) in methanol (25 ml) was stirred in hydrogen atmosphere (1 atm.) for 24 hr at 30° C. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 4-hydroxy-3-isopropylpiperidine as oil. Yield 1.6 g (80%), C8H17NO, m/z 144 (M+1) PMR (CDCl3): 0.9 (6H, m, 2×CH3), 1.1-1.64 (2H, m, CH & H3), 1.66-2.42 (3H, m, H5, & OH, D2O exchangeable), 2.62 (1H, m, H2), 3.02 (2H, m, H6), 3.45 (1H, bs, NH, D2O exchangeable), 3.54 (1H, m, H6), 4.18 (1H, m, H4).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1>>[NH2:11][C:10]1[C:5]([C:3]([OH:2])=[O:4])=[N:6][C:7]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][C:20]=2[CH3:27])=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: Cc1cc(Cl)ccc1B(O)O
Product: Cc1cc(Cl)ccc1-c1nc(C(=O)O)c(N)cc1C(F)(F)F

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 4-chloro-2-methylphenylboronic acid analogously to Intermediate H; LC-MS Rt=1.53 mins, [M+H]+ 331 (Method 2 min LC_v002).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CN.[C:23]([BH3-])#[N:24].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]2[NH:24][CH3:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCc2ccccc2C1c1ccc(Cl)c(Cl)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC1CCc2ccccc2C1c1ccc(Cl)c(Cl)c1
Reaction time: 20 h
Yield: 66 %

Procedure:
To a solution of tetralone 35 (400mg, 1.374 mmol) in THF (10 mL) and methanol (15mL) was added methylamine hydrochloride (1.12 g, 10 eq). The resultant mixture was stirred at 50° C. After dissolution (10 min), sodium cyanoborohydride (6.9 mL, 1M in THF, 5 eq) was added in a single portion. After 20 hours, the organic layer was evaporated, filtered through silica and an aminopropyl cartridge. The crude oil was then diluted with sodium bicarbonate solution and extracted with MTBE to give the amine (280 mg, 66%) as a mixture of four stereoisomers (1:1:1:1).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:26][O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[CH3:26][O:27][C:28](=[O:45])[CH2:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][C:7]=1[N+:16]([O-:18])=[O:17])(=[O:3])[CH3:2].[BH4-].[Li+].O>O1CCCC1>[OH:11][CH2:10][C:9]1[CH:14]=[CH:15][C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[C:7]([N+:16]([O-:18])=[O:17])[CH:8]=1
Reactant: COC(=O)c1ccc(CNC(C)=O)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCc1ccc(CO)cc1[N+](=O)[O-]
Yield: 87.2 %

Procedure:
A solution of methyl 4-acetamidomethyl-3-nitrobenzoate (20 g) and lithium borohydride (1.7 g) in tetrahydrofuran (200 ml) was stirred at 40-50° C. for 2.5 hr. The reaction mixture was poured into water (150 ml) and extracted with ethylacetate (100 ml×3). The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (15.5 g). The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) to give a pale-brown solid (13.5 g). The obtained solid was crystallized from ethyl acetate/ethanol/hexane (30:2:5) to give the title compound (12 g) as yellow white crystals.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[CH2:3][CH2:2]1.O.[CH3:14][N:15]=[C:16]=[O:17]>C1C=CC=CC=1>[CH3:14][NH:15][C:16]([O:12][N:11]=[C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:1][CH2:2][CH2:3]1)=[O:17]
Reactant: CN=C=O
Reactant: ON=C1CCOc2ccccc21
Solvent: O
Solvent: c1ccccc1
Product: CNC(=O)ON=C1CCOc2ccccc21
Reaction time: 8 h

Procedure:
A 60 g (0.37 mole) portion of 4-chromanone oxime in 770 ml of benzene was refluxed until all water was removed via a Dean-Stark trap, 0.5 hrs. The solution was cooled to 25-30°, treated with 0.5 ml of triethylamine followed by the dropwise addition of 20 ml (0.33 mole) of methyl isocyanate at less than 70°. The reaction mixture was refluxed for 3 hrs., stored at room temperature overnight, filtered, and stripped of benzene under reduced pressure. The residue was treated with 200 ml of ether, cooled 20 min. and filtered. The white crystalline product was washed with 100 ml of ether and dried, m.p. 123°-126°. Yield: 64 g (88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH2:52])=[N:48]2)([OH:45])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:40][CH2:41][C:42]([CH2:46][N:47]2[CH:51]=[CH:50][C:49]([NH:52][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:31])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]3)=[O:30])=[N:48]2)([OH:45])[CH2:43][CH2:44]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cn2ccc(N)n2)CC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)n2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (500 mg, 1.0 mmol), 4-(3-amino-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (592 mg, 2.0 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 593 mg, 1.5 mmol) and iPr2NEt (0.718 mL, 4 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford rac-4-(3-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-pyrazol-1-ylmethyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester as a white powder (480 mg, 64.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:21])[CH2:15][CH:16](OC)[O:17]C)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[ClH:22]>>[ClH:22].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][N:14]([CH3:21])[CH2:15][CH:16]=[O:17])=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(CN(C)Cc1c[nH]nc1-c1ccc(F)cc1)OC
Agent: Cl
Product: CN(CC=O)Cc1c[nH]nc1-c1ccc(F)cc1

Procedure:
A solution of N-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2,2-dimethoxy-N-methylethanamine (3.92 g, 13.36 mmol, 1.00 equiv) in 6N hydrochloric acid (40 mL) was stirred at 80° C. for 2 h. The resulting mixture was concentrated under vacuum to yield 3.82 g of crude 2-(((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)(methyl)amino)acetaldehyde hydrochloride as a yellow solid. 1H NMR (300 MHz, DMSO) δ: 9.43 (s, 1H), 8.07 (s, 1H), 7.73-7.52 (m, 2H), 7.41-7.21 (m, 2H), 4.54-4.25 (m, 2H), 4.12-4.00 (m, 2H), 2.55 (s, 3H) ppm. LCMS (method C, ESI): RT=0.59 min, m/z=266.0 [M+H+H2O]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(N(CC)CC)C.[N-:20]=[N+:21]=[N-:22].[Na+].Cl>CN1CCCC1=O>[N+:9]([C:5]1[CH:4]=[C:3]([C:1]2[NH:22][N:21]=[N:20][N:2]=2)[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Temperature: 160 °C
Yield: 88.9 %

Procedure:
To a solution of 3-cyanonitrobenzene (20 g, 0.13 mol) in 1-methyl-2-pyrrolidinone (200 mg) was added triethylamine hydrochloride (27.9 g, 0.20 mol) followed by sodium azide (26.4 g, 0.40 mol). The mixture was heated at 160° C. for 1.5 h, then cooled to ambient temperature, poured into ice water (100 mg) and acidified using 5M HCl. The solid which precipitated from the mixture was filtered, washed with water and dried under vacuum at 50° C. to afford the title tetrazole (22.1 g, 86%) as a beige powder, mp 154°-156° C. 1H NMR (360 MHz, CDCl13) δ 7.59 (1H, t, J=8 Hz), 8.19 (1H, d, J=8 Hz), 8.36 (1H, d, J=8 Hz), 8.86 (1H, s).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[N:10]([C:25](=[O:35])[CH:26]([NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]([CH3:29])[CH3:28])[CH2:9]1)=O)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.C(Cl)(=O)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl>[CH3:34][O:33][C:31](=[O:32])[NH:30][CH:26]([C:25]([N:10]1[CH:11]([C:13]2[N:14]=[CH:15][CH:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:17]=2)[CH2:12][N:8]([C:6](=[O:5])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:9]1)=[O:35])[CH:27]([CH3:29])[CH3:28]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1C1=NC(c2ccc(Br)cc2)C=N1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(4-Bromo-phenyl)-3′-(2-methoxycarbonylamino-3-methyl-butyryl)-2′,3′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-1′-carboxylic acid tert-butyl ester (55.6 mg, 0.101 mmol) was dissolved in dichloromethane (0.5 mL) and HCl (4M dioxane, 0.5 mL) was added. The resultant suspension was stirred at room temperature for 20 minutes, after which all volatiles were removed in vacuo. The crude material was dissolved in THF (1 mL) and diisopropyl ethylamine (26.0 mg, 0.202 mmol) was added, followed by benzoyl chloride (15.6 mg, 0.11 mmol). The reaction was stirred at room temperature. After 10 minutes, all starting material was consumed. All volatiles were removed in vacuo and the crude brown solid {1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester was used in the coupling reaction without further analysis or purification: LCMS-ESI+: calc'd for C26H28BrN5O4: 554.4 (M+). Found: 554.3/556.4 (M+H+).
Reaction SMILES: [OH:1][C:2]([C@@:4]1([O:50][C@@H:49]([C@@H:51]([C@@H:53]([CH2:55][OH:56])[OH:54])[OH:52])[C@H:44]([NH:45][C:46]([CH3:48])=[O:47])[C@@H:42]([OH:43])[CH2:41]1)[O:5][C@H:6]1[C@@H:36]([OH:37])[C@@H:35]([CH2:38][OH:39])[O:34][C@@H:8]([O:9][C@@H:10]2[C@@H:16]([CH2:17][OH:18])[O:15][CH:13]([OH:14])[C@H:12]([NH:19][C:20]([CH3:22])=[O:21])[C@H:11]2[O:23][C@@H:24]2[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]2[OH:26])[C@@H:7]1[OH:40])=[O:3].C[C@@H]1O[C@@H](O[C@@H]([C@H]([O:78][C@@H:79]2[O:84][C@H:83]([CH2:85][OH:86])[C@H:82]([OH:87])[C@H:81](O[C@@]3(C(O)=O)O[C@@H]([C@H](O)[C@H](O)CO)[C@H](NC(C)=O)[C@@H](O)C3)[C@H:80]2[OH:109])[C@H](O)CO)[C@@H](NC(C)=O)C=O)[C@@H](O)[C@H](O)[C@@H]1O>>[OH:3][C:2]([C@@:4]1([O:50][C@@H:49]([C@@H:51]([C@@H:53]([CH2:55][OH:56])[OH:54])[OH:52])[C@H:44]([NH:45][C:46]([CH3:48])=[O:47])[C@@H:42]([OH:43])[CH2:41]1)[O:5][C@H:6]1[C@@H:36]([OH:37])[C@@H:35]([CH2:38][OH:39])[O:34][C@@H:8]([O:9][C@@H:10]2[C@@H:16]([CH2:17][OH:18])[O:15][C@@H:13]([O:14][C@H:81]3[C@@H:82]([OH:87])[C@@H:83]([CH2:85][OH:86])[O:84][C@@H:79]([OH:78])[C@@H:80]3[OH:109])[C@H:12]([NH:19][C:20]([CH3:22])=[O:21])[C@H:11]2[O:23][C@@H:24]2[O:32][C@@H:31]([CH3:33])[C@@H:29]([OH:30])[C@@H:27]([OH:28])[C@@H:25]2[OH:26])[C@@H:7]1[OH:40])=[O:1]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@H]3[C@H](O[C@@H]4O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]4O)[C@@H](NC(C)=O)C(O)O[C@@H]3CO)[C@@H]2O)(C(=O)O)C[C@@H]1O
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@@H]([C@H](O[C@@H]3O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]3O)[C@H](C=O)NC(C)=O)[C@H](O)CO)[C@@H]2O)(C(=O)O)C[C@@H]1O
Product: CC(=O)N[C@H]1[C@H](O[C@@H]2[C@@H](O)[C@H](O)O[C@H](CO)[C@@H]2O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O[C@]3(C(=O)O)C[C@H](O)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O3)[C@H]2O)[C@@H]1O[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
NeuAcα2→3Galβ1→4(Fucα1→3)GlcNAc=Slex.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:18][C:17]=1[CH2:16][NH:15][CH:12]1[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]1
Reactant: Brc1ccccc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccccc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (1.0 g, 2.55 mmol) is coupled to bromobenzene (0.32 mL, 3.0 mmol) using Method A to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:60][C:61]1[CH:70]=[CH:69][C:64]([C:65]([NH:67][CH3:68])=[O:66])=[CH:63][CH:62]=1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:60][C:61]3[CH:62]=[CH:63][C:64]([C:65](=[O:66])[NH:67][CH3:68])=[CH:69][CH:70]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Reactant: CNC(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)cc1
Reaction time: 1 h
Yield: 28.4 %

Procedure:
3-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (58 mg, 148 μmol), HOBt (34.0 mg, 222 μmol) and EDCI (42.6 mg, 222 μmol) were combined with DMF (10 mL) to give a light yellow suspension. After 1 h, a clear yellow solution had been generated. DIPEA (47.9 mg, 64.7 μL, 370 μmol) and 4-amino-N-methylbenzamide (31.2 mg, 207 μmol) were added. After 15 h the mixture was concentrated in vacuo then diluted with water (10 mL) and filtered. The collected solid was washed with water (3×3 mL) and dried in vacuo. Purification by chromatography (silica, 50 g, Supelco VersaFlash, 0-5% methanol in dichloromethane, gradient over 15 min) gave a residue that was recrystallized from methanol to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (22 mg, 42.0 μmol, 28%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.60 (s, 1H) 9.98 (s, 1H) 8.62 (s, 1H) 8.53 (s, 1H) 8.36 (d, J=4.91 Hz, 1H) 8.16-8.27 (m, 2H) 8.10 (d, J=7.93 Hz, 1H) 7.87 (d, J=1.51 Hz, 4H) 7.61-7.76 (m, 2H) 7.42 (d, J=8.31 Hz, 1H) 7.13 (d, J=8.31 Hz, 1H) 4.03 (s, 3H) 3.77 (s, 3H) 2.79 (d, J=4.53 Hz, 3H); LC/MS: 524.1 [MH]+.