Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26]([OH:28])=O)[C:21]=4[CH3:29])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:30]=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][CH2:36][CH2:35]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[N:37]([C:26]([C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:30]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[C:21]=1[CH3:29])=[O:28])[CH2:36][CH2:35]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)O)c3C)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3ncnc(C(=O)N4CCc5cc(F)ccc54)c3C)CC1)C(=O)N2

Procedure:
70 mg (0.17 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-5-methyl-pyrimidine-4-carboxylic acid, 26.1 mg (0.19 mmol) 5-fluoroindoline, 61 mg (0.19 mmol) TBTU and 0.027 mL (0.19 mmol) TEA were stirred in 1 mL DMF for 3 h at RT. The reaction mixture was purified by HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:16]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]Cl)[CH:20]([CH2:21][CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(C(C)C)CC)(C)C.[I-].[K+].Cl>CN(C)C=O>[CH:20]12[N:23]([C:24](=[O:35])[CH:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27][N:13]3[CH2:14][CH2:15][N:10]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)[CH2:11][CH2:12]3)[CH:16]([CH2:22][CH2:21]1)[CH2:17][CH2:18][CH2:19]2
Reactant: O=C(C(CCCl)c1ccccc1)N1C2CCCC1CC2
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(CCN1CCN(c2cccc3[nH]ccc23)CC1)c1ccccc1)N1C2CCCC1CC2

Procedure:
The title compound was prepared from 4-(1H-indol-4-yl)-piperazine (1.0 g, 4.97 mmole), 1-(8-aza-bicyclo[3.2.1]oct-8-yl)-4-chloro-2-phenyl-butan-1-one (1.6 g, 4.97 mmole), diisopropylethylamine (0.65 g, 4.97 mmole) and potassium iodide (0.83 g, 4.97 mmole) in dimethylformamide (8 mL) in the manner described in example 2 to yield 0.6 g of product as the hydrochloride 0.75 hydrate, m.p. 150°-170° C.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].[CH2:9]([OH:12])[CH:10]=[CH2:11].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:9]([O:12][CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4])[CH:10]=[CH2:11]
Reactant: C=CCO
Reactant: CON(C)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCOCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Scheme 1, steps A and B: Bromoacetyl bromide (1.06 equiv.) is added to a solution of N,O-dimethylhydroxylamine hydrochloride (1.0 equiv.) (Volumes are in mL/g of this compound) in a stirring mixture of water (4 mL/g), toluene (4 mL/g), and K2CO3 (1.15 equiv.) at 0° C. After warming to room temperature over 1 hour, the layers are separated and the aqueous layer is extracted with toluene (2 mL/g). The combined organic layers are concentrated to give the intermediate 2-bromo-N-methoxy-N-methyl-acetamide containing about 20% toluene. 2-Bromo-N-methoxy-N-methyl-acetamide is added to a mixture of allyl alcohol (6.3 equiv) and K2CO3 (2 equiv.) over 3 hours at 30° C. After 2 hours at 30° C., toluene (4 mL/g) is added, the mixture is cooled to 0° C., and filtered. The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) and the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g). The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol. The concentrated toluene solution is washed with water (0.5 g/g), further concentrated to remove most of the toluene, and then distilled to give the title compound. LC-MS (m/z): 160 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:17][C:18]1([CH2:24][C:25]([NH2:27])=[O:26])[CH2:21][S:20](=[O:23])(=[O:22])[CH2:19]1>>[NH2:27][C:25](=[O:26])[CH2:24][C:18]1([NH:17][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH2:15][F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:19][S:20](=[O:22])(=[O:23])[CH2:21]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: O=C(O)c1cc(OCCF)c(C2CC2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCCF)c(C3CC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2-fluoroethoxy)-pyridine-2-carboxylic acid (example 146b) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (30 mg, 34%); MS (ESI, m/z): 386.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][F:22]>CN(C)C=O>[F:22][CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: FCCBr
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(C(F)(F)F)cc1
Yield: 43.4 %

Procedure:
Using 0.23 g of (4-(trifluoromethyl)benzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.13 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(2-fluoroethyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (64)).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:16]1([C:22]#[CH:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.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>[C:16]1([C:22]#[C:23][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Brc1ccncc1
Reactant: C#Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C(#Cc1ccncc1)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a suspension of 4-bromopyridine hydrochloride (3.9 g, 20 mmol), tetrakis(triphenylphosphine)palladium (2.32 g, 2.0 mmol), triethylamine (16.8 mL, 120 mmol) in dry DMF (150 mL) is added phenylacetylene (4.2 mL, 40 mmol) at room temperature. After stirring for 3 hours at 80° C., the reaction mixture is concentrated. The residue is dissolved in CH2Cl2 (100 mL), washed with H2O, brine (50 mL), dried (MgSO4) and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 10/90) to afford the title compound as a solid (3.25 g, 91%). Mp 51-53° C. MS (+) ES: 180 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-])=O.[OH-].[Na+].[C:17](=[S:19])=[S:18].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[S:19][C:17](=[S:18])[NH:12][C:3]=2[CH:4]=1)([OH:11])=[O:10]
Reactant: S=C=S
Reactant: O=C(O)Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2sc(=S)[nH]c2c1
Temperature: 115 °C
Yield: 54.3 %

Procedure:
A solution of 4-chloro-3-nitro-phenylacetic acid (25.0 g, 0.116 mol) in 1N aqueous NaOH (143 mL, 0.143 mol) was added to preformed polysulfide solution (from 72.42 g, 0.301 mol of Na2S.9H2O, 26.87 g, 0.837 mol of S, and 74 mL of H2O) at 50° C. The resulting mixture was mechanically stirred as the temperature of the oil bath was gradually increased to 115° C. over 10 min. The mixture was stirred at that temperature for two hours then allowed to cool to room temperature over two hours. Carbon disulfide (13.9 mL, 0.231 mol) was added and the reaction flask was placed in a 50° C. oil bath. The reaction mixture was stirred at that temperature for 18 hours then cooled in an ice bath, stirred, and acidified by cautious addition of glacial acetic acid (50 mL). The mixture was filtered and the filter cake was washed with water. The solid was stirred with sodium carbonate (30.7 g, 0.29 mol) in water then filtered to remove sulfur. The filtrate was cooled in an ice-bath and gradually acidified to pH 3.3 by addition of 6N HCl (100 mL). The precipitate was collected, washed with ice-cold water (100 mL) and dried in vacuo to a pale brown solid (21.5 g, 82%). This crude product was recrystallized from ethanol to afford 5-carboxymethyl-2-thioxo-2,3-dihydrobenzothiazole as a pale brown solid (14.2 g).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)Cl)cn1

Procedure:
6-Methyl nicotinic acid (138 mg, 1.00 mmol) was dissolved in dichloromethane (15 mL) and N,N-dimethylformamide (0.10 mL), and in an ice bath oxalic chloride (192 mg, 1.51 mmol) was added dropwise slowly. Upon completion of the dropwise addition, it was moved to react at room temperature for 3 hours, and concentrated under reduce pressure to obtain 6-methyl nicotinoyl chloride as a white solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([F:30])[CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[N:37]=[C:36]([C:38]#[N:39])[C:35](Br)=[CH:34][CH:33]=1>>[NH2:31][C:32]1[N:37]=[C:36]([C:38]#[N:39])[C:35]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:9]([S:6]([NH:5][C:1]([CH3:2])([CH3:3])[CH3:4])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:16][C:17]=2[F:30])=[CH:34][CH:33]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: N#Cc1nc(N)ccc1Br
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing N-(tert-butyl)-3′-fluoro-4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-sulfonamide and 6-amino-3-bromo-2-cyanopyridine. MS (ESI): mass calcd. for C22H21FN4O2S, 424.14; m/z found, 424.9 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.11-8.04 (d, J=7.9, 1H), 7.71-7.64 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.48 (m, 1H), 7.45-7.36 (dd, J=19.2, 9.2, 2H), 7.36-7.30 (dd, J=7.9, 1.6, 1H), 6.89-6.83 (d, J=8.7, 1H), 6.83-6.75 (d, J=10.0, 3H), 1.03 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:28]4[C:19](=[C:20]5[C:25](=[CH:26][CH:27]=4)[N:24]=[CH:23][CH:22]=[CH:21]5)[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c1ccc1ncccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc3ncccc3c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-1,2,3,4-tetrahydro-[3,7]phenanthroline to provide the title compound in moderate yield.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C([O:6][C:7](=O)[NH:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[CH:10][C:11]#[N:12])C.[CH3:22][CH:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]([NH:33][NH2:34])=O)[CH2:27][CH2:26]1)[CH3:24].O>CN1CCCC1=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:9]1[NH:8][C:7](=[O:6])[N:34]2[N:33]=[C:31]([CH:28]3[CH2:29][CH2:30][N:25]([CH:23]([CH3:24])[CH3:22])[CH2:26][CH2:27]3)[N:12]=[C:11]2[CH:10]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
In a round-bottom flask fitted with reflux condenser and a drying tube filled with calcium chloride, 500 mg (1.70 mmol) of ethyl[2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate and 310 mg (1.70 mmol) of 1-(1-methylethyl)piperidin-4-carbohydrazide (Example 38A) were dissolved in 2 ml of 1-methyl-2-pyrrolidone, and the reaction mixture was stirred at 160° C. for 3 h. The reaction solution was cooled to 100° C., water (20 ml) was added and the mixture was then cooled to RT and stirred for 15 min. The reaction mixture was extracted with dichloromethane (3×50 ml), and the combined organic phases were dried over magnesium sulfate and concentrated. The crude product was chromatographed on basic aluminum oxide (mobile phase dichloromethane/methanol 10:1, then dichloromethane/methanol/17% strength aqueous ammonia solution 15:2:0.2). This gave 2.55 g (78% of theory) of the product.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=O)=O.[Br-:24].[Mg+2].[Br-].O>CCOCC>[CH2:6]([Br:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: [Br-]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOS(C)(=O)=O
Agent: [Mg+2]
Solvent: O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCBr
Reaction time: 21 h
Yield: 109.6 %

Procedure:
A mixture of linoleyl methane sulfonate (6.2 g, 18 mmol) and magnesium bromide etherate (17 g, 55 mmol) in anhydrous ether (300 mL) was stirred under argon overnight (21 hours). The resulting suspension was poured into 300 mL of chilled water. Upon shaking, the organic phase was separated. The aqueous phase was extracted with ether (2×150 mL). The combined ether phase was washed with water (2×150 mL), brine (150 mL), and dried over anhydrous Na2SO4. The solvent was evaporated to afford 6.5 g of colourless oil. The crude product was purified by column chromatography on silica gel (230-400 mesh, 300 mL) and eluted with hexanes. This gave 6.2 g (approximately 100%) of linoleyl bromide (II). 1H NMR (400 MHz, CDCl3) δ: 5.27-5.45 (4H, m, 2×CH═CH), 3.42 (2H, t, CH2Br), 2.79 (2H, t, C═C—CH2-C═C), 2.06 (4H, q, 2× allylic CH2), 1.87 (2H, quintet, CH2), 1.2-1.5 (16H, m), 0.90 (3H, t, CH3) ppm.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11]([CH:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13]>>[CH2:11]([CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([C:7]1[CH:8]=[C:2]([C:1]([OH:10])=[O:9])[C:3]([OH:4])=[CH:5][CH:6]=1)=[O:16])[CH2:12][CH3:13]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: O=C(O)c1ccccc1O
Product: CCCC(CCC)C(=O)c1ccc(O)c(C(=O)O)c1
Yield: 52 %

Procedure:
This compound is prepared by a Friedel-Crafts reaction from salicylic acid and 2-propylpentanoyl chloride. The acid yield is 52%. The recrystallization is done in petroleum ether. The melting point is 118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([C@H:16]([CH2:20][O:21][CH3:22])[CH2:17][CH:18]=O)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:25]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][C@H:28]2[OH:33])[CH2:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([C@H:16]([CH2:20][O:21][CH3:22])[CH2:17][CH2:18][N:30]2[CH2:31][CH2:32][C:27]3([CH2:25][CH2:26]3)[C@H:28]([OH:33])[CH2:29]2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@H](CC=O)N1C[C@@H](C)N(C(=O)OC(C)(C)C)CCC1=O
Reactant: O[C@@H]1CNCCC12CC2
Agent: Cl
Product: COC[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1C[C@@H](C)N(C(=O)OC(C)(C)C)CCC1=O
Yield: 94 %

Procedure:
In analogy to the procedure described for example 58D, (R)-4-((S)-1-methoxymethyl-3-oxo-propyl)-2-methyl-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 94% yield as yellow viscous oil. MS: 440.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:29])[C:13]3[C:14](=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:51][N:52](C)[CH2:53]CO>O>[CH3:51][N:52]([CH3:53])[CH2:2][CH2:1][O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:29])[C:13]3[C:14](=[C:16]([CH2:26][CH2:27][CH3:28])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:39][CH3:40])[CH2:35][CH2:34]2)(=[O:31])=[O:32])=[CH:6][N:5]=1
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Reactant: CN(C)CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCN(C)C)[nH]c(=O)c2nn1Cc1ccccn1
Temperature: 90 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of the title compound of Example 26 (200 mg, 0.35 mmol), potassium bis(trimethylsilyl)amide (352 mg, 1.76 mmol) and 2-dimethylaminoethanol (1.5 ml) was stirred at 90° C. for 18 hours, then allowed to cool. Water (5 ml) was added, the mixture extracted with ethyl acetate (3×5 ml) and the combined extracts dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane:methanol (95:5 to 90:10), to give the title compound (147 mg, 68%) as an off-white foam. Found: C, 56.35; H, 6.37; N, 20.12. C29H39N9O4S; 0.50H2O requires C, 56.29; H, 6.52; N, 20.37%. δ (CDCl3): 0.94 (3H, t), 1.04 (3H, t), 1.72 (2H, m), 2.43 (8H, m), 2.56 (4H, m), 2.74 (2H, t), 2.95 (2H, t), 3.15 (4H, m), 4.80 (2H, t), 5.67 (2H, s), 7.07 (1H, d), 7.21 (1H, m), 7.61 (1H. m), 8.56 (1H, d), 8.62 (1H, s), 8.75 (1H, s), 12.23 (1H, s). LRMS: m/z 610 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(I)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Temperature: 100 °C
Yield: 86.2 %

Procedure:
A mixture of 5-iodopyridin-2-amine (25.5 g), 4-methylbenzene-1-sulfonyl chloride (23.2 g) and pyridine (250 ml) was heated at 100° C. overnight. The mixture was poured into water (1.2 L) with stirring, and the resulting precipitate was collected by filtration. The solid was washed with water and Et2O successively, and dried in vacuo to give the title compound (37.4 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[OH:4].CCN(C(C)C)C(C)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>C(Cl)Cl>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH:23][CH:24]([CH3:26])[CH3:25])[N:17]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH2:2][NH:1][S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)CN)cc3)no2)nc(NC(C)C)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccc(C(O)CNS(C)(=O)=O)cc3)no2)nc(NC(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a solution of rac-2-amino-1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol (39 mg, 0.11 mmol) and DIPEA (30 μL, 0.176 mmol) in DCM (6 mL) at 0° C. is added dropwise a solution of mesylchloride (10 μL, 0.132 mmol) in DCM (2 mL). The reaction mixture is stirred at 0° C. for 1 h, and then at rt for another hour. The reaction mixture is evaporated and purified by prep. TLC eluting with DCM/7M NH3 in MeOH 10:1 to give rac-N-(2-hydroxy-2-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl)-methanesulfonamide (19 mg) as a white solid; tR=0.89 min; [M+H]+=432.99.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@H:10]([C@H:11]([OH:16])[C@H:12]([OH:15])[CH2:13][OH:14])[O:9][C@:8]([O:20]P(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)(O)=O)([C:17]([OH:19])=[O:18])[CH2:7][C@@H:6]1[OH:41])=[O:3].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)O)=O.CC(NC1C(C(O)C(O)CO)OC(OP(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)([O-])=O)(C(O)=O)CC1O)=O.[Na+].[O:105]=[CH:106][C@@H:107]([C@H:109]([C@H:111]([C@@H:113]([CH2:115][OH:116])[OH:114])[OH:112])O)[OH:108]>>[OH:19][C:17]([C@@:8]1([O:9][C@@H:10]([C@@H:11]([C@@H:12]([CH2:13][OH:14])[OH:15])[OH:16])[C@H:5]([NH:4][C:2]([CH3:1])=[O:3])[C@@H:6]([OH:41])[CH2:7]1)[O:20][C@H:109]1[C@@H:111]([OH:112])[C@@H:113]([CH2:115][OH:116])[O:114][C@@H:106]([OH:105])[C@@H:107]1[OH:108])=[O:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@](OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: CC(=O)NC1C(O)CC(OP(=O)([O-])OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)OC1C(O)C(O)CO
Agent: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: [Na+]
Product: 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](O)O[C@H](CO)[C@@H]2O)(C(=O)O)C[C@@H]1O

Procedure:
The resulting CMP-sialic acid analogue (which in FIG. 3 is illustrated as the CKP derivative of Neu5Ac, i.e., CMP-Neu5Ac) is then combined with the derivatized βGal(1→3)βGlcNAc--OR compound in the presence of the βGal(1→3/4)βGlcNAc α(2→3)sialyltransferase under conditions wherein sialic acid is transferred to the 3 position of the galactose to form a αNeu5Ac(2→3)βGal linkage. Suitable conditions, known in the art, include the addition of the sialyltransferase to a mixture of the derivatized βGal(1→4)βGlcNAc--OR compound and of the CMP-sialic acid in a appropriate buffer such as 0.1M sodium cacodylate in appropriate conditions of pH and temperature such as at a pH of 6.5 to 7.5 and a temperature between 25° and 45° C., preferably 35°-40° C., while incubating for 12 hours to 4 days. The resulting sialylated product can be isolated and purified using conventional methodology comprising HPLC, ion exchange-, gel-, reverse-phase- or adsorption chromatography.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH:21]1([C:24]2[NH:25][CH:26]=[CH:27][N:28]=2)[CH2:23][CH2:22]1>[Pd]>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:25]4[CH:26]=[CH:27][N:28]=[C:24]4[CH:21]4[CH2:23][CH2:22]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: c1c[nH]c(C2CC2)n1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: [Pd]
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3C3CC3)nc2N1C1CCCC1

Procedure:
Intermediate B was reacted via palladium coupling with 2-cyclopropyl-1H-imidazole (synthesized according to U.S. Pat. No. 6,610,723, column 91, Example 409, the disclosure of which is hereby incorporated by reference with respect to this compound) to provide the title compound. 1H NMR (CD3OD) δ: 8.05 (s, 1H), 8.04 (d, J=2.2 Hz, 1H), 7.46 (d, J=2.2 Hz, 1H), 4.43 (pent, J=3.7 Hz, 2H), 3.40 (s, 3H), 3.21 (pent, J=3.3 Hz, 1H), 2.20-2.05 (m, 1H), 2.05-1.77 (m, 7H), 1.75-1.60 (m, 2H), 1.36 (d, J=7.5 Hz, 2H), 1.30-1.10 (m, 2H), 0.87 (t, J=7.5 Hz, 3H); LCMS: 367.1 m/z (M+H)+; ret. Time: 6.70 min (Analytical Method C).