Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl.[Cl:14][CH2:15][C:16]([NH2:18])=[NH:17].C(N(CC)CC)C>CO>[Cl:14][CH2:15][C:16]1[NH:18][C:4](=[O:5])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:17]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: N=C(N)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=c1[nH]c(CCl)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 60 h
Yield: 12.9 %

Procedure:
To a solution of ethyl 2-cyclohexanone-carboxylate (5.5 g, 32 mmol) in methanol was added chloroacetamidine hydrochloride (4.2 g, 32 mmol) and triethylamine (14 mL, 97 mmol). The mixture was stirred at ambient temperature for 60 h. It was then concentrated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (0.82 g, 13% yield). 1H NMR (400 MHz, CD3OD) δ 4.40 (s, 2H), 2.61 (t, J=6.3 Hz, 2H), 2.45 (t, J=6.3 Hz, 2H), 1.68-1.87 (m, 4H). MS m/z 199.2 (M+1), retention time=0.94 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][CH2:21][C:18]1[S:19][CH:20]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=2)[N:17]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(F)cc2)cs1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(-c2csc(CBr)n2)cc1
Temperature: 80 °C
Yield: 101.3 %

Procedure:
N-Bromosuccinimide (3.22 g, 18.13 mmol) was added to a solution of 4-(4-fluorophenyl)-2-methylthiazole (3.5 g, 18.13 mmol) in CCl4 (30.0 mL) and the reaction was refluxed at 80° C. overnight. The reaction mixture was then diluted with CH2Cl2, washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield crude 2-(bromomethyl)-4-(4-fluorophenyl)thiazole (5 g), which was carried through without further purification. 1H NMR (400 MHz, DMSO) δ 8.18 (s, 1H), 7.93-8.01 (m, 2H), 7.26-7.31 (m, 2H), 5.07 (s, 2H). MS (ESI) m/z: Calculated for C10H7BrFNS: 272.94. found: 273.9 (M+H)+
Reaction SMILES: C1([N:4]2[C:13]3[C:8](=[CH:9][C:10](F)=[C:11](N4CCNCC4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)CC1.BrCC(OCC)=O.C(N(CC)CC)C.[I-].[K+]>CN(C)C=O.O>[O:21]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][CH:5]=[C:6]1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: CCOC(=O)CBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
3.3 g (0.01 mole) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid in 50 ml of dimethylformamide are heated at 90° C. with 2.5 g (0.015 mole) of ethyl bromoacetate, 2.1 g (0.02 mole) of triethylamine and 2.5 g of potassium iodide for 5 hours. The reaction mixture is poured into 30 ml of water and the precipitate is filtered off with suction, washed with water and recrystallised from methanol. 2.5 g of 1-cyclopropyl-6-fluoro-7-[4-ethoxycarbonylmethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 192° to 194° C. are obtained.
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.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH:29]=O>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cc2ccccc2s1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cc5ccccc5s4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-benzothiophene-2-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-(1-benzothiophen-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=CNN=1.CO[C:9](=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:19])([F:18])[F:17]>>[O:20]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([F:17])([F:18])[F:19])[CH2:6][C:2]#[N:1]
Reactant: Nc1cc[nH]n1
Reactant: COC(=O)c1ccccc1C(F)(F)F
Product: N#CCC(=O)c1ccccc1C(F)(F)F
Yield: 94 %

Procedure:
The product was prepared according to the general procedure for aminopyrazole synthesis (route A1) from 2-trifluoromethyl-benzoic acid methyl ester (3.1 g, 14.0 mmol, 1.0 eq). The crude was precipitated from HCl to give the title product as a yellow solid (2.8 g, yield: 94%).
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:25][C:26](=[O:28])[CH3:27])C=CC=CC=1>C(Cl)Cl>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[CH:25][C:26](=[O:28])[CH3:27])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)C=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 350 mg (1.50 mmol) sample of CBZ-L-prolinal, from step 23b above, dissolved in 5 mL of methylene chloride was added 576 mg of 1-triphenylphosphoranylidene-2-propanone (Aldrich, 1.81 mmol). The reaction was stirred at room temperature for 45 min, then heated at reflux for 1.3 hr. The solution was cooled, and a precipitate formed. The mixture was extracted with methylene chloride (3×10 mL). The combined organics were washed with brine and dried over MgSO4. The residue was chromatographed on silica gel, eluting with 25-35% ether in hexane. The title compound was isolated by removal of solvent (279 mg). Anal. Calcd for C16H19NO3 : C, 70.31; H, 7.01; N, 5.12; Found: C, 70.20; H, 7.02; N, 5.10.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([CH2:26][CH2:27][CH3:28])[C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>CN(C=O)C>[CH2:40]([O:39][C:37](=[O:38])[C:36]([CH3:43])([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]([CH2:26][CH2:27][CH3:28])[C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)=[CH:4][CH:3]=1)[CH3:42])[CH3:41]
Reactant: CCCn1c(CCc2ccc(O)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCn1c(CCc2ccc(OC(C)(C)C(=O)OCC)cc2)nn(-c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a mixture of 5-[2-(4-Hydroxyphenyl)ethyl]-4-propyl-2-(4-trifluoromethylphenyl)-2,4-dihydro-[1,2,4]triazol-3-one (0.10 g, 0.26 mmol) and cesium carbonate (0.16 g, 0.49 mmol) in anhydrous DMF (2.5 mL) was added ethyl 2-bromoisobutyrate (81.1 mg, 60.6 □L, 0.42 mmol). The reaction mixture was heated to 75° C. overnight. More ethyl 2-bromoisobutyrate (30.3 □L) was added and the mixture was stirred at 110° C. overnight and ambient temperature over the weekend. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with 5% aqueous lithium chloride solution, water, brine, dried and evaporated. Chromatotron chromatography (gradient of ethyl acetate in hexanes) gave the pure compound (94 mg, 70.7%): 1HNMR (400 MHz, CDCl3) δ 8.14 (m, 2H), 7.65 (m, 2 H,), 7.10 (m, 2H), 6.80 (m, 2H), 4.23 (m, 2H), 3.53 (m, 2 H), 3.05 (m, 2H), 2.83 (m, 2H), 1.70 (m, 2H), 1.57 (s, 6 H), 1.26 (m, 6H); ESMS m/z (relative intensity) 506.1 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]2[NH:7][C:8]([S@:10]([CH2:12][C:13]3[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=3)=[O:11])=[N:9][C:5]=2[CH:4]=1.[C:25](=[O:37])([O:34][CH2:35][CH3:36])[O:26][CH2:27][CH2:28][N:29]([C:31](Cl)=[O:32])[CH3:30].C(N(CC)CC)C.C(=O)(OCCN(C(N1C2C=C(OC)C=CC=2N=C1[S@](CC1C(C)=C(OC)C(C)=CN=1)=O)=O)C)OCC>O1CCCC1.CN(C)C1C=CN=CC=1>[C:25](=[O:37])([O:26][CH2:27][CH2:28][N:29]([C:31]([N:7]1[C:6]2[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=[C:8]1[S@:10]([CH2:12][C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[CH:15][N:14]=1)=[O:11])=[O:32])[CH3:30])[O:34][CH2:35][CH3:36]
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Reactant: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: CCOC(=O)OCCN(C)C(=O)n1c([S@@](=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)cc21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCN(C)C(=O)n1c([S@@](=O)Cc2ncc(C)c(OC)c2C)nc2cc(OC)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (1.34 g) synthesized by a method described in Synthetic Example 1 of JP-A 10-504290 in tetrahydrofuran (10 mL) were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.9 mL) obtained in Reference Synthetic Example 34, triethylamine (1.08 mL) and 4-dimethylaminopyridine (0.010 g), and stirred at 60° C. for 6 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2, then 1:1) to give a mixture of 3:2 of title compound and ethyl 2-[[[(S)-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](methyl)amino]ethyl carbonate as pale yellow amorphous solid (0.92 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:17][CH2:18][C:19]#[N:20])[CH2:6][CH2:7][N:8]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:10][C:11]#[N:12])#[N:2].[H][H]>O1CCOCC1>[NH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][N:5]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:4][CH2:3][CH2:1][NH2:2]
Reactant: [H][H]
Reactant: N#CCCN(CCC#N)CCN(CCC#N)CCC#N
Solvent: C1COCCO1
Product: NCCCN(CCCN)CCN(CCCN)CCCN
Yield: 96.1 %

Procedure:
5.00 g of N,N,N′,N′-tetrakis(2-cyanoethyl)ethylenediamine, 0.50 g of Raney Co and 50 mL of dioxane were charged in an autoclave and a hydrogenation reaction was carried out at an initial hydrogen pressure of 8.0 MPa at 100° C. for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated to dryness to give 5.09 g of the title compound as a pale red oil.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:29])=[C:5]([C:20]([O:27]C)=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:22]1[C:3](=[O:2])[C:4]([CH3:29])=[C:5]([CH2:6][C:7]2[C:8]([O:16][C:17](=[O:19])[CH3:18])=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])[C:20](=[O:27])[C:21]=1[O:25][CH3:26]
Reactant: COc1c(C)c(Cc2cccc(C(=O)O)c2OC(C)=O)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Yield: 99.8 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-acetoxybenzoic acid (0.300 g, 0.663 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.909 g, 1.658 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.248 g, 0.662 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21]4[CH2:26]CN(C)CC4)=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.CN1CCN([C:35](Cl)=[O:36])CC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([O:12][N:11]=2)[CH2:18][CH2:17][N:16]([C:19]([N:21]([O:36][CH3:35])[CH3:26])=[O:20])[CH2:15]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CN1CCN(C(=O)N2CCC3(CC(C#Cc4cccc(Cl)c4)=NO3)C2)CC1
Product: CON(C)C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Yield: 54.1 %

Procedure:
The title compound was synthesized using the method described for the compound of Example 104, replacing N-methoxy-N-methylcarbamoyl chloride for 4-methyl-1-piperazinecarbonyl chloride. After evaporation, the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient petroleum ether-EtOAc 8:2 to 4:6) to afford a pale yellow solid. Yield: 54.1%.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][OH:7])(=[O:3])[CH3:2].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[C:1]([NH:4][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][O:7][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CO)NC(C)=O
Reactant: C1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](COC1CCCCO1)NC(C)=O
Reaction time: 7 h

Procedure:
To a solution of about 4.50 g of N-acetyl-L-serine, methyl ester in about 100 ml of dry methylene chloride was added about 2.93 ml of distilled tetrahydro-2H-pyran and about 0.34 ml of borontrifluoroetherate. The mixture was stirred under argon for about 7 hours, then washed with saturated sodium bicarbonate and brine, dried and the solvent removed under reduced pressure, giving about 6 g of the desired title compound.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=1[N+:17]([O-:19])=[O:18].[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([Br:30])=[C:25]([SH:31])[CH:24]=1>ClCCl.O>[CH3:20][O:21][C:22](=[O:32])[C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([Br:30])=[C:25]([S:31][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[N+:17]([O-:19])=[O:18])[CH:24]=1
Reactant: COC(=O)c1cc(C)c(Br)c(S)c1
Reactant: O=[N+]([O-])c1c(Cl)cccc1CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C)c(Br)c(SCc2cccc(Cl)c2[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (1.16 mL, 8.61 mmol) was added to a stirred solution of compound of Example 37a (2.87 g, 11.78 mmol) and compound of Example 1f (1.5 g, 5.74 mmol) in dry dichloromethane (75 mL). The reaction mixture was stirred at 0° C. for 20 min, was poured in water (100 mL) and extracted with chloroform (2×50 mL). The combined extract was washed with water (50 mL), brine (50 mL) and concentrated under vacuum to obtain the crude product, which was purified by column chromatography (silica gel, 5% ethyl acetate in pet ether 60-80° C.) to obtain the title compound. Yield: 1.93 g, (77.82%); 1H NMR (DMSO-d6, 300 MHz): δ 2.55 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 4.25 (s, 2H, CH2), 7.45 (s, 1H, Ar), 7.50-7.60 (m, 2H, Ar), 7.75 (s, 1H, Ar), 7.85 (s, 1H, Ar); MS: m/e (ES−) 431 (M−1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[N:19]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]([CH3:23])=[CH:21][CH:20]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](OCC)=[O:37]>C1COCC1>[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[O:37])[CH2:23][C:22]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: Cc1ccnc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: O=C(Cc1ccnc2ccccc12)c1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48.3 %

Procedure:
To a solution of diisopropylamine (44.9 mL, 320 mmol) in THF (500 mL) at −78° C. add 1.6 M n-butyl lithium in hexane (200 mL, 320 mmol). Stir for 10 minutes and add dropwise a solution of lepidine (42.9 g, 300 mmol) in THF (200 mL) over 20 minutes at −78° C. and quickly add a solution of ethyl picolinate (48.3 g, 320 mmol). Allow the reaction to warm slowly to 0° C. and quench by pouring into water (1 L). Add ethyl acetate (1 L). Dissolve residual solids by adding Acetic acid (20 mL). Separate the layers and extract the aqueous layer with one portion of ethyl acetate (100 mL). Combine the organic extracts, dry over sodium sulfate, and concentrate in vacuo. Triturate the crude oil with hexane/ether to give 36 g of the title compound. Concentrate the filtrate. Chromatograph the residue on silica gel (elute with 10:9:1 CH2Cl2, ether, MeOH). Precipitate the purified product from ether/hexane to give 21 g of the title compound. Combined yield: 57 g (76%) of title compound as a yellow crystalline solid. MS ES+ m/e 249.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:12]1[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccccc2Br)CC1

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (50 mg, 0.20 mmol), tert-butyl piperidin-4-ylcarbamate (49 mg, 0.25 mmol), and diisopropylethyl amine (0.101 mL, 0.59 mmol) in CH2Cl2 was stirred for 90 min at rt. The reaction mixture was then concentrated to dryness to give the title compound in quantitative yield. The product was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].C(N(CC)CC)C.[Cl:19][C:20]1[CH:21]=[C:22]([N:31]=[C:32]=[O:33])[CH:23]=[CH:24][C:25]=1[O:26][C:27]([F:30])([F:29])[F:28].Cl>O1CCOCC1>[Cl:19][C:20]1[CH:21]=[C:22]([NH:31][C:32]([CH:8]2[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]2=[O:7])=[O:33])[CH:23]=[CH:24][C:25]=1[O:26][C:27]([F:30])([F:29])[F:28]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN1C(=O)C(C(=O)Nc2ccc(OC(F)(F)F)c(Cl)c2)C(=O)N(C)C1=O
Reaction time: 5 h
Yield: 83.8 %

Procedure:
7.8 g (0.05 mol) of 1,3-dimethylbarbituric acid were suspended in 150 ml of dioxane and 5 g (0.05 mol) of triethylamine, and 11.85 g (0.05 mol) of 3-chloro-4-trifluoromethoxy-phenyl isocyanate were added. The mixture was stirred for 5 hours under reflux. When it had cooled, the reaction mixture was brought to a pH value of 3 with 2 N hydrochloric acid and was concentrated in vacuo by distilling off the solvent. The residue was mixed with 200 ml of water, filtered off, mixed with 100 ml of isopropanol, again filtered off and dried. 16.5 g (74% of theory) of 5-(3'-chloro-4'-trifluoromethoxy-phenyl-carbamoyl)-1,3-dimethyl-barbituric acid, of melting point 160° C., were obtained.
Reaction SMILES: [Na+].[P:2]([O:10][CH2:11][C@H:12]1[O:16][C@@H:15]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[C@H:14]([OH:27])[C@@H:13]1[OH:28])([O:5][P:6]([O-:9])([O-:8])=[O:7])(=[O:4])[O-:3].[Na+].[Na+].N1C=CC=CC=1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>ClCCl>[P:2]([O:10][CH2:11][C@H:12]1[O:16][C@@:15]([Si:38]([CH3:40])([CH3:39])[CH3:37])([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[C@H:14]([OH:27])[C@@H:13]1[OH:28])([O:5][P:6]([OH:8])([OH:9])=[O:7])(=[O:3])[OH:4]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)([O-])OP(=O)([O-])[O-])[C@@H](O)[C@H]1O
Reactant: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[Si](C)(C)[C@@]1(n2cnc3c(N)ncnc32)O[C@H](COP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a 500 mL round-bottomed flask was added 3 g (21.7 mmol) adenosine-5′-diphosphate sodium salt and 200 mL pyridine. After the salt had dissolved. the solution was cooled to 0° C. under nitrogen atmosphere. Trimethylsilyl chloride (85 g, 800 mmol) in 200 mL dichloromethane was added slowly to the solution. After this addition was complete, the reaction was stirred at 35° C. for 8 hr. The pyridine hydrochloride salt was removed by filtration and excess pyridine and dichloromethane removed under high vacuum for 24 hr to yield 19.3 g (21.3 mmol) of TMS-ADP. The product was used without further purification. This synthesis is illustrated in FIG. 4E.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[C:16](F)[CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH:26](C)[CH3:27])(=[O:24])=[O:23].FC1C(C=O)=CC=CC=1NS(CCC)(=O)=O>>[F:11][C:12]1[C:17]([C:18]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([I:1])[CH:3]=3)[NH:8][CH:9]=2)=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23]
Reactant: CC(C)CS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: Ic1cnc2[nH]ccc2c1
Agent: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(I)cc23)c1F

Procedure:
was prepared similarly to the protocol of Scheme 10, replacing 5-bromo-1H-pyrrolo[2,3-b]pyridine 55 with 5-iodo-1H-pyrrolo[2,3-b]pyridine 24 and 2-methyl-propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 59 with propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide 67 in step 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][C:3]1([CH3:27])[CH3:26].[CH3:28][Li]>O1CCCC1>[CH3:26][C:3]1([CH3:27])[C:2]([CH3:28])([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4]1
Reactant: [Li]C
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)(C)C3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(C)(O)C(C)(C)C3)c(F)c2)C(=O)O1
Yield: 69 %

Procedure:
By reacting (S)-N-{3-[4-(4-oxo-3,3-dimethyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.3 mmol) and methyl lithium (2.3 mmol) in tetrahydrofuran (20 ml) followed by silica gel chromatographic separation of diastereomer the compound was obtained in 69% yield. M.P. 114-116° C. and MS (M+1)=394 (MH+, 100%) for M.F.=C20H28FN3O4.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:27])[CH2:12][N:13]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:51][C@H:52]1[CH2:56][CH2:55][C@@H:54]([CH2:57]O)[O:53]1>CN(C)C=O>[CH2:3]([O:10][C:11]([C:12]1([N:13]=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:57][CH:54]2[O:53][CH:52]([CH2:56][CH2:55]2)[CH2:51]1)=[O:27])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC[C@@H]1CC[C@H](CO)O1
Reactant: O=C(CN=C(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1(N=C(c2ccccc2)c2ccccc2)CC2CCC(C1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.41 grams, 17.1 mmole) in N,N-dimethylformamide (50 mL) at 0° C. is added dropwise a solution of N-diphenylmethylene glycine benzyl ester (7.8 mmole) in N,N-dimethylformamide (50 mL). After stirring for 30 minutes at room temperature, a solution of cis-2,5-bis(hydroxymethyl)-tetrahydrofuran ditosylate (4.1 grams, 9.3 mmole,)(prepared by literature methods such as those described in JOC, 47, 2429-2435 (1982)) in N,N-dimethylformamide (50 mL) is added dropwise. The reaction mixture is gradually heated to 100° C. in an oil bath and stirred at this temperature overnight. The solvent is evaporated under vacuum and the residue is taken up in water and extracted twice with diethyl ether. The combined organic extracts are washed with brine, dried over magnesium sulfate and concentrated to a crude product.