Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:16]2[CH:20]=[C:19]([C:21](=[O:24])[CH2:22][CH3:23])[N:18]([CH2:25][CH3:26])[CH:17]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:34][CH2:35][CH3:36]>CN(C=O)C>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:16]2[CH:20]=[C:19]([C:21](=[O:24])[CH2:22][CH3:23])[N:18]([CH2:25][CH3:26])[CH:17]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:34][CH2:35][CH3:36])[CH:10]=2)[N:3]=1
Reactant: CCC(=O)c1cc(C2(c3cccc(O)c3)N=C(N)N(C)C2=O)cn1CC
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1cccc(C2(c3cc(C(=O)CC)n(CC)c3)N=C(N)N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-amino-5-(1-ethyl-5-propionyl-1-H-pyrrol-3-yl)-5-(3-hydroxy-phenyl)-3-methyl-3,5-dihydro-imidazol-4-one (0.08 g, 0.225 mmol) in DMF (5 mL) was treated with Cs2CO3 (0.15 g, 0.45 mmol) and iodopropane (0.046 g, 0.27 mmol). The reaction mixture was sealed and stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was dissolved in CHCl3 and filtered. The filtrate was evaporated. The resultant residue was purified by combi flash chromatography (ethyl acetate/methylene chloride/methyl alcohol/triethyl amine, 5/4.4/0.5/0.1) to give the title compound as a white solid (0.04 g, 45% yield), mp 95° C., 1H NMR (400 MHZ, DMSO-d6) δ 0.89-0.99 (dt, 6H), 1.15 (t, 3H), 1.64-1.66 (m, 2H), 2.64-2.68 (m, 2H), 2.9 (s, 3H), 3.81 (m, 2H), 4.20 (m, 2H), 6.50 (bs, 2H), 6.72-6.74 (m, 1H), 6.87 (s, 1H), 7.0-7.02 (m, 3H), 7.14 (m, 1H), MS m/e (M+H)+ 397.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([C:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=2)=[CH:6][N:7]=1.C(Cl)Cl>CO>[NH2:1][C:2]1[C:3]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[C:16]([F:27])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3=CC(=O)CC3)cnc2N)cc1F
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(=O)C3)cnc2N)cc1F
Yield: 58.1 %

Procedure:
To tert-butyl 4-(3-amino-6-(3-oxocyclopent-1-en-1-yl)pyrazin-2-yl)-2-fluorobenzoate (650 mg, 1.760 mmol) in MeOH (15 ml) was added 15 ml of DCM under stirring until a clear solution was obtained. The solution was purged by nitrogen for 5 min, then Pd/C (300 mg, 10%, Degussa type) was added, and the resultant mixture was degassed by N2 stream for 15 min. After equipped with hydrogen gas balloon, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrated solution was concentrated, and the crude material was purified by ISCO. (24 g silica gel, 20 to 80% EtOAc in heptane) to afford 380 mg of the desired product as a light yellow solid. 58.1% yield. LC-MS (m/z): (MH+) 372.1, 0.829 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[S:13])[NH:11][CH:12]=1.[CH3:15]I.[OH-].[Na+].O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[C:8](=[O:14])[NH:9][C:10]([S:13][CH3:15])=[N:11][CH:12]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc(Cc2cccs2)c(=O)[nH]1
Yield: 89 %

Procedure:
5-(2-Thienylmethyl)-2-thiouracil (4.5 g) was warmed at 65° with a mixture of methyl iodide (2.8 g), sodium hydroxide (0.8 g), water (75 ml) and ethanol (150 ml) to give 5-(2-thienylmethyl)-2-methylthio-4-pyrimidone (89%) m.p. 170.5°-171.5° (ethanol).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([O:17][C:15]([CH2:14][CH2:13][C:10]1[S:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
0.564 g (2 mmol) of 5-(2-ethoxycarbonyl-ethyl)-thiophene-2-carboxylic acid tert-butyl ester were dissolved in 10 ml of dichloromethane. 2.5 ml of trifluoroacetic acid were added dropwise with stirring at room temperature. Stirring was continued for 5 hours until the starting compound was no more detectable by thin layer chromatography (TLC). The solvents were evaporated in vacuo to give 0.45 g of a crystalline residue which was sufficiently pure for use in the subsequent step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35]([C:6]2[CH:7]=[CH:2][CH:3]=[C:4]([C:8]3[CH:9]=[C:10]([C:15]4[CH:16]=[N:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)[CH:11]=[C:12]([CH3:14])[N:13]=3)[CH:5]=2)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 6′-(3-bromo-phenyl)-2′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl (example B.12) (0.197 g, 0.5 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.142 g, 0.55 mmol) according to the general procedure III. Obtained as a white foam (0.245 g, 93%). MS (ISP) 526.7 [(M+H)+].
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][O:7][CH:6]([C:10]([O:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][CH2:16][CH2:17]3)=[O:11])[CH2:5]1)([CH3:3])[CH3:2].[Mg].[CH3:23]Br>O1CCCC1>[OH:11][C:10]([O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][CH2:16][CH2:17]2)([CH:6]1[O:7][CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]1)[CH3:23]
Reactant: CC(C)N1CCOC(C(=O)Oc2cccc3c2CCC3)C1
Reactant: CBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)N1CCOC(C(C)(O)Oc2cccc3c2CCC3)C1
Temperature: 0 °C

Procedure:
A solution of 1.2 g. (0.004 mole) of 4-isopropyl-2-(1-oxo-4-indanyloxymethyl)morpholine in 5 ml. of anhydrous tetrahydrofuran was added gradually under ice-cooling in a nitrgen gas stream to a solution of a Grignard reagent prepared from 0.41 g. (0.017 atom) of magnesium and methyl bromide using 30 ml. of anhydrous tetrahydrofuran as a solvent and thereafter the mixture was stirred for 2 hours at room temperature. Then, to the reaction mixture was added ice water and the product was extracted thrice each with 30 ml. of methylene chloride. The organic layer was recovered, washed with water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure and the residue formed was subjected to a silica gel column chromatography (column diameter 1.5 cm., height 20 cm.), whereby 1.1 g. of 2-(1-hydroxy-1-methyl-4-indanyloxymethyl)-4-isopropyl morpholine was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:24])(=[O:23])[NH:10][C:11]3[C:20]2=[CH:19][CH:18]=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4].C(Cl)(Cl)[Cl:26]>>[CH3:1][O:2][C:3]([C:5]1[CH:22]=[C:21]2[C:8]([S:9](=[O:24])(=[O:23])[NH:10][C:11]3[C:20]2=[CH:19][C:18]([Cl:26])=[C:17]2[C:12]=3[N:13]=[CH:14][CH:15]=[CH:16]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: ClC(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Product: COC(=O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 57 %

Procedure:
In a similar fashion using route 51 general procedure 117,6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid methyl ester 307 (1.1 g, 3.2 mmol), 1,3-dichloro-5,5-dimethylhydantion (765 mg, 3.8 mmol) in chloroform (40 ml), gave the title compound (1.6 g, 57%) after washing with MeOH/DCM.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.COCCOC.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:51])[F:50])([C:45]([F:48])([F:47])[F:46])[OH:44])=[N:24]1.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:7]=[N:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=3)=[CH:30][CH:29]=2)[CH2:26][C:25]([C:43]([C:49]([F:52])([F:50])[F:51])([C:45]([F:46])([F:47])[F:48])[OH:44])=[N:24]1
Reactant: CC1(C)OB(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)OC1(C)C
Reactant: CSc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cc2)cn1
Temperature: 88 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To 5-bromo-2-(methylthio)pyridine (14.0 mg, 0.07 mmol), were added 1,2-dimethoxyethane (1.5 mL) and Pd(PPh3)4 (8.4 mg, cat.). To the reaction mixture, were added 1-(2-chloro-phenyl)-5-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (25.0 mg, 0.05 mmol) prepared in Step 1, ethanol 183.0 uL, and a 2N sodium carbonate solution (183.0 uL). The reaction mixture was stirred at 88° C. for 2 hours and then distilled water was added thereto. The reaction mixture was extracted with diethyl ether two times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 8.0 mg of the titled compound as a white liquid.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:11])=[CH:8]/[CH2:9][OH:10].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][C:29](Cl)=[O:30]>N1C=CC=CC=1>[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]([C:24]1[S:23][CH:27]=[CH:26][CH:25]=1)[C:29]([O:10][CH2:9]/[CH:8]=[C:7](\[CH3:11])/[CH2:6][CH2:5]/[CH:4]=[C:3](/[CH2:2][OH:1])\[CH2:12][CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[O:30]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Solvent: c1ccncc1
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/COC(=O)C(c1cccs1)c1cccs1)CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1.0 g of (E,Z,E) and (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol in 5 ml of anhydrous pyridine was added dropwise 2 ml of 2-thienylacetyl chloride under ice-cooling. After 1 hour, ice-water was added and extraction was done with ethyl ether. The ether layer was washed successively with dilute hydrochloric acid, aqueous sodium hydrogencarbonate and water and dried over anhydrous sodium sulfate. The solvent was distilled off to give an oily substance, which was then purified by a column chromatography with silica gel (15 g) to afford 1.1 g of the end product.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:21]3=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][N:20]3[N:19]=2)=[CH:14][CH:13]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:21]3=[CH:30][C:31]([C:33]([N:3]([CH3:4])[CH3:2])=[O:34])=[CH:32][N:20]3[N:19]=2)=[CH:14][CH:13]=1
Reactant: CNC
Reactant: Nc1ccc(-c2nc(N3CCOCC3)c3cc(C(=O)O)cn3n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3ccc(N)cc3)nn2c1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
Dimethylamine hydrochloride (686 mg, 8.4 mmol) was added to 30 mL of anhydrous N,N-dimethylformamide, and potassium carbonate (3.48 g, 25.2 mmol) was added and stirred for minutes at room temperature. Then compound 11a (4.2 mmol), HBTU (benzotriazole-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 4.77 g, 12.6 mmol), and triethylamine (2.9 mL, 21 mmol) were added and reacted overnight at room temperature under nitrogen atmosphere. The reaction mixture was poured into water and filtered. The filtrate was extracted once with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was combined with the filter cake. The crude product was purified by column chromatography (dichloromethane:methanol=100:1) to give white compound 12a (922 mg, 60.0%). m.p. 238-239° C. 1H NMR (300 MHz, CDCl3): δ 8.08 (d, J=8.6 Hz, 2H), 7.82 (d, J=1.4 Hz, 1H), 7.02 (d, J=1.4 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 4.11 (t, J=4.4 Hz, 4H), 3.86 (t, J=4.4 Hz, 4H), 3.20 (br, s, 6H). MS (EI) m/e (%): 366 (M+, 100).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.CS(C)=O.Cl.[NH2:38][OH:39]>C(N(CC)CC)C>[OH:39][NH:38][C:29](=[NH:30])[CH2:28][CH:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[N:15][C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:32])([F:31])[F:1])=[CH:4][CH:5]=4)=[CH:11][CH:12]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: N#CCC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: N=C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)NO
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of (4-{4-[6-(6-Trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetonitrile (0.15 g, 0.34 mmol, 1.0 equiv) in 4 Ml DMSO was added hydroxylamine hydrochloride (0.12 g, 1.7 mmol, 5.0 equiv) and triethylamine (0.25 Ml, 1.8 mmol, 5.2 equiv). The yellow solution was heated to 120° C. using microwave heating for 10 min. Additional portions of hydroxylamine hydrochloride and triethylamine were added, and the reaction was allowed to stir overnight at 75° C. The reaction was partitioned between EtOAc and water, and the organic extracts were washed with saturated NaHCO3 followed by brine. The organic layer was then dried over sodium sulphate, filtered, and concentrated in vacuo to afford the title compound which was used without further purification: (M+H)+471.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27]C)=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][NH:15][C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:25]([OH:27])=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:32])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (28 mg, 0.074 mmol) in anhydrous DMF under inert atmosphere was added sodium hydride (3 mg, 0.111 mmol, 95% dispersion in oil). The mixture was treated with iodomethane (6 μL, 0.089 mmol) and stirred at room temperature for 1 hour. When the methylation was complete, several drops of H2O were added and the mixture stirred at room temperature for 1 hour. The mixture was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions yielded the title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 12.90 (s, 1H), 7.51-7.49 (m, 2H), 7.39-7.31 (m, 6H), 7.01-7.00 (m, 2H), 5.80 (s, 1H), 5.27 (dd, J=11.2, 25.2 Hz, 2H), 4.21 (d, J=4.8 hz, 1H), 4.18 (d, J=4.4 Hz, 1H), 2.92 (s, 3H); ES MS (M+1)=378.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([Cl:24])[CH:3]=1.[F-].[Cs+].[CH2:27]([Sn](CCCC)(CCCC)C#CC)[CH2:28][CH2:29]C.CN(C)C=O>O.CCOCC.[Cu]I.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:8][C:6]1[CH:7]=[C:2]([C:27]#[C:28][CH3:29])[CH:3]=[C:4]([Cl:24])[C:5]=1[C:9]1[C:10](=[O:23])[CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:12][C:13]=1[O:14][CH3:15]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: COC1=C(c2c(Cl)cc(Br)cc2Cl)C(=O)C(Cc2ccccn2)C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC#Cc1cc(Cl)c(C2=C(OC)CC(Cc3ccccn3)C2=O)c(Cl)c1
Temperature: 120 °C
Yield: 32.1 %

Procedure:
A microwave vial was charged with 2-(4-bromo-2,6-dichloro-phenyl)-3-methoxy-5-(2-pyridylmethyl)cyclopent-2-en-1-one (90 mg, 0.21 mmol), caesium fluoride (CsF, 64 mg, 0.42 mmol), copper(I) iodide (CuI, 8 mg, 0.042 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (23 mg, 0.032 mmol), tributyl(prop-1-ynyl)stannane (83 mg, 0.25 mmol) and N,N-dimethylformamide (0.9 ml), sealed and heated at 120°C. under microwave irradiation for 30 minutes. Further caesium fluoride (32 mg, 0.21 mmol), copper(I) iodide (4 mg, 0.021 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (12 mg, 0.016 mmol) and tributyl(prop-1-ynyl)stannane (42 mg, 0.13 mmol) were added and the reaction heated at 120°C. under microwave irradiation for a further 30 minutes. The reaction was allowed to cool to room temperature, diluted with water (10 ml) and Et2O (10 ml) and filtered through Celite. The filtrate phases were separated and the aqueous phase extracted with further Et2O (2×10 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude product was dissolved in EtOAc, absorbed onto silica and purified by flash chromatography on silica using an EtOAc/isohexane gradient to give the desired product (26 mg, 32%). 1H NMR (400 MHz, CDCl3)δ ppm 8.50 (d, 1H), 7.60 (dd, 1H), 7.30 (2×s, 2×1H), 7.25 (d, 1H), 7.15 (dd, 1H), 3.75 (s, 3H), 3.40-3.35 (m, 1H), 3.20-3.10 (m, 1H), 3.00-2.90 (m, 1H), 2.85-2.80 (m, 2H), 2.05 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].CN(C=O)C.Cl[C:49]1[CH:50]=[CH:51][C:52]2[N:53]([CH:55]=[C:56]([NH:58][C:59](=[O:61])[CH3:60])[N:57]=2)[N:54]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([C:49]2[CH:50]=[CH:51][C:52]3[N:53]([CH:55]=[C:56]([NH:58][C:59](=[O:61])[CH3:60])[N:57]=3)[N:54]=2)=[CH:3][C:4]=1[NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)ccc2n1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
To a 25-mL, round-bottomed flask was added N-(5-bromo-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.15 g, 0.41 mmol), bis(pinacolato)diboron (0.16 g, 0.62 mmol), potassium acetate (0.16 g, 1.6 mmol) and 1,4-dioxane (4.0 mL). The mixture was carefully evacuated and backfilled with N2. To the solution was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.030 g, 0.041 mmol). The mixture was carefully evacuated and backfilled with N2 again then stirred at 90° C. for 6 h. The reaction mixture was cooled to rt and treated with DMF (4.0 mL, 52 mmol), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (0.055 g, 0.26 mmol) and 2.0 M aq. sodium carbonate (0.78 mL, 1.6 mmol). The mixture was carefully evacuated and backfilled with N2. To the solution was added trans-dichlorobis(triphenylphosphine)palladium(II) (0.018 g, 0.026 mmol) and then the solution was carefully evacuated and backfilled with N2 again. The mixture was stirred at 90° C. for 16 hours then poured into aq. NaCl (100 mL) and extracted with 25% iPrOH/CHCl3 (3×75 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to remove the DMF. The solution was then taken up in MeOH/CH2Cl2 and concentrated onto silica. Purification by silica gel chromatography (0.5 to 5.0% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a yellow solid. MS (ESI pos. ion) m/z: 461 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (s, 1H), 10.57 (s, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.31-8.36 (m, 2H), 8.13 (d, J=9.4 Hz, 1H), 7.80-7.88 (m, 3H), 7.39-7.48 (m, 2H), 2.13 (s, 3H).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].B(O)(O)O.C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:1][CH:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: O=C[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: OB(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: OC[C@H]1OC(O)[C@H](O)[C@H]1O
Temperature: 50 °C

Procedure:
L-xylose of formula 10 (5.00 g, 33.3 mmol) and boric acid (4.53 g, 73.3 mmol) were dissolved in acetic acid (120 mL), followed by heating at 50° C. for 1 hour with stirring. Acetic anhydride (120 mL) was added thereto. The reaction mixture was heated at 50° C. for 3 days and then cooled down at room temperature, followed by extraction by using water (600 mL) and ethyl acetate (3×300 mL). The ethyl acetate extract was washed with saturated sodium_bicarbonate solution and brine, and moisture remained in the solvent was dried over magnesium sulfate. The extract was concentrated to give xylofuranose, the compound of formula 5, as a syrup (10.45 g, 32.8 mmol, 99%, α:β=1:1.8).
Reaction SMILES: [NH2:1][CH:2]([CH:8]([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11](Cl)(=[O:13])[CH3:12].Cl>[OH-].[Na+].O1CCOCC1>[F:9][CH:8]([F:10])[CH:2]([NH:1][C:11](=[O:13])[CH3:12])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(=O)Cl
Reactant: NC(CCC(=O)O)C(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)NC(CCC(=O)O)C(F)F

Procedure:
To a solution of 2 mmole of 4-amino-4-difluoromethylbutyric acid in 5 ml of 1 N sodium hydroxide at 0° C. are added simultaneously from two syringes 160 mg of acetyl chloride diluted in 1 ml of dioxane and 2 ml of 1 N sodium hydroxide. After 30 minutes at 0° C. the solution is acidified by the addition of 6 N hydrochloric acid, then extracted well with dichloromethane. The organic phase is dried and concentrated to afford 4-difluoromethyl-4-(1-oxoethylamino)butyric acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: COc1ccc(F)c(B(O)O)c1
Product: COc1ccc(F)c(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)c1
Yield: 3.4 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 2-fluoro-5-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (6 mg, 3.4%) which was obtained as a white solid. MS (ESI): m/e=350.0 [M+H]+.