Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][SiH:26]([CH3:28])[Cl:27]>ClCCl.C(O)(C)C>[C:1]1([C@@H:7]([NH:10][C:11](=[O:24])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([N+:21]([O-:23])=[O:22])[CH:13]=2)[CH2:8][CH2:9][Si:26]([Cl:27])([CH3:28])[CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[SiH](C)Cl
Reactant: C=C[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: C[Si](C)(Cl)CC[C@H](NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1ccccc1
Reaction time: 6 h

Procedure:
1 g (3.06 mmol) of amide 5 was dispersed in an inert atmosphere in 10 ml of dry dichloromethane. 12 mg of H2PtCl6.xH2O was dispersed in 0.25 ml isopropanol and the obtained brown suspension was added to the reaction mixture. Afterwards, 10 ml of dimethylchlorosilane (92 mmol) was added and the reaction mixture was stirred on a reflux temperature for six hours. The transparent yellow solution was evaporated to paste remain which was dissolved in 5 ml of dry dichloromethane and again evaporated until dry.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.CN(C=O)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:28]2[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: OC1CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(O)C3)sc2Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The solution is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 3-pyrrolidinol (0.3 ml; 3.61 mmol; 5 eq) are added successively. DMF (0.2 ml) is added and the reaction mixture is stirred for 1 hour at room temperature. It is then washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (310 mg; 83%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:35])[C@@H:6]([NH:16][C:17](=[O:34])[C:18]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:20]([C:21]([N:23]([CH2:27][CH2:28][CH3:29])[CH2:24][CH2:25][CH3:26])=[O:22])[CH:19]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1)=[N+]=[N-].[C:36]([O:39]CC)(=[O:38])[CH3:37]>C(O)(=O)C.[Pd]>[C:36]([OH:39])(=[O:38])[CH3:37].[NH2:1][CH2:4][C@@H:5]([OH:35])[C@@H:6]([NH:16][C:17](=[O:34])[C:18]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:20]([C:21]([N:23]([CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH3:29])=[O:22])[CH:19]=1)[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN=[N+]=[N-])c1
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CN)c1
Reaction time: 2 h

Procedure:
N1-[(1S,2R)-3-azido-1-(3,5-difluorobenzyl)-2-hydroxypropyl]5-methyl -N3,N3-dipropylisophthalamide (XV, EXAMPLE 167, 0.3 9, 0.62 mmole) in ethyl acetate (20 ml) and acetic acid (5ml) is placed in a Parr pressure bottle. Palladium on carbon (10%, 5 g) is added and the mixture shaken under hydrogen at 50 psi for 2 hours. The mixture is filtered through a diatomaceous earth and the filtrate is concentrated to give the title compound; MS (MH+)=462.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)O)c1C(=O)O
Reaction time: 13 h
Yield: 84 %

Procedure:
10% Pd/C (2.5 g), 3-nitrophthalic acid (75.0 g, 355 mmol) and ethanol (1.5 L) were charged to a 2.5 L Parr hydrogenator, under a nitrogen atmosphere. Hydrogen was charged to the reaction vessel for up to 55 psi. The mixture was shaken for 13 hours, maintaining hydrogen pressure between 50 and 55 psi. Hydrogen was released and the mixture was purged with nitrogen 3 times. The suspension was filtered through a celite bed and rinsed with methanol. The filtrate was concentrated in vacuo. The resulting solid was reslurried in ether and isolated by vacuum filtration. The solid was dried in vacuo to a constant weight, affording 54 g (84% yield) of 3-aminopthalic acid as a yellow product. 1H-NMR (DMSO-d6) δ: 3.17 (s, 2H), 6.67 (d, 1H), 6.82 (d, 1H), 7.17 (t, 1H), 8-10 (brs, 2H). 13C-NMR (DMSO-d6) δ: 112.00, 115.32, 118.20, 131.28, 135.86, 148.82, 169.15, 170.09.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[C:4]=1[C:17]([OH:19])=O)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:31][C:32]1[CH:53]=[CH:52][C:35]([O:36][C:37]2[CH:38]=[CH:39][C:40]3[N:41]([CH:43]=[C:44]([NH:46][C:47]([CH:49]4[CH2:51][CH2:50]4)=[O:48])[N:45]=3)[CH:42]=2)=[C:34]([F:54])[CH:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:49]1([C:47]([NH:46][C:44]2[N:45]=[C:40]3[CH:39]=[CH:38][C:37]([O:36][C:35]4[CH:52]=[CH:53][C:32]([NH:31][C:17]([C:4]5[C:5](=[O:16])[N:6]([C:9]6[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=6)[N:7]([CH3:8])[C:3]=5[CH2:1][CH3:2])=[O:19])=[CH:33][C:34]=4[F:54])=[CH:42][N:41]3[CH:43]=2)=[O:48])[CH2:50][CH2:51]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: CCc1c(C(=O)O)c(=O)n(-c2ccc(F)cc2)n1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCc1c(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n(-c2ccc(F)cc2)n1C
Yield: 47 %

Procedure:
In the same manner as in Example 77 and using 5-ethyl-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (250 mg, 0.94 mmol), tetrahydrofuran (9 mL), N,N-dimethylformamide (1 drop), oxalyl dichloride (160 μL, 1.9 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (250 mg, 0.78 mmol) and N,N-dimethylacetamide (12 mL) as starting materials, the title compound (210 mg, 47%) was obtained as a white solid.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(O)CO.CN(C)C=O.[N:39]1[CH:44]=[CH:43][C:42]([SH:45])=[CH:41][CH:40]=1>[Cu]I>[N:18]1([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:8]3[N:7]=[CH:6][C:5]4=[CH:4][CH:3]=[C:2]([S:45][C:42]5[CH:43]=[CH:44][N:39]=[CH:40][CH:41]=5)[N:10]4[N:9]=3)=[CH:13][CH:14]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: Sc1ccncc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: CN(C)C=O
Product: c1cc(Sc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)ccn1
Temperature: 135 °C

Procedure:
Into a sealed tube, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine (0.174 g, 0.465 mmol), Sodium tert-butoxide (134 mg, 1.40 mmol), Copper(I) iodide (8.8 mg, 0.046 mmol), 1,2-Ethanediol (52.1 uL, 0.934 mmol), N,N-Dimethylformamide (6.5 mL, 84 mmol), and Pyridine-4-thiol (0.207 g, 1.86 mmol) were added. The reaction was heated at 135° C. for 2 days. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN as eluant (5 to 35% ACN). The collected fractions were lyophilized to give a yellow solid. (33 mg, 14%). LCMS (E/I+) 405.7 (M+H). NMR 1H (DMSO-d6)-9.25 (s, 1H), 9.10 (s, 1H), 8.56 (bs, 1H), 7.40 (d, 2H, J=6.68 Hz), 7.33 (d, 2H, J=8.91 Hz), 7.19 (d, 1H, J=4.45 Hz), 7.04 (d, 1H, J=4.45 Hz), 6.70 (d, 2H, J=9.65 Hz), 3.74 (t, 4H, J=5.08 Hz), 302 (t, 4H, J=5.08 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24].C1CCCCC1.ClCCl>C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:24]
Reactant: COC(=O)/C=C/c1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)CCc1c(-c2ccccc2)n(C)c(=O)c2ccccc12
Reaction time: 1 h

Procedure:
0.25 g of 5% palladium-on-charcoal is added to a solution of 3.8 g (11.9 mmol) of methyl (E)-3-(2-methyl-1-oxo-3-phenyl-1,2-dihydroisoquinol-4-yl)prop-2-enoate in 100 ml of acetic acid and the suspension is subjected to hydrogenation in a Parr apparatus under pressure of approximately 0.3 MPa for 1 h at room temperature and then for 3 h at approximately 50° C. The catalyst is removed by filtering, the filtrate is concentrated under reduced pressure, ice-cold water, 200 ml of dichloromethane and 100 ml of 1N sodium hydroxide are added to the residue, the organic phase is separated, washed with water and dried over sodium sulphate and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a mixture of dichloromethane and ethyl acetate ranging from 100/0 to 70/30. After recrystallizing from a mixture of cyclohexane and dichloromethane, 2.69 g (8.37 mmol) of white solid are obtained. Melting point: 134°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Br)[N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:22]=[C:23]1[NH:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:25]=[CH:24]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:9]=[C:10]([CH2:14][N:28]3[C:23](=[O:22])[CH:24]=[CH:25][C:26]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[C:32]#[N:33])=[N:27]3)[CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: BrCc1cccc(-c2ncc(Br)cn2)n1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(Br)cn4)n3)n2)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
2.3 54.6 mg (0.166 mmol) of 5-bromo-2-(6-bromomethylpyridin-2-yl)-pyrimidine and 54.1 mg (0.166 mmol) of caesium carbonate are added to a suspension of 32.7 mg (0.166 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile in 0.5 ml of DMF, and the mixture is stirred for 18 hours at 80° C. The reaction mixture is added to water. The precipitate formed is filtered off with suction, washed with water and dried in vacuo, giving 3-{1-[6-(5-bromopyrimidin-2-yl)pyridin-2-ylmethyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile as slightly brownish crystals; ESI 445, 447;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][C:9]([CH3:15])([CH:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:3][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(Br)cc1
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc(N2CCCCC2)cc1
Temperature: 80 °C
Yield: 82 %

Procedure:
A mixture of methyl 3-(4-bromophenyl)-2,2-dimethyl-3-phenylpropanoate (250 mg, 0.72 mmol), piperidine (3 mL), palladium acetate (32 mg, 0.144 mmol), 2-(di-tert-butylphosphino)-biphenyl (87 mg, 0.29 mmol), and sodium tert-butoxide (166 mg, 1.73 mmol) in toluene (5 ml) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature, the solid was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography using 10% ethyl acetate in hexanes to give methyl 2,2-dimethyl-3-phenyl-3-(4-(piperidin-1-yl)phenyl)propanoate as a white solid (207 mg, 82%). LC/MS (m/z) 352.24 [(M+H)+]; HPLC Rt: 2.448 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[CH2:17]([C:19]1[NH:20][C:21]2[C:22]([N:29]=1)=[N:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[CH3:18].O.[OH-].[Li+]>CN(C=O)C>[CH2:17]([C:19]1[N:29]([CH2:2][C:3]2[CH:16]=[CH:15][C:6]([C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:8])=[CH:5][CH:4]=2)[C:22]2=[N:23][C:24]([CH3:28])=[CH:25][C:26]([CH3:27])=[C:21]2[N:20]=1)[CH3:18]
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: CCc1nc2nc(C)cc(C)c2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
Commercially available 4-bromomethylbenzophenone (5.00 g, 18.2 mmol) was dissolved in DMF (100 mL), and 2-ethyl-5,7-dimethylimidazo[4,5-b]pyridine (3.82 g, 21.8 mmol) and lithium hydroxide monohydrate (0.920 g, 21.9 mmol) was added to the solution, followed by stirring at room temperature for 3 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), and recrystallized from ethanol to obtain Compound 1 (5.33 g, yield 79%).
Reaction SMILES: [CH3:1][NH2:2].[OH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2>CN(C=O)C.O=[Mn]=O>[N:2]1[C:5]2=[C:6]3[C:10](=[CH:11][CH:12]=[C:4]2[O:3][CH:1]=1)[NH:9][CH:8]=[CH:7]3
Reactant: CN
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: c1cc2c(ccc3ocnc32)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.5 mmol of methylamine and 4.13 mmol of MnO2 are added to a solution of 0.4 mmol of 5-hydroxy-1H-indole in 3 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The suspension is filtered through Celite and subjected to conventional work-up, giving 6H-oxazolo[4,5-e]indole; ESI 159.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=2)=[CH:9][CH:8]=1)(=O)=O.O1CCOCC1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(OCC)(=O)C>CO>[N:30]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:21][C:16]4=[N:17][CH:18]=[CH:19][N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: C1CCNC1
Reactant: O=S(=O)(Oc1ccc(-c2cc3nccnc3[nH]2)cc1)C(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: c1cnc2[nH]c(-c3ccc(N4CCCC4)cc3)cc2n1
Temperature: 200 °C

Procedure:
A mixture of 6-(4-trifluoromethanesulfonyloxyphenyl)-5H-pyrrolo[2,3-b]pyrazine [20 mg, Reference Example 18(e)], dioxane (3 mL) and pyrrolidine (0.2 mL) was heated at 200° C. in a microwave oven for 1 hour. The reaction mixture was then evaporated and the residue was subjected to chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give, after trituration with a mixture of ethyl acetate and methanol, the title compound (11 mg) as a yellow solid. MS: 265.1 (MH+). RT=2.92 minutes.
Reaction SMILES: C1(C([NH:9][CH2:10][CH:11]2[CH2:15][O:14][C:13](=[O:16])[C:12]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C)C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].CO>[OH:14][CH2:15][CH:11]1[CH2:10][NH:9][C:13](=[O:16])[C:12]1([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: CC(NCC1COC(=O)C1(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1NCC(CO)C1(c1ccccc1)c1ccccc1
Temperature: 70 °C

Procedure:
To 750 ml. of methanol and 80.0 g. (0.22 mole) of 4-(1-phenylethylaminomethyl)-4,5-dihydro-3,3-diphenylfuran-2(3H)one was added 3.0 g. of palladium hydroxide catalyst and the mixture was shaken in 3 atmospheres of hydrogen at 70° C. for 18 hrs. Upon filtering starting material was found to be present; fresh catalyst was added to the solution which was shaken in 3 atmospheres of hydrogen at 70° C. for 3 more hours. After filtering the filtrate was concentrated in vacuo. The residue was dissolved in 100 ml. of ethyl acetate, and 100 ml. of isopropyl ether was added. A portion of the crystallized material was recrystallized from the same solvent system to give product melting at 145°-148° C.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][C:16]([SH:18])=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>ClCCCl>[CH3:29][N:30]([CH3:34])[C:31](=[O:32])[S:18][C:16]1[CH:15]=[CH:14][N:13]2[C:9]([CH2:8][O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:10]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:12]2[CH:17]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)c1nc2cc(S)ccn2c1COC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2cc(SC(=O)N(C)C)ccn2c1COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
3-Cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine-7-thiol (210 mg, 0.691 mmol) obtained in step 1 was dissolved in 1,2-dichloroethane (2.0 mL). Under ice-cooled condition, triethylamine (0.140 mL, 1.00 mmol) and dimethylcarbamoyl chloride (0.0770 mL, 0.834 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After adding a saturated sodium hydrogen carbonate aqueous solution to the reaction mixture, the reaction mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give S-3-(cyclohexyloxymethyl)-2-isopropylimidazo[1,2-a]pyridin-7-yl dimethylthiocarbamate (121 mg, yield 47%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:3]1.Cl[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:14]=1>CCOC(C)=O>[F:30][C:24]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][S:21][C:15]1[N:14]=[C:13]([NH:11][S:8]([N:4]2[CH2:5][CH2:6][NH:7][C:2](=[O:1])[CH2:3]2)(=[O:10])=[O:9])[CH:18]=[C:17]([O:19][CH3:20])[N:16]=1
Reactant: NS(=O)(=O)N1CCNC(=O)C1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Solvent: CCOC(C)=O
Product: COc1cc(NS(=O)(=O)N2CCNC(=O)C2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from 3-oxopiperazine-1-sulfonamide (the product of step i) (0.22 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (1:1) as eluent to give a white solid. This solid was dissolved in EtOAc and Et2O and extracted with 1N sodium hydroxide. The basic solution was washed with Et2O, acidified with dilute hydrochloric acid and extracted with EtOAc. The organic solution was washed with H2O, dried (MgSO4) and the solvent evaporated in vacuo to give the product as a yellow foam. Yield: 40 mg
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[C:8]1[C:12]([C:13](O)=[O:14])=[C:11]([CH:16]([CH3:18])[CH3:17])[O:10][N:9]=1.C(N(CC)CC)C.C(OC(Cl)=O)(C)C.C1(C)C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[C:8]1[C:12]([CH2:13][OH:14])=[C:11]([CH:16]([CH3:17])[CH3:18])[O:10][N:9]=1
Reactant: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1C(=O)O
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
A solution of 3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylic acid (0.54 g, 1.8 mmol) in THF (9 mL), was stirred as triethylamine (0.25 mL, 1.8 mmol) was added. The solution was cooled in ice bath before the addition of a 1 N solution of isopropylchloroformate in toluene (1.8 mL, 1.8 mmol). The solution was allowed to stir for 30 minutes before being filtered into a solution of sodium borohydride (91 mg, 2.4 mmol) in water (0.62 mL). The mixture was allowed to warm to room temperature and stir for 3 days. The mixture was filtered and the filtrate was partitioned between brine and ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 2:3 ethyl acetate:hexanes) to provide [3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (0.32 g, 57% as 0.3 ethyl acetate). 1H NMR (400 MHz, DMSO-d6): δ 8.79 (s, 2H), 4.96 (t, J=5 Hz, 1H), 4.20 (d, J=5 Hz, 2H), 3.35 (septet, J=7 Hz, 1H), 1.29 (d, J=7 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:28])[CH2:21][C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:28])[CH2:21][C:22]1[N:23]=[C:24]([NH:27][C:12]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=2)=[O:14])[S:25][CH:26]=1)[CH3:18]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)c1cccn1Cc1ccc(F)cc1
Product: CCOC(=O)Cc1csc(NC(=O)c2cccn2Cc2ccc(F)cc2)n1
Yield: 61.9 %

Procedure:
(2-{[1-(4-Fluorobenzyl)-1H-pyrrole-2-carbonyl]-amino}-thiazol-4-yl)acetic acid ethyl ester (60 mg) was prepared from 1-(4-fluorobenzyl)-pyrrole-2-carboxylic acid (55 mg, 0.25 mmol) and 2-aminothiazol-4-yl acetic acid ethyl ester (47 mg, 0.25 mmol) following the general procedure F.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:20][C:21]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:20][C:21]1[N:28]=[CH:27][C:26]([C:18]2[N:13]3[C:14]([S:15][C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:12]3)=[N:16][CH:17]=2)=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: CC1(C)OB(c2cnc(N)c(C#N)c2)OC1(C)C
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4cnc(N)c(C#N)c4)cnc3s2)cc1OC
Temperature: 110 °C
Yield: 21.5 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.1 g, 0.258 mmol, 1 eq), 2-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinonitrile (0.11 g, 0.449 mmol, 1.74 eq), PdCl2(Ph3P)2 (36 mg, 0.052 mmol, 0.2 eq) and Na2CO3 (2 M aqueous solution, 0.5 mL) in dioxane was heated at 110° C. for 2.5 h. The reaction was cooled down to it and solvents were removed under reduced pressure. The residue was treated with water, sonicated and then filtered. The solid was washed with water, Et2O, Et2O/MeOH (9:1), and dried. The residue was purified on silica gel (isolute flash Si II, DCM/MeOH 5 to 10% MeOH and biotage, MeOH/DCM, 0% to 10%) to give the desired product (21 mg, 22%). HPLC-MS: (5-100% B in 8 min, 0.8 mL/min, 50° C.): tR=4.68 min, [M+H]+ m/z 379.1; 1H NMR (300 MHz, DMSO) δ 8.91 (d, J=2.4 Hz, 1H), 8.45 (d, J=2.4 Hz, 1H), 7.72 (s, 2H), 7.56 (dd, J=8.4, 2.1 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.17 (m, 3H), 3.89 (s, 3H), 3.86 (s, 3H).