Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([C:72]1[CH:77]=[CH:76][C:75]([CH2:78][CH2:79][C:80]([C:86]([F:89])([F:88])[F:87])([OH:85])[C:81]([F:84])([F:83])[F:82])=[C:74]([CH3:90])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([CH2:54][CH3:55])([C:72]3[CH:77]=[CH:76][C:75]([CH2:78][CH2:79][C:80]([OH:85])([C:86]([F:88])([F:89])[F:87])[C:81]([F:84])([F:83])[F:82])=[C:74]([CH3:90])[CH:73]=3)[CH2:51][CH3:52])=[CH:57][C:58]=2[CH3:71])=[CH:44][C:43]=1[F:49]
Reactant: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
A solution of palladium acetate (2.3 mg, 0.0104 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (8.6 mg, 0.0209 mmol) and potassium phosphate (44.4 mg, 0.20 mmol) in water (0.040 mL) and toluene (0.150 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 22.6 mg, 0.11 mmol) and 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-butan-2-ol (Example 27-(2); 42.8 mg, 0.0747 mmol) in toluene (0.230 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for three hours. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (13% ethyl acetate/hexane) to give the title compound (21.9 mg, 47%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19]([CH3:18])=[N:20][C:21]=2[CH:27]=1
Reactant: Cc1nc2ccc(N)cc2[nH]1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]c(C)nc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 150, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 294.4 mg (2.0 mmol) of 2-methyl-5-aminobenzimidazol and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 4 hr. The work up gave 220.2 mg (61.3%) of the product as a sand color solid, m.p. 207° C. (dce.), mass (electrospray, m/e): M+H 359.9. HRCIMS: calcd 359.138 for C20H17N5O2 (M+), obsd 359.1403.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.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>[C:32]([C:29]1[N:30]=[CH:31][C:26]([C:2]2[C:3]([F:17])=[CH:4][C:5]3[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=3[CH:16]=2)=[CH:27][CH:28]=1)#[N:33]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CCNC(=O)Nc1nc2cc(Br)c(F)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3ccc(C#N)nc3)c(F)cc2s1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
A solution of 1-(5-bromo-6-fluoro-benzothiazol-2-yl)-3-ethyl-urea (0.10 g, 0.31 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (0.144 g, 0.63 mmol) and K3PO4 (0.133 g, 0.63 mmol) in DMF-H2O (5.0 mL, 4:1) was degassed by flushing with nitrogen for 15 min. Dichlorobis(triphenylphosphine)-palladium(II) (0.022 g, 0.03 mmol) was then added to the reaction mixture followed by degassing with nitrogen for another 15 min. The resulting reaction mixture was then heated to 100° C. for 2 h. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to room temperature and poured onto ice-cold water followed by extraction with EtOAc (2×50 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was then purified over silica gel (100-200 M, 2.50% MeOH-DCM) to obtain the desired product (0.075 g, 71%). 1H-NMR (400 MHz, DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 3.20 (m, 2H), 6.71 (br s, 1H), 7.90 (d, J=6.80 Hz, 1H), 8.03 (d, J=10.80 Hz, 1H), 8.15 (m, 1H), 8.31 (m, 1H), 9.0 (s, 1H) and 10.90 (br s, 1H). MS: 340.06 (M−H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N#CC1(c2ccc(N)cc2)CCCCC1
Temperature: 50 °C
Yield: 100 %

Procedure:
A solution of 1-(4-nitro-phenyl)-cyclohexanecarbonitrile (0.500 g, 2.17 mmol, as prepared in the previous step) in EtOH (6 mL) and water (6 mL) was treated with NH4Cl (1.16 g, 21.7 mmol) and Fe powder (606 mg, 10.9 mmol) and heated to 50° C. for 2 h. The cooled mixture was filtered through Celite, and the filter cake was washed with MeOH. The solvents were evaporated in vacuo. The residue was partitioned between water (50 mL) and EtOAc (75 mL), and the layers were separated. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (488 mg, 100%) as an orange oil. The compound was used in the following step without purification. Mass spectrum (ESI, m/z): Calcd. for C13H16N2, 201.1 (M+H). found 201.3.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([F:12])[CH:8]=[C:7]([OH:13])[C:6]=2[C:5]([CH2:14][CH2:15][N:16]2[CH2:24][C:23]3[C:18](=CC=CC=3)C2)=[CH:4]1)[CH3:2].C(N1CCCC(C2C3C(=CC(F)=CC=3OCC3C=CC=CC=3)N(CC)C=2)=C1)C1C=CC=CC=1>>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([F:12])[CH:8]=[C:7]([OH:13])[C:6]=2[C:5]([CH:14]2[CH2:18][CH2:23][CH2:24][NH:16][CH2:15]2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(CCN2Cc3ccccc3C2)c2c(O)cc(F)cc21
Agent: CCn1cc(C2=CN(Cc3ccccc3)CCC2)c2c(OCc3ccccc3)cc(F)cc21
Product: CCn1cc(C2CCCNC2)c2c(O)cc(F)cc21
Yield: 59 %

Procedure:
Following the procedure (step 3 scheme 31 used to prepare compound 31-4 compound 38-3 gave compound 38-4 (113 mg, 59%) as a light tan-colored solid. 1H NMR (300 MHz, MeOD-d6): δ (ppm) 6.80 (s, 1H), 6.49 (dd, J=10.0, 2.1 Hz, 1H), 6.13 (dd, J=11.4, 2.1 Hz, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.53-3.40 (m, 2H), 3.05 (d, J=11.4 Hz, 1H), 2.55 (dt, J=23.0, 11.7 Hz, 2H), 2.14 (dd, J=8.8, 6.1 Hz, 1H), 1.85-1.56 (m, 3H), 1.34 (t, J=7.2 Hz, 3H). LCMS: calc 262.1 and found: 263.1 [MH]+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:20])[O:12][C@H:11]([CH2:13][CH2:14][C:15](OCC)=[O:16])[CH2:10][O:9]1>O1CCCC1>[CH3:7][C:8]1([CH3:20])[O:12][C@H:11]([CH2:13][CH2:14][CH2:15][OH:16])[CH2:10][O:9]1
Reactant: CCOC(=O)CC[C@@H]1COC(C)(C)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC[C@@H](CCCO)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of lithium aluminium hydride (1.40 g, 35.6 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a tetrahydrofuran solution (30 mL) of ethyl 3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]propanoate (6.00 g, 29.7 mmol) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature overnight, then quenched with the addition of water (1.4 mL) and 10% aqueous sodium hydroxide (1.4 mL). The white solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic phase was washed with brine, dried (sodium sulfate), and concentrated in vacuo to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 4.03-4.13 (m, 2H), 3.65-3.69 (m, 2H), 3.50-3.55 (m, 1H), 1.61-1.69 (m, 4H), 1.32 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [H-].[Na+].[N:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][OH:12].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[Si:17]([O:12][CH2:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH2:9][OH:10])[N:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: OCc1cccc(CO)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 60% NaH (1.45 g, 35.9 mmol) in DMF (60 mL), which was stirred and cooled with ice, was added a solution of 2,6-pyridinedimethanol (5.00 g, 35.9 mmol) in DMF (30 mL), and stirred for 1 hour at a room temperature under Ar atmosphere. To the mixture was added a solution of tert-butyldimethylchlorosilane (6.54 g, 43.3 mmol) in DMF (40 mL), and stirred for additional 12 hours. TLC was used to confirm there was no starting material in the reaction mixture. Then, the mixture was subjected to extraction with EtOAc and 10% NaHCO3 aq. The organic layer was washed with sat. NaClaq., dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (Hex:EtOAc=5:1) to give 2-[(tert-butyldimethylsilyloxy)methyl]-6-hydroxymethylpyridine (1) (4.46 g, 49%) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][S:13]([C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19])(=[O:15])=[O:14].Cl>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:13]([CH3:12])(=[O:15])=[O:14])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CS(=O)(=O)c1ccccc1CN
Reactant: Clc1nc2c(Br)cccn2n1
Agent: Cl
Product: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12

Procedure:
(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (470.0 mg, 2.022 mmol) and 2-methanesulfonyl-benzylamine; hydrochloride (500.0 mg, 2.255 mmol) in a manner analogous to Example 2d. Product isolated as a yellow solid (0.45 g, 66%). MP=161-163° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.6 Hz, 1H), 7.92 (d, J=6.6 Hz, 1H), 7.64-7.60 (m, 2H), 7.56-7.51 (m, 1H), 6.88 (t, J=7.5 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 5.43 (t, J=5.9 Hz, 1H), 4.98 (d, J=6.1 Hz, 2H), 3.15 (s, 3H). MS=337, 339 (MH)+.
Reaction SMILES: Cl.C([O:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[CH:12]=1)=[O:10])=C>C(O)C>[OH:4][CH2:5][CH2:6][O:7][NH:8][C:9]([C:11]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[Cl:29])=[C:19]([F:30])[C:14]2[N:15]=[CH:16][N:17]([CH3:18])[C:13]=2[CH:12]=1)=[O:10]
Reactant: C=COCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Solvent: CCO
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)NOCCO)cc21
Reaction time: 24 h
Yield: 102.4 %

Procedure:
Hydrochloric acid (14 mL, 1.0 M aqueous solution, 14 mmol) is added to a suspension of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy -ethoxy)-amide 29a (2.18 g, 4.50 mmol) in ethanol (50 mL) and the reaction mixture allowed to stir for 24 hours. The reaction mixture is concentrated to dryness by rotary evaporation and the solids partitioned between 3:1 ethyl acetate/tetrahydrofuran and saturated potassium carbonate. The aqueous phase is extracted with 3:1 ethyl acetate/tetrahydrofuran (3×), the combined organics dried (Na2SO4), and concentrated to provide 2.11 g (100%) 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy -ethoxy)-amide as an off-white solid. MS ESI (+) m/z 457, 459 (M+, Br pattern) detected. 1H NMR (400 MHz, MeOH-d4) δ 8.26 (s, 1H), 7.78 (s, 1H), 7.57 (d, 1H), 7.24 (dd, 1H), 6.40 (dd, 1H), 3.86 (s, 3H), 3.79 (m, 2H), 3.49 (m, 2H). 19F NMR (376 MHz, MeOH-d4) −133.68 (s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[N:25]1.N1C=CC=CC=1.O>ClCCl>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[S:29]([C:26]2[CH:27]=[CH:28][N:24]([CH3:23])[N:25]=2)(=[O:31])=[O:30])[CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Reactant: CC(C)(C)OC(=O)c1cccc(NCc2ccc(Cl)cc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cn1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)c2cccc(C(=O)OC(C)(C)C)c2)n1
Yield: 9.6 %

Procedure:
A solution of 3-(4-chloro-benzylamino)-benzoic acid tert-butyl ester (1 g, 0.03 mol), 1-Methyl-1H-Pyrazole-3-sulfonyl chloride (1.13 g, 0.06 mol) and pyridine (0.5 ml, 0.06 mol) in dichloromethane (40 ml) were refluxed for 48 hrs. On cooling, water (50 ml) was added with stirring, the organic layer was separated, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/dichloromethane 0% to 10% v/v) to afford the title compound as a clear oil (1.33 g). Mass spectrum (ES+) m/z 49 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=O)[O:16][CH:17]=3)=[CH:12][C:3]1=2.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C>[CH3:1][C:2]1([CH3:20])[C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[N:22][OH:23])[O:16][CH:17]=3)[CH:10]=[CH:9][C:4]=2[NH:5][C:6](=[O:8])[O:7]1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3coc(C=O)c3)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC1(C)OC(=O)Nc2ccc(-c3coc(C=NO)c3)cc21

Procedure:
A mixture of 4-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-furan-2-carbaldehyde (2.7 g, 10 mmol), hydroxylamine hydrochloride (0.75 g, mmol) and sodium acetate (0.87 g, 10.6 mmol) was heated at reflux in 80% ethanol (25 mL) for 2 hours. The title compound crystallized from the cooled reaction mixture as tan crystals (1.5 g, 52.4%): mp 236-238° C. 1H NMR (DMSO-d6) δ 11.97 (s, 1H), 10.26 (s, 1H), 8.2 (s, 1H), 7.63 (s, 1H), 7.56-7.52 (m, 3H), 6.91-6.88 (d, 1 H, J=8.1 Hz), 1.66 (s, 6H). MS ESI m/z 285 [M−H]−. Anal. Calcd. For C15H14N2O4: C, 62.93; H, 4.93; N, 9.79. Found C, 62.77; H, 5.00; N, 9.79.
Reaction SMILES: Cl.Cl.C([O:6][C@@H:7]1[C@@H:48]([O:49]C(=O)C)[C@H:47]([O:53]C(=O)C)[C@@H:46]([CH2:57][O:58]C(=O)C)[O:45][C@H:8]1[O:9][C:10]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][C:28]4([CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][NH2:39])[CH2:33][CH2:32]4)[CH2:27]3)=[CH:18][C:17]=2[CH3:41])=[C:13]([CH:42]([CH3:44])[CH3:43])[NH:12][N:11]=1)(=O)C.C(N(C(C)C)CC)(C)C.[CH2:71]([N:75]=[C:76]=[O:77])[CH:72]([CH3:74])[CH3:73].N>ClCCl.C(#N)C>[C@@H:8]1([O:9][C:10]2[C:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][C:28]5([CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][NH:39][C:76]([NH:75][CH2:71][CH:72]([CH3:74])[CH3:73])=[O:77])[CH2:33][CH2:32]5)[CH2:27]4)=[CH:18][C:17]=3[CH3:41])=[C:13]([CH:42]([CH3:44])[CH3:43])[NH:12][N:11]=2)[O:45][C@H:46]([CH2:57][OH:58])[C@@H:47]([OH:53])[C@H:48]([OH:49])[C@H:7]1[OH:6]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)CN)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)CN=C=O
Agent: Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(/C=C/CCN2CCCC3(CCN(C(=O)CNC(=O)NCC(C)C)CC3)C2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 67.9 %

Procedure:
A mixture of 4-(4-{(1E)-4-[9-(aminoacetyl)-2,9-diazaspiro[5.5]undec-2-yl]but-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside dihydrochloride (11.70 g; 13.04 mmoles) in dichloromethane (33 mL) and diisopropylethylamine (13.65 mL; 78.27 mmoles) is stirred for 10 minutes to dissolve. The mixture is cooled to 5° C. and isobutyl isocyanate (2.59 g, 26.09 mmoles) is added dropwise over 5 minutes. When the addition is complete the cooling bath was removed. After 15 minutes, the mixture is concentrated under reduced pressure. The residue is treated with ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) and stirred at ambient temperature for 1.5 hours. Further ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) is added and the reaction is stirred overnight. The mixture is warmed to 40° C. and ammonia (2M in methanol; 35.00 mL, 70.00 mmoles) is added. The mixture is stirred for 160 minutes, and then concentrated. The residue is purified by reverse phase (C18) flash column chromatography eluting with 20:80 to 80:20 10 mM ammonium bicarbonate in water:acetonitrile to give the title compound (6.686 g, 68% yield). Mass spectrum (m/z): 755.5 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1)(=[O:28])=[O:27])[CH:20]=[CH:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1)(=[O:27])=[O:28])[CH:20]=[CH:19]2
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1
Agent: [Li+]
Product: CCOC(=O)C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1C(=O)c1nc2c(s1)CNC(C)C2

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[ethoxycarbonyl]piperazine
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([O:17]C)=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:20].CO>ClCCl>[BrH:20].[NH2:2][C:3]1[C:4]([OH:17])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrB(Br)Br
Reactant: COc1c(N)cccc1-c1csc(C(=O)O)c1
Agent: Br
Solvent: CO
Solvent: ClCCl
Product: Nc1cccc(-c2csc(C(=O)O)c2)c1O
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 19b (360 mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane followed by dropwise addition of boron tribromide (2.8 mL, 5.6 mmol). The reaction mixture was reacted at room temperature for 4.5 hours. The reaction mixture was added with 5 mL of methanol and concentrated under reduced pressure. The residue was diluted with 10 mL of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-amino-2-hydroxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 19c (80 mg, yield 17.5%) as a grey solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[S:39]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:41])=[O:40]
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4c(Cl)cccc4Cl)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2,6-dichlorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 587.1 ([M+H]+)
Reaction SMILES: Cl[C:2]1[C:3]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[N:7]=1.[CH3:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[CH:37][C:36]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[F:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([F:33])[C:26]=1[N:21]1[C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]4)[CH2:10][CH2:9]3)[N:7]=[C:2]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][C:35]=3[CH3:34])[C:39]([OH:41])=[O:40])[C:3]=2[CH:24]=[CH:23][C:22]1=[O:25]
Reactant: CC1CCN(C2CCN(c3nc(Cl)c4ccc(=O)n(-c5c(F)cccc5F)c4n3)CC2)CC1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 150 °C
Yield: 68 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (47.5 mg, 0.1 mmol) in dioxane (3 mL) and water (1 mL) were added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (38.4 mg, 0.15 mol), potassium carbonate (83 mg, 0.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.6 mL, 0.005 mmol). The mixture was heated with microwave at about 150° C. for about 15 min. The mixture was concentrated & then mixed with DMSO (0.75 mL) and water (0.25 mL). Separation by HPLC afforded the title compound (39 mg, 68%). LC-MS m/z 574 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl>C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: Cc1ncc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a flask was added N-(5-nitro-2-methyl-pyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (18.0 g) and THF (200 mL) and the solution was cooled to 0-5° C. To the solution was added LiAlH4 (about 2.2 g in total) in several portions and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was acidified to pH=5-6 using 1N HCl and then extracted with CH2Cl2 (2×100 mL ). The organic extracts were combined, dried, filtrated and concentrated to afford N-(5-amino-2-methylpyrid-3-yl)-4-(pyrid-3-yl)-2-pyrimidinamine (12 g).