Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[CH3:17].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC.CN(C=O)C.[F-].[K+]>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>[CH3:17][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:6]=[CH:7][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1cc(-c2nc3ccccc3o2)ccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3o2)ccc1-c1ccccn1
Temperature: 100 °C

Procedure:
Polyphosphoric acid (100 mL) was added to a beaker containing 2-aminophenol (17.7 g, 162 mmol) and 4-bromo-3-methylbenzoic acid (13.6 g, 64 mmol). The mixture was heated at 200° C. for 1 h, then poured into ice water (1 L) and allowed to stand overnight. The mixture was filtered and dried to afford 2-(4-bromo-3-methyl(phenyl))-benzoxazole as a colorless solid. A solution of 2-(4-bromo-3-methyl(phenyl))-benzoxazole (670 mg, 2.3 mmol), 2-(tributylstannyl)pyridine (850 mg, 2.3 mmol), Pd(Ph3P)4 (270 mg, 0.23 mmol) and DMF (23 mL) was degassed with bubbling argon for 15 min. The reaction mixture was heated at 100° C. for 8 h. The reaction was cooled to rt, and KF (500 mg) and H2O (250 mL) were added. The mixture was extracted with MTBE (3×50 mL), and the combined organic extracts were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), and concentrated to afford an oil. Purification of the oil by flash chromatography on silica gel (EtOAc:hexanes 1:2) afforded the desired 2-(3-methyl-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.91 (d, 1H), 8.52 (t, 1H), 8.19 (s, 1H), 8.15 (d, 1H), 7.97 (br t, 1H), 7.89 (d, 1H), 7.70–7.72 (m, 1H), 7.61 (d, 1H), 7.51–7.54 (m, 1H), 7.30–7.33 (m, 2H), 2.45 (s, 3H), MS (ESI) 287 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1O[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>>[CH3:1][C:2]1[N:24]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1nc2c(=O)c3ccccc3ccc2o1
Product: COc1ccc(Cn2c(C)nc3c(=O)c4ccccc4ccc32)cc1
Temperature: 100 °C

Procedure:
A stirred mixture of the product from step (i) (5.07 g) and 4-methoxybenzylamine (12 ml) was heated at 100° C. for 24 h. The excess 4-methoxybenzylamine was distilled off under reduced pressure. The remaining residue was purified by recrystallisation from ethyl acetate to give the subtitle product as a pale yellow powder.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5](B(O)O)=[CH:6][CH:7]=1)=[O:2].[CH3:11][CH:12]([NH:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27]([S:28][C:29]2[CH:34]=[C:33]3[O:35][CH2:36][O:37][C:32]3=[CH:31][C:30]=2I)=[N:26][C:20]2[C:21]([NH2:25])=[N:22][CH:23]=[N:24][C:19]1=2)[CH3:13].C([O-])(O)=O.[Na+].CN(C=O)C>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.O>[NH2:25][C:21]1[N:22]=[CH:23][N:24]=[C:19]2[C:20]=1[N:26]=[C:27]([S:28][C:29]1[C:30]([C:5]3[O:4][C:3]([CH:1]=[O:2])=[CH:7][CH:6]=3)=[CH:31][C:32]3[O:37][CH2:36][O:35][C:33]=3[CH:34]=1)[N:18]2[CH2:17][CH2:16][CH2:15][NH:14][CH:12]([CH3:11])[CH3:13]
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2-c2ccc(C=O)o2)OCO3)nc2c(N)ncnc21
Temperature: 90 °C
Yield: 33.8 %

Procedure:
2-Formyl-5-furanylboronic acid (12.3 mg, 0.0877 mmol) was added to PU-H71 (30 mg, 0.0585 mmol) and NaHCO3 (14.7 mg, 0.1755 mmol). DMF (1 mL) was added and the reaction mixture was evacuated and back filled with nitrogen. This was repeated four times then nitrogen was bubbled through the reaction mixture for 10 minutes. Then H2O (0.1 mL) and Pd(PPh3)2Cl2 (4 mg, 0.00584 mmol) were added and the reaction mixture was heated under nitrogen at 90° C. for 4 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (hexane:CH2Cl2:EtOAc:MeOH—NH3 (7N), 2:2:1:0.5) to give 9.5 mg (34%) of DZ3-33. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 9.57 (s, 1H), 8.18 (s, 1H), 7.36 (d, J=3.8 Hz, 1H), 7.32 (s, 1H), 7.07 (s, 1H), 6.98 (d, J=3.8 Hz, 1H), 6.12 (s, 2H), 4.32 (t, J=6.7 Hz, 2H), 3.31 (septet, J=6.6 Hz, 1H), 2.93 (t, J=6.8 Hz, 2H), 2.30 (m, 2H), 1.42 (d, J=6.6 Hz, 6H); 13C NMR (125 MHz, CDCl3/MeOH-d4) δ 177.5, 156.8, 154.5, 152.2, 151.9, 151.4, 150.1, 149.7, 148.1, 127.5, 124.3, 119.2, 118.7, 115.7, 112.7, 109.9, 102.9, 51.3, 41.8, 40.4, 26.4, 19.2; HRMS (ESI) m/z [M+H]+ calcd. for C23H25N6O4S, 481.1658; found. 481.1657; HPLC: method A Rt=5.87, method B Rt=5.93.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:18][NH2:19])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH2:18][CH:17]([CH:14]1[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1)[C:20]1[CH:21]=[N:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC(c1ccc(C(F)(F)F)nc1)C1CCOCC1
Product: O=C(NCC(c1ccc(C(F)(F)F)nc1)C1CCOCC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=413.0, tR (minutes, Method E)=0.64
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:10]([S:15][CH2:16][CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)(=[O:20])=[O:19])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[C:4]([O:33]C)[CH:3]=1.B(Br)(Br)Br.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([NH:8][C:9]2[C:10]([S:15][CH2:16][CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)(=[O:20])=[O:19])=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:7])=[C:4]([OH:33])[CH:3]=1
Reactant: COc1cc(F)ccc1C(=O)Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.9 %

Procedure:
A solution of 515 mg (1.0 mmol) 4-fluoro-2-methoxy-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]benzamide (example compound 50) in DCM (5 ml) was cooled to −78° C. 5 ml (1 M in DCM, 5.0 mmol) BBr3 were added at this temperature and the mixture was stirred for 1 h at −78° C. Then the reaction solution was poured into an iced water mixture and it was adjusted to pH 8 with NaHCO3. Then it was extracted with DCM and the organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. 290 mg of 4-fluoro-2-hydroxy-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]benzamide were obtained as residue. MS: m/z 501.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.N1CCCCC1.[C:15]([CH2:17][C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:25][CH:24]=1)=[O:19])#[N:16]>C(O)C>[C:15](/[C:17](=[CH:7]\[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)/[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][O:31][CH3:32])=[CH:27][CH:28]=1)=[O:19])#[N:16]
Reactant: COCOc1ccc(CCNC(=O)CC#N)cc1
Reactant: O=Cc1cccnc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COCOc1ccc(CCNC(=O)/C(C#N)=C/c2cccnc2)cc1
Yield: 63.6 %

Procedure:
Then, ethanol (10 ml), 3-pyridinecarbaldehyde (0.62 g, 5.8 mmol) and a drop of piperidine were added to the resulting 2-cyano-N-(4-methoxymethoxyphenethyl)acetamide (0.96 g, 3,87 mmol) and refluxed under heating for 19 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=19:1) and recrystallized to yield the titled compound (0.83 g, 64%). Properties: mp 105-106° C. (ethyl acetate-hexane)
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[H-].[Na+].[CH2:36](Br)[CH:37]=[CH2:38]>CN(C=O)C>[CH2:38]([O:5][C@@H:4]1[C@@H:6]([CH2:7][OH:8])[O:9][C@@H:1]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@@H:2]1[OH:3])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
Adenosine (20 g, 74.84 mmol) was dried over P2O5 under high vacuum at 40° C. for two days. It was then suspended in DMF under inert atmosphere. Sodium hydride (2.5 g, 74.84 mmol, 60% dispersion in mineral oil), stirred at room temperature for 10 minutes. Then allyl bromide (7.14 mL, 82.45 mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. DMF was removed under vacuum and residue was washed with ethyl acetate (100 mL). Ethyl acetate layer was decanted. Filtrate obtained contained product. It was then placed on a flash column and eluted with 10% MeOH in CH2Cl2 to get 109 (15.19 g, 66%). Rf 0.4, 0.4a ((10% MeOH in CH2Cl2)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([NH:26][CH2:25][C:22]2[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=2)=[O:17])[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Cc1ncc(CN)cn1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Reaction time: 3 h

Procedure:
A round bottom flask was charged with 5-bromo-4′-methylbiphenyl-3-carboxylic acid (1.00 g, 2.75 mmol), (2-methylpyrimidin-5-yl)methanamine (0.406 g, 3.30 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumh (2.40 g, 6.32 mmol), N,N-diisopropylethylamine (1.91 mL, 11.0 mmol) and N,N-dimethylformamide (10 mL, 100 mmol) and the reaction stirred for 3 hours. The reaction was then quenched with water and extracted with ethyl acetate and washed with brine. The solvents were removed under reduced pressure and the residue purified by flash chromatography followed by prep HPLC to get the product as light yellow solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([O:43][CH3:42])[CH:45]=3)(=[O:52])=[O:51])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2C#N)c1
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 477 mg, 95%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:41]#[N:42])=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][N:17]([CH:22]([CH2:38][CH3:39])[C:23]([NH:25][C:26]3[CH:35]=[C:34]([F:36])[C:29]([C:30]([O:32]C)=[O:31])=[C:28]([F:37])[CH:27]=3)=[O:24])[C:16](=[O:40])[CH:15]=2)[CH:13]=1>CO.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:41]#[N:42])=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][N:17]([CH:22]([CH2:38][CH3:39])[C:23]([NH:25][C:26]3[CH:35]=[C:34]([F:36])[C:29]([C:30]([OH:32])=[O:31])=[C:28]([F:37])[CH:27]=3)=[O:24])[C:16](=[O:40])[CH:15]=2)[CH:13]=1
Reactant: CCC(C(=O)Nc1cc(F)c(C(=O)OC)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CCC(C(=O)Nc1cc(F)c(C(=O)O)c(F)c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
67 mg (0.20 mmol, 2 eq.) of caesium carbonate were added to a solution of 53 mg (0.10 mmol) of methyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)-2,6-difluorobenzoate (racemate) in 1.25 ml of a mixture of methanol/water (4/1), and the resulting suspension was stirred at 60° C. for 1 h. Methanol was removed at 30° C. under reduced pressure. The reaction mixture was cooled to RT and adjusted to pH 3 using aqueous hydrochloric acid (1N). The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (water/acetonitrile/0.1% formic acid gradient). Yield: 11 mg (21% of theory)
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][S:13][CH2:14][CH2:15][CH2:16][NH2:17].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH2:15][CH2:14][S:13][CH3:12])=[O:6]
Reactant: CSCCCN
Reactant: Nc1c(I)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CSCCCNC(=O)c1cccc(I)c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL round-bottomed flask was added 2-amino-3-iodobenzoic acid (1.50 g, 5.70 mmol, Bosche Scientific) and 3-(methylthio)propylamine (0.72 mL, 6.84 mmol, Acros) in EtOAc (15 mL) followed by DIEA (1.19 mL, 6.84 mmol) and 1-propanephosphonic acid cyclic anhydride (3.99 mL, 6.27 mmol, 50% in EtOAc, Sigma Aldrich). The reaction was stirred at RT for 4 h, and then quenched with sat. NaHCO3. The layers were separated and the organic layer was washed with sat. NaHCO3, brine, then dried (MgSO4), filtered and concentrated to give the crude product. MS (ESI, pos. ion) m/z: 350.9 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (1H, dd, J=7.6, 1.4 Hz), 7.30 (1H, dd, J=7.8, 1.4 Hz), 6.41 (1H, t, J=7.8 Hz), 6.32 (1H, br. s.), 3.54 (2H, q, J=6.7 Hz), 2.61 (2H, t, J=6.9 Hz), 2.09-2.17 (3H, m), 1.92 (2H, quin, J=6.8 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([Cl:19])=[O:8]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Br)ccc1Cl
Temperature: 0 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
Under Ar protection, 5-bromo-2-chloro-benzoic acid (35 g, 148.6 mmol) was dissolved in toluene (230 ml), followed by addition of DMF (0.5 mL) at room temperature, then the reaction mixture was cooled to 0° C. The reaction mixture was heated to 100° C. after thionyl chloride (44 g, 372 mmol) was dropwise added. After 5 hours, the reaction mixture was concentrated under reduced pressure to obtain the title compound 5-bromo-2-chloro-benzoyl chloride 12n (35.5 g, pale yellow grease), yield: 94.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[C:29]2[S:25][C:26](=[O:31])[NH:27][C:28]2=[O:30])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(C=O)cc3Cl)c2n1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(C=C4SC(=O)NC4=O)cc3Cl)c2n1
Yield: 73.3 %

Procedure:
A suspension of methyl 3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg, 0.582 mmol), thiazolidine-2,4-dione (82 mg, 0.698 mmol) and piperidine (25 mg, 0.291 mmol) in ethanol (4 ml) was refluxed under heating overnight. The reaction mixture was cooled, and the precipitated crystals were filtrated to give the objective compound (189 mg) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH2:5].[NH:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH:4]([N:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1
Reactant: OC1CCNCC1
Reactant: C=C(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)C(CN1CCC(O)CC1)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2-(di-tert-butoxycarbonylamino)-acrylic acid methyl ester (1.0 g, 3.0 mmol) in acetonitrile (10 mL) was added piperidin-4-ol (0.33 g, 1.1 equiv). A gentle stream of nitrogen was placed over the reaction while it stirred overnight. The crude oil which resulted was dissolved in ethyl acetate, washed with water, then brine, dried over magnesium sulfate, and concentrated to give 1.38 g (quant.) as an oil which was used without purification. Mass spec.: 403.42 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:11][C:12](=[O:13])[CH3:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=CC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
4-Methoxybenzaldehyde (1e, 0.63 ml, 5.2 mmol) and acetone (19, 4.00 ml, 54.0 mmol) were combined in ethanol (4 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (4 ml) was added dropwise and the mixture stirred for 1 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ether/hexane to give 0.57 g (62%) of a yellow solid: mp 71-73° C. [expected mp 68° C.]; 1H NMR: δ 2.34 (s, 3H), 3.83 (s, 3H), 6.59 (d, 1H, J=16.3 Hz), 6.90 (d, 2H, J=8.7 Hz), 7.46 (d, 1H, J=16.3 Hz), 7.48 (d, 2H, J=8.7 Hz); 13C NMR: δ 27.5, 55.4, 114.4, 125.0, 127.1, 129.9, 143.1, 161.5, 198.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]3[CH2:25][CH2:24][C:19]4([O:23][CH2:22][CH2:21][O:20]4)[CH2:18][CH2:17]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[H][H].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1.C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][C:19]4([O:20][CH2:21][CH2:22][O:23]4)[CH2:24][CH2:25]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C2=CCC(CCC3CCC4(CC3)OCCO4)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Clc1ccc([C@H]2CC[C@H](CCC3CCC4(CC3)OCCO4)CC2)cc1
Temperature: 0 °C

Procedure:
A solution of 35.0 g of 4-chloro-1-[4-(2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl)-1-cyclohexenyl]benzene in 1 l of toluene is treated with 2.6 g of palladium/carbon (10%) and hydrogenated at room temperature under normal pressure until the uptake of hydrogen comes to a standstill. Thereafter, the reaction mixture is filtered and the filtrate is concentrated, there being obtained crude 4-chloro-1-[4-(2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl)cyclohexyl]benzene. A suspension of 32.8 g of aluminium chloride in 215 ml of methylene chloride is treated at 18° C. while stirring and gassing with nitrogen within 10 minutes with a solution of the crude product obtained in 110 ml of methylene chloride and stirred at 0° C. for a further 30 minutes. Subsequently, the reaction mixture is poured on to 600 ml of ice/water, stirred for 10 minutes and then extracted three times with methylene chloride. The organic phases are washed in succession with water, with saturated sodium hydrogen carbonate solution and with water, then dried over sodium sulphate and filtered. Concentration of the filtrate gives 4-chloro-1-[trans-4-[2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl]cyclohexyl]benzene.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]([OH:18])=O)[C:12](=[O:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[C:1]([C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:18])[C:12](=[O:14])[CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(C)(C)C)cc2=O)n1

Procedure:
Using the method described in Example 49, 2-[4-(2-tert-butyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 68) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-tert-butyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide was obtained as an off-white solid (1.05 g, 77%); ES+-HRMS m/e calcd for C29H39N5O4 [M+H+] 522.3075 found 522.3077. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 8H), 1.32 (s, 9H), 1.37-1.78 (m, 7H), 1.81-2.02 (m, 1H), 2.17-2.36 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=10.7, 4.3 Hz, 1H), 5.79 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.23-7.30 (m, 1H), 7.31-7.38 (m, 1H), 7.50 (dd, J=7.8, 1.4 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)[CH3:2].[C:10](Cl)(=[O:12])[CH3:11]>C(Cl)Cl>[C:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CCc1ccc(O)cc1
Solvent: ClCCl
Product: CCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-ethylphenol (3.38 g, 27.67 mmol) in DCM (50 mL) in an ice bath was added TEA (7.2 mL, 55.34 mmol), followed by the dropwise addition of acetyl chloride (2.2 mL, 30.44 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with water (40 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure and purified by silica gel chromatography to obtain the title compound.