Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](Cl)[CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH3:37][N:38](C=O)C>[C-]#N.[Zn+2].[C-]#N.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:37]#[N:38])[CH:18]=2)[C:13]=1[O:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Cl)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(C#N)ccc2c1OS(=O)(=O)C(F)(F)F
Temperature: 110 °C

Procedure:
A mixture of (S)-ethyl 2-tert-butoxy-2-(6-chloro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate (0.546 g, 1.13 mmol), zinc(II) cyanide (0.080 g, 0.678 mmol), XPhos Palladacycle (Strem, 0.083 g, 0.113 mmol) and sodium bicarbonate (0.009 g, 0.113 mmol) in DMF (3.0 mL) was sparged with nitrogen for 5 minutes. The reaction mixture was heated in microwave at 110° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with 5% lithium chloride solution (2×), brine and dried (MgSO4) and filtered. Concentration and purification by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) gave the title compound. NMR (400 MHz, CDCl3) δ 8.19 (s, H), 8.13 (d, J=8.8 Hz, H), 7.74 (s, H), 7.71 (d, J=8.8 Hz, H), 5.73 (s, H), 4.27-4.09 (m, 2H), 2.59 (s, 3H), 1.21 (s, 9H), 1.17 (t, J=7.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](C2C=CN=C(Cl)C=2)[CH:5]=[C:4]([Cl:15])[C:3]=1[S:16]([NH:19][C:20]1[C:21]([CH3:27])=[N:22][N:23]([CH3:26])[C:24]=1[CH3:25])(=[O:18])=[O:17].[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>O=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:26][N:23]1[C:24]([CH3:25])=[C:20]([NH:19][S:16]([C:3]2[C:4]([Cl:15])=[CH:5][C:6]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([CH:28]=[O:29])[CH:31]=3)=[CH:7][C:2]=2[Cl:1])(=[O:18])=[O:17])[C:21]([CH3:27])=[N:22]1
Reactant: Cc1nn(C)c(C)c1NS(=O)(=O)c1c(Cl)cc(-c2ccnc(Cl)c2)cc1Cl
Reactant: O=Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=O
Solvent: ClCCl
Solvent: O
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1c(Cl)cc(-c2cccc(C=O)c2)cc1Cl
Yield: 82.3 %

Procedure:
Prepared from the sulphonamide of intermediate 2 (1.0 g, 2.43 mmol), 3-formylphenylboronic acid (440 mg, 2.91 mmol), tribasic potassium phosphate (620 mg, 2.91 mmol), Pd(dppf)Cl2.DCM (100 mg, 0.12 mmol) and water (0.5 ml) in oxygen-free DMF (6.0 ml) at 130° C. for 1 h according to the method of intermediate 11, to give the title compound as a white solid (870 mg, 2.0 mmol, 82%). δ H (D-6 DMSO, 300K) 10.12 (1H, s), 9.68 (1H, s), 8.42 (1H, s), 8.21 (1H, d J 7.9 Hz), 8.07 (2H, s), 8.01 (1H, d J 7.5 Hz), 7.74 (1H dd J 7.5 Hz 7.9 Hz), 3.58 (3H, s), 1.50 (3H, s), 1.75 (3H, s). m/z (ES+, 70V) 439.2 (MH+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)s2)cc1
Yield: 27.7 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, starting from 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.05 mmol) and 4-methylbenzene boronic acid (8 mg, 0.06 mmol) giving 5.5 mg (28%) of the title compound. MS (ESI+) calcd for C18H15N5O2S2 397.066716, found 397.066596.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:12](=[N:13]O)[CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[OH-:17].[Na+]>O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[C:12](=[O:17])[NH:13][CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: [OH-]
Reactant: ON=C1CCCc2oc3cc(Br)ccc3c21
Agent: [Na+]
Solvent: O
Product: O=C1NCCCc2oc3cc(Br)ccc3c21
Temperature: 110 °C
Yield: 82 %

Procedure:
A mixture of the product of step B (1.05 g, 3.74 mmol) and polyphosphoric acid (15 g) was heated to 110° C. for 5 h. After cooling to ambient temperature, the reaction mixture was diluted with water, basified with 10 N NaOH and filtered. The solid obtained was washed with water and dried in vacuo at 70° C. to give 8-bromo-2,3,4,5-tetrahydro-1H-benzofuro[3,2-c]azepin-1-one (858 mg, 82%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.06-7.95 (m, 2H), 7.86 (d, J=1.8 Hz, 1H), 7.45 (dd, J=8.4, 1.8 Hz, 1H), 3.28-3.20 (m, 2H), 3.15 (t, J=6.6 Hz, 2H), 2.07-1.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:26]#[N:27])=[C:11]([C:19]2[CH:24]=[CH:23][N:22]=[C:21](F)[CH:20]=2)[S:12][C:13]=1[C:14]1[NH:18][CH:17]=[N:16][N:15]=1.[NH3:28].CO>>[NH2:28][C:21]1[CH:20]=[C:19]([C:11]2[S:12][C:13]([C:14]3[NH:18][CH:17]=[N:16][N:15]=3)=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:10]=2[C:26]#[N:27])[CH:24]=[CH:23][N:22]=1
Reactant: N#Cc1c(-c2ccnc(F)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Reactant: N
Solvent: CO
Product: N#Cc1c(-c2ccnc(N)c2)sc(-c2nnc[nH]2)c1-c1ccc(Cl)cc1Cl
Yield: 44 %

Procedure:
A mixture of 4-(2,4-dichlorophenyl)-2-(2-fluoropyridin-4-yl)-5-(4H-1,2,4-triazol-3-yl)thiophene-3-carbonitrile (0.600 g, 0.00144 mol) and 7 M ammonia in methanol (40 mL, 0.280 mol) was irradiated in a microwave at 150° C. for 8 hours. Solvent was evaporated and the residue was purified by column chromatography on silica gel (40 g), gradient DCM to 6% MeOH in DCM over 30 minutes to afford the title compound as yellow solid (0.26 g, 44%). LCMS: (FA) ES+, 413, 415. 1H NMR (400 MHz, d4-Methanol) 8.40 (s, 1H), 8.05 (dd, J=5.16, 1.10 Hz, 1H), 7.61 (dd, J=1.54, 0.76 Hz, 1H), 7.46-7.42 (m, 2H), 7.03-7.00 (m, 2H)
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[C-:20]#[N:21].[K+].O>CS(C)=O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:4]=[C:3]([CH2:2][C:20]#[N:21])[CH:7]=[N:6]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole, prepared as in EP No. 350 237, was treated with potassium cyanide in dimethyl sulphoxide at room temperature for two hours. The mixture was added to water and extracted with diethyl ether. The extract was worked up to give crude 2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazol-4-ylacetonitrile. In a similar manner to Example 6, this compound was converted to 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-[(1H-imidazol-2-yl)methyl]-2H-1,2,3-triazole,. (Compound 29a).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH:5]=[CH:6][C:7](=O)[CH2:8]C(OC)=O.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][O:23][C:24](=[O:29])/[CH:25]=[C:26](\[NH2:28])/[CH3:27]>CCO>[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][O:23][C:24]([C:6]1[CH:5]([C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([Br:1])[CH:3]=2)[C:25]([C:24]([O:23][CH2:22][CH:18]2[CH2:19][CH2:20][CH2:21][O:17]2)=[O:29])=[C:26]([CH3:27])[NH:28][C:7]=1[CH3:8])=[O:29]
Reactant: C/C(N)=C/C(=O)OCC1CCCO1
Reactant: COC(=O)CC(=O)C=Cc1cccc(Br)c1
Solvent: CCO
Product: CC1=C(C(=O)OCC2CCCO2)C(c2cccc(Br)c2)C(C(=O)OCC2CCCO2)=C(C)N1
Temperature: -10 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
A solution of 15 g (0.05 mol) of methyl 3-bromobenzylideneacetoacetate and 9.81 g (0.05 mol) of (tetrahydrofuran-2-ylmethyl)-3-aminocrotonate in 55 ml of abs ethanol, was refluxed with stirring, in the absence of light, for 10 hours. The reaction mixture was then cooled to −10° C., yielding a white solid (mp 138-40° C., EtOH) with a yield of 85%.
Reaction SMILES: Cl[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:13]/[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])/[CH:3]=1.[CH3:22][N:23]1[C:27]([SH:28])=[N:26][N:25]=[N:24]1>C1COCC1>[CH3:22][N:23]1[C:27]([S:28][C:2]2[C:11](=[O:12])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[N:13][S:14]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)(=[O:16])=[O:15])[CH:3]=2)=[N:26][N:25]=[N:24]1
Reactant: Cn1nnnc1S
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc21
Solvent: C1CCOC1
Product: Cn1nnnc1SC1=CC(=NS(=O)(=O)c2cccs2)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
36 mg (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)-thiophene-2-sulfonamide (12a) was dissolved in 3 ml THF, to which was added 11.7 mg 1-methyl-tetrazole-5-thiol. The reaction mixture was stirred at r.t. for 2 hrs and concentrated via rotavap. The residue was dissolved in dichloromethylene and triturated with hexane. The precipitate was filtered and washed with dichloromethylene/hexane (1:1) affording the title compound 28.8 mg (68.9%) as an orange-red solid, m.p.: 172° C. (dec.).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[NH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2>>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:4]2[NH:3][C:2]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[C:20]4[C:25]=3[CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]4)=[N:6][C:5]=2[CH:7]=1
Reactant: Nc1cccc2c1CC(O)CC2
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Product: OC1CCc2cccc(Nc3nc4cc(C(F)(F)F)ccc4[nH]3)c2C1

Procedure:
The reaction of 2-chloro-6-(trifluoromethyl)-1H-benzo[d]imidazole (154 mg, 0.7 mol, prepared according to the procedure described in WO 2004/035549 A1) with 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (83 mg, 0.5 mmol, prepared according to the procedure described in WO 2003/095420 A1) under the condition of Example 21(b) afforded the title compound. MS (ESI, pos. ion) m/z: 348 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.Cl.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][NH2:28])=[CH:23][CH:22]=1)#[N:20].O>C(O)(=O)C.CN(C)C=O>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]([C:12]([F:15])([F:14])[F:13])=[N:28]2)=[CH:23][CH:22]=1)#[N:20]
Reactant: N#Cc1ccc(NN)cc1
Reactant: CSc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(C#N)cc2)cc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 101.4 %

Procedure:
A mixture of 1-[4-(methylthio)phenyl]-4,4,4-trifluorobutane-1,3-dione (1.8 g) and 4-cyanophenylhydrazine hydrochloride (1.2 g) in acetic acid (30 ml) and N,N-dimethylformamide (1 ml) was stirred at 110° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and evaporated to give a brown powder of 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]-3-(trifluoromethyl)pyrazole (2.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[C:3]=1[Cl:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[CH:7]=[N:8][C:4]=2[C:3]=1[Cl:11]
Reactant: Clc1c(Br)ccc2[nH]cnc12
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: C1CCOC1
Product: Clc1c(Br)ccc2c1ncn2C1CCCCO1
Yield: 90.1 %

Procedure:
To a solution of 128 (22 g, 0.095 mol) in dry THF (660 mL) was added 3,4-dihydro-2H-pyran (24 g, 0.286 mol) and camphorsulfonic acid (2.2 g, 0.00948 mol) and the solution was heated to reflux for 16 h. The resulting mixture was concentrated, and the residue obtained was purified by SiO2 chromatography eluting with 20% EtOAc/petroleum ether to afford 27 g (90%) of 5-bromo-4-chloro-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (130) as pale yellow solid.
Reaction SMILES: [Li+].[BH4-].[F:3][C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH3:16])[C:5]=1[C:6](OC)=[O:7].O>C1COCC1>[F:3][C:4]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([O:15][CH3:16])[C:5]=1[CH2:6][OH:7]
Reactant: COC(=O)c1c(F)cc(F)cc1OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)cc(F)c1CO
Temperature: 25 °C
Reaction time: 23 h
Yield: 98.4 %

Procedure:
A solution of LiBH4 (2M in THF, 6.28 mL, 12.6 mmol) was added to a solution of methyl 2,4-difluoro-6-methoxybenzoate (1.15 g, 5.71 mmol) in THF (30 mL). The solution was stirred at rt for 23 h, then at 60° C. for 4.5 h, and reflux for 18.5 h. After cooling to rt, H2O (20 mL) was added dropwise and the mixture stirred for 5 min before being partially concentrated in vacuo. DCM (20 mL) was added, the phases were separated, and the aqueous phase was extracted with DCM (2×10 mL). The organic layers were concentrated in vacuo to yield the title compound (978 mg, 5.62 mmol).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]1([CH2:19]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH2:19][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCC1CCCCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution comprised of sodium (6.9 g, 0.3 mmol) in ethanol (250 mL) was treated sequentially with diethyl malonate (53.127 g, 0.3 mol) and then cyclohexylmethyl bromide (46 mL, 0.33 mol) at ambient temperature. The mixture was heated to 70° C. and stirred for approximately 12 hours. The mixture was cooled and solvent was removed by evaporation. The residue was diluted with ice water and the dilution was extracted with ethyl acetate (4×). The combined extracts were washed with water (4×) and brine, dried (MgSO4) and concentrated to provide diethyl 2-cyclohexylmethylmalonate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[NH:5][CH:6]=1.[C:16](O)(=[O:19])[C:17]#[CH:18].N1(C(N2C=CN=C2)=O)C=CN=C1>>[C:8]([C:7]1[CH:18]=[CH:17][C:16](=[O:19])[N:5]2[CH:6]=[C:2]([Br:1])[NH:3][C:4]=12)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CC(=O)O
Reactant: O=C(Cc1nc(Br)c[nH]1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(c1ccccc1)c1ccc(=O)n2cc(Br)[nH]c12

Procedure:
The compound is prepared as described in example 6 with 96.50 mg (0.36 mmol) of 2-(4-bromo-1H-imidazol-2-yl)-1-phenylethanone (example XXXXIII), 39.84 mg (0.55 mmol) of propiolic acid and 106.24 mg (0.66 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[CH3:26])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[CH:25][C:16]([O:15][CH3:14])=[CH:17][CH:18]=4)[CH:23]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: COc1ccc2c(c1)C(C)NCC2
Product: COc1ccc2c(c1)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])([CH3:3])[CH3:2].[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)Cl>[Cl:12][S:13]([C:8]1[CH:7]=[CH:6][C:5]([O:10][CH3:11])=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=1)(=[O:15])=[O:14]
Reactant: COc1ccccc1C(C)C
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1C(C)C
Temperature: 0 °C

Procedure:
To a solution of 2-isopropylanisole (0.40 g, 2.66 mmol) in CH2Cl2 (9 mL) cooled with an ice water bath was added slowly chlorosulfonic acid (4 mL). After 1.5 h of cooling, the mixture was poured into a flask containing ice (25 g). The product was extracted with CH2Cl2 (50 mL). The organic extract was washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 0.62 g of grayish oil as crude product. The crude product was purified by chromatography using the ISCO Combiflash SQ16x system (0 to 20% EtOAc in hexane, 20 min gradient, 35 g Redisep silica gel column) to give 0.56 g (84%) of compound 50a as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].CN(C=O)C.S(Br)([Br:22])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][Br:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: OCc1ccc(OC(F)(F)F)c(Br)c1
Reactant: O=S(Br)Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(CBr)cc1Br
Temperature: 23 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
To a solution of (3-bromo-4-(trifluoromethoxy)phenyl)methanol 19.1 (6.78 g, 25 mmol) in 30 mL of DCM, was added DMF (0.5 mL) and thionyl bromide (2 mL, 26 mmol). The mixture was stirred at 23° C. for 4 hours. DCM (120 mL) was added to the reaction mixture, and the resulting mixture was washed with aqueous saturated NaHCO3. The organic layer was dried over Na2SO4 and concentrated to give 19.2 (8.3 g, 99% yield) as a yellow oil, which was used directly in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.74 (1 H, d, J=2.0 Hz), 7.38-7.53 (2 H, m), 4.53 (2 H, d, J=5.6 Hz).
Reaction SMILES: NC(N)=N.[N+]([O-])(O)=O.NC(N)=N.C([O:16][CH:17]1[CH:18]([CH3:66])[CH2:19][CH2:20][CH:21]([O:57][Si:58]([CH2:64][CH3:65])([CH2:62][CH3:63])[CH:59]([CH3:61])[CH3:60])[CH2:22][C:23]([O:25][CH:26](/[C:31](/[CH3:56])=[CH:32]/[CH:33]=[CH:34]/[C:35]([OH:55])([CH3:54])[CH2:36][CH:37]2[O:53][CH:38]2[CH:39]([CH3:52])[CH:40]([O:43][Si:44]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH:45]([CH3:47])[CH3:46])[CH2:41][CH3:42])[CH:27]([CH3:30])[CH:28]=[CH:29]1)=[O:24])(=O)C>C(OCC)(=O)C>[CH2:64]([Si:58]([CH2:62][CH3:63])([CH:59]([CH3:60])[CH3:61])[O:57][CH:21]1[CH2:20][CH2:19][CH:18]([CH3:66])[CH:17]([OH:16])[CH:29]=[CH:28][CH:27]([CH3:30])[CH:26](/[C:31](/[CH3:56])=[CH:32]/[CH:33]=[CH:34]/[C:35]([OH:55])([CH3:54])[CH2:36][CH:37]2[O:53][CH:38]2[CH:39]([CH3:52])[CH:40]([O:43][Si:44]([CH2:48][CH3:49])([CH2:50][CH3:51])[CH:45]([CH3:47])[CH3:46])[CH2:41][CH3:42])[O:25][C:23](=[O:24])[CH2:22]1)[CH3:65]
Reactant: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(OC(C)=O)C=CC1C
Agent: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(O)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(OC(C)=O)/C=C/C1C
Agent: N=C(N)N
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: CCC(O[Si](CC)(CC)C(C)C)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)C(C)C)CCC(C)C(O)C=CC1C
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A 0.2M guanidine/guanidine nitrate solution (methanol-methylene chloride, 9:1)(3.9 mL, 0.78 mmol) was added to (8E,12E,14E)-7-acetoxy-3,21-bis(diethylisopropylsiloxy)-16-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (307 mg, 0.3868 mmol), and the reaction mixture was stirred at room temperature for 13 hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with an aqueous solution of ammonium chloride. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:4) to obtain the title compound (271.5 mg, 93%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:20])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)=[O:12].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].O.O.O.[F-].C[N+](C)(C)C.CCCCCCC>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:20])[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)([OH:12])[C:22]([F:24])([F:23])[F:21]
Reactant: COc1ccc(C(C)C(=O)c2ccnc(Cl)c2)c(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: C[N+](C)(C)C
Agent: [F-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C(O)(c2ccnc(Cl)c2)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a solution of 2-(2-chloro-4-methoxy-phenyl)-1-(2-chloro-pyridin-4-yl)-propan-1-on (14.75 g, 0.0475 mol) in tetrahydrofuran (900 ml) was added a solution of (trifluoromethyl)-trimethylsilane (14.89 g, 0.104 mol) in tetrahydrofuran (100 ml) at 0° C. (duration: 5 min.). Tetramethylammonium fluoride trihydrate 1M in THF (4.76 ml, 4.76 mmol) was added and the mixture was stirred at r.t. for 3 h. A second portion of Tetramethylammonium fluoride trihydrate 1M in THF (4.76 ml, 4.47 mmol) was added and the mixture was stirred at r.t. for 1 h. The mixture was poured in ice water and extracted twice with AcOEt. The organic phases were washed with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to give an oil, which solidified over night. The residue was treated with heptane, filtered off and dried to give the title compound (13.85 g) as a light yellow crystalline product. MS (m/e, ISP neg. ion)=378.4 [M−H+].
Reaction SMILES: [NH2:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[C:23]([F:29])[CH:22]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:19]=[CH:18][C:13]3[NH:14][C:15](=O)[O:16][C:12]=3[CH:11]=2)=[CH:8][N:9]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][CH:2]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([F:29])[CH:22]=1)[CH2:3][NH:4][C:5]1[S:6][C:7]([C:10]2[CH:19]=[CH:18][C:13]3[N:14]=[CH:15][O:16][C:12]=3[CH:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(CC(N)CNc2ncc(-c3ccc4[nH]c(=O)oc4c3)s2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC(CNc1ncc(-c2ccc3ncoc3c2)s1)Cc1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a 25 mL round-bottomed flask was added 6-(2-(2-amino-3-(3-fluoro-4-methoxyphenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2(3H)-one (Example 129) (60 mg, 145 μmol) and 3 mL of DCM. The solution was cooled to −78° C., and treated dropwise with boron tribromide, 1.0 M in DCM (497 μL, 2895 μmol) via a syringe. The solution was stirred at −78° C. for 1 hour and then allowed to warm to room temperature overnight. The reaction mixture was concentrated, and 2 mL of MeOH was added dropwise. The reaction mixture was purified by preparative LC to give 6-(2-(2-amino-3-(3-fluoro-4-hydroxyphenyl)propylamino)thiazol-5-yl)benzo[d]oxazol-2((H)-one (20 mg, 35% yield). MS m/z: 401 (M+1). 1H NMR (400 MHz, CD3OD) δ ppm 2.85-2.98 (m, 2H), 3.47-3.53 (m, 1H), 3.62-3.71 (m, 2H), 6.92-6.97 (m, 2H), 7.05-7.10 (m, 2H), 7.26 (dd, J=8.02, 1.57 Hz, 1H), 7.37 (s, 1H), 7.38 (d, J=1.37 Hz, 1H).