Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:49]([O:51][CH2:52][CH3:53])=[O:50].C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:52]([O:51][C:49](=[O:50])[NH:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1)[CH3:53]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (20 mg, 0.037 mmol) in DCM (1 ml) was added pyridine (0.1 ml) followed by ethyl chloroformate (10.70 μl, 0.111 mmol). The vial was capped and the contents stirred at room temperature for 16 h. Un-reacted chloroformate was quenched by adding MP-Trisamine (91 mg, 0.186 mmol) and tumbling the vial for an additional 3 h. The resin was filtered and the volatiles removed in vacuo to afford crude (R)-ethyl(6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate which was taken forward without purification. MS ESI calc'd. For C37H35N6O3 [M+H]+ 611. found 611.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11]1.N12CCCN=C1CCCCC2.[Cl-].[Na+]>C(O)C>[CH3:9][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14](=[O:15])[CH:13]=[C:12]([CH:16]=[CH:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[O:11]1
Reactant: CC1=CC(=O)C(C)(c2ccccc2)O1
Reactant: O=Cc1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CC1(c2ccccc2)OC(C=Cc2ccncc2)=CC1=O
Temperature: 60 °C
Yield: 37 %

Procedure:
To a solution of 4-pyridinecarboxaldehyde (1.4 mL, 14.9 mM) and 2,5-dimethyl-2-phenyl-3(2H)-furanone (2.0 g, 10.6 mM) in ethanol (50 mL), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 323 mg, 2.1 mM). The reaction solution was heated at 60° C. for 4 hours. After the reaction solution cooled to room temperature, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a red gummy product. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to give a white crystalline solid (1.1 g, 37% yield), m.p. 165°-166° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([OH:28])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][C:37]#[N:38]>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][C@H:14]([CH3:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][C@H:11]2[CH3:25])=[O:9])=[C:4]([CH:3]=1)[O:28][CH2:36][C:37]#[N:38]
Reactant: N#CCBr
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1OCC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
To a solution of 2-(4-chloro-2-hydroxy-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (0.10 g, 0.24 mmol), and cesium carbonate (0.12 g, 0.38 mmol) in dioxane (1 mL) was added bromoacetonitrile (0.034 g, 0.28 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction was diluted with ethyl acetate and washed with water. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give the title compound (0.11 g).
Reaction SMILES: O[C:2]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[C:2]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2C2(O)CCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: C1=C(c2cccc3c2OCCNC3)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A mixture of tert-butyl 9-(1-hydroxycyclopentyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (30.0 mg, 0.0899 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (4 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (18.0 mg, 79.3%) as a solid.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C.[Cu]I.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:9]1([C:15]#[C:16][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1ccncc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: C(#Cc1ccncc1)c1ccccc1
Yield: 31.1 %

Procedure:
A mixture of 4-bromopyridine hydrochloride (9.75 g, 50 mmol), phenylacetylene (11 ml, 10.2 g; 100 mmol), copper (I) iodide (50 mg) and bis(triphenylphosphino)palladium (II) chloride (200 mg) in dry triethylamine (60 ml) was stirred under reflux for 16 h, the cooled reaction mixture filtered, and the filtrate evaporated. The residual black oil was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (2×50 ml) and HCl (1M, 4×25 ml). The acidic washings were extracted with ethyl acetate (2×25 ml) and then basified (5M NaOH). The resulting suspension was extracted with dichloromethane (4×25 ml), the combined organic layers washed with water (25 ml), dried (MgSO4), evaporated, and the residue chromatographed on silica gel, eluting with 7:3 ethyl acetate/60°-80° petrol to give the product as a buff solid (2.79 g, 31%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:10])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].I[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.CN[C@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[NH2:10][C:7]1[N:8]([C:13]2[CH:12]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:18])[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1
Reactant: Oc1cccc(I)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccccc2O)n1
Yield: 85.5 %

Procedure:
A mixture of 5-tert-butyl-2H-pyrazol-3-ylamine (1 g, 7.18 mmol), 3-iodophenol (1.74 g, 7.90 mmol), copper (I) iodide (68 mg, 0.36 mmol), (1S,2S)—N,N′-dimethyl cyclohexane-1,2-diamine (204 mg, 1.44 mmol) and potassium carbonate (2.08 g, 15.09 mmol) in toluene (8 mL) was de-gassed and flushed with argon (3×). The reaction mixture was then treated with microwave irradiation, at 150° C. for 1 h. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous layer was extracted with a further 20 mL EtOAc and the combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue obtained was purified by FCC, using 0-100% EtOAc in cyclohexane to afford the title compound as a brown gum (1.42 g, 86%). LCMS (Method 3): Rt 2.21 min, m/z 232 [MH+].
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:31][CH2:30][C:25]5([O:29][CH2:28][CH2:27][O:26]5)[CH2:24][CH2:23]4)[CH2:18][CH:17]=3)=[C:12]([F:32])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[H][H]>C1(C)C=CC=CC=1.C(O)(C)C.[Pd]>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:17][CH2:18][CH:19]([CH:22]4[CH2:31][CH2:30][C:25]5([O:26][CH2:27][CH2:28][O:29]5)[CH2:24][CH2:23]4)[CH2:20][CH2:21]3)=[C:12]([F:32])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC1CCC(c2ccc(C3=CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCOC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1

Procedure:
The compound (24) was dissolved in a mixed solvent of toluene (150 ml) and isopropyl alcohol (150 ml), and then Pd/C (2.35 g) and potassium carbonate (0.40 g) were added thereto. The mixture was stirred at room temperature under a hydrogen atmosphere until hydrogen absorption had ceased. After the reaction had been completed, Pd/C was removed and then the solvent was distilled off. The residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and dried, giving 31.4 g of 8-(4-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)cyclohexyl)-1,4-dioxaspiro[4,5]decane (25). The yield based on the compound (24) was 66.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc(C)c1-c1ccc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 47.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2,6-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.034 g (47%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′,6′-dimethylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:5])=[O:4].Cl[C:7]1[CH:12]=C[CH:10]=[CH:9][CH:8]=1>>[CH:3]12[CH2:5][CH:8]([CH2:9][CH2:10]1)[CH:7]=[CH:12]2.[C:3]([O:2][CH3:1])(=[O:4])[CH3:5]
Reactant: Clc1ccccc1
Solvent: COC(C)=O
Product: C1=CC2CCC1C2

Procedure:
Methyl acetate norbornene (MeOAc NB, CAS 10471-2406) (2.99 g, 17.99 mmol), CANB (0.36 g, 2.02 mmol), 1-hexene (0.19 g, 0.0022 mol), DAN FABA (0.00321 g, 0.004 mmol) and anisole (14 mL) were combined in a dry 30 mL Wheaton bottle. The anisole was degassed to remove any dissolved oxygen by passing a stream of nitrogen gas through the liquid for 30 minutes. To this solution was added Pd 785 (0.0090 g, 0.004 mmol) dissolved in dichloroethane (0.5 mL). After addition, the solution was processed as in S9 and after drying, 3.21 g (95.8%) of copolymer was obtained. The molecular weight was determined by GPC in monochlorobenzene to be Mw=714,346 and Mn=89,454 daltons and Polydispersity Index=7.98. The composition of the copolymer was determined by 1H-NMR to be 91 mole % MeOAc NB and 9 mole % CANB.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5](=O)[CH:6]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:7]([C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[C:12]([OH:17])=[CH:11][C:10]=1[OH:18])=[O:8])[CH3:2].CCOC(C)=O.CCCCCC>Cl.CO>[CH2:1]([O:3][C:4]([C:5]1[O:18][C:10]2[C:9]([C:7](=[O:8])[C:6]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:14][C:13]([CH2:15][CH3:16])=[C:12]([OH:17])[CH:11]=2)=[O:27])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C(=O)c1cc(CC)c(O)cc1O)c1ccc(F)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1oc2cc(O)c(CC)cc2c(=O)c1-c1ccc(F)cc1

Procedure:
4-(5-Ethyl-2,4-dihydroxy-phenyl)-3-(4-fluoro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.22 g, 8.6 mmol) was refluxed in a mixture of 0.8M HCl and MeOH (20 ml/20 ml) for 3 hours at 100° C. After that, MeOH was evaporated and the aq. layer was extracted with EtOAc (2×60 ml). The combined organic layers were washed with sat. NaHCO3 (1×80 ml), brine (2×80 ml), water (1×80 ml) and dried with Na2SO4. After purification with decolourising charcoal and evaporation of the solvent, brown sticky solids were obtained. They were then extracted with hot ether, dark yellow solids were obtained (0.26 g). Rf=0.43 (EtOAc:n-hexane/1:2). LCMS: (M+1)+=357.3 (RT=7.83). 1H NMR (d6-acetone) δ=9.75 (1H, s); 7.80 (1H, s); 7.25 (2H, m); 7.10 (1H, m); 6.90 (1H, s); 4.05 (2H, q); 2.70 (2H, q); 1.20 (3H, t) and 0.95 (3H, t).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[OH:19][CH:17]([CH:7]([N:6]1[C:2]2[N:1]=[C:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)[NH:22][C:20](=[O:21])[C:3]=2[CH:4]=[N:5]1)[CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:18]
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Reactant: Cc1ccc(CC(=O)Cl)cc1
Product: Cc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1

Procedure:
Starting from 400 g (1.32 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 578 mg (3.44 mmol) of 4-methylphenylacetylchloride, the title compound is prepared analogously to the protocol of Example 13. This gives 117 mg (21%) of the diastereomer which elutes more rapidly, M.p.: 133° C., and 75 mg (13.6%) of the diastereomer which elutes more slowly, M.p.: 136° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccccc2C(F)(F)F)c1
Temperature: 110 °C

Procedure:
Under an atmosphere of argon, 500 mg (2.31 mmol) of methyl 2-bromoisonicotinate and 694 mg (3.47 mmol) of 2-(trifluoromethyl)phenylboronic acid were dissolved in 10 ml of toluene. 106 mg (0.12 mmol) of tris(dibenzylideneacetone)dipalladium, 91 mg (0.23 mmol) of tri-tert-butylphosphine and 982 mg (4.63 mmol) of potassium phosphate were then added, and under argon the mixture was heated to 110° C. for 20 h. For work-up, the mixture was diluted at RT with 15 ml of ethyl acetate and 15 ml of water, the organic phase was separated off and the aqueous phase was extracted two more times with in each case 15 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1, then 10:1). This gave 498 mg (59% of theory) of the target compound in a purity of 77%. A second product fraction of lower purity was purified further according to Method 19. This gave a further 54 mg (8% of theory) of the target compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.[CH3:28][N:29]1[C@@H:34]([CH3:35])[CH2:33][NH:32][CH2:31][C@H:30]1[CH3:36].C[C@H]1CNC[C@@H](C)N1CC#N.C(N(C(C)C)C(C)C)C>CS(C)=O.CO>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH2:17][O:16][C:14]2[CH:15]=[C:11]([NH:10][C:8]([C:5]3[CH:4]=[N:3][C:2]([N:32]4[CH2:33][C@H:34]([CH3:35])[N:29]([CH3:28])[C@H:30]([CH3:36])[CH2:31]4)=[CH:7][N:6]=3)=[O:9])[NH:12][N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: COc1cc(COc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C[C@@H]1CNC[C@H](C)N1C
Agent: C[C@@H]1CNC[C@H](C)N1CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1cc(COc2cc(NC(=O)c3cnc(N4C[C@@H](C)N(C)[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (273 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and 2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol) in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The reaction was incomplete and N-ethyl-N-propan-2-ylpropan-2-amine (0.24 ml, 1.40 mmol) was added and the solution was stirred at 60° C. for a further 2 h. The reaction mixture was diluted with methanol (20 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (248 mg, 74%) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](=[O:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[CH3:22][O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](=[O:21])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]([O:23][CH3:22])=[O:33])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: O=C(CCc1ccc(O)cc1)N1CCc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccccc1COc1ccc(CCC(=O)N2CCc3ccccc3C2)cc1
Yield: 57 %

Procedure:
4-[3-(3,4-dihydroisoquinolin-2(1H)-yl)-3-oxopropyl]phenol (155 mg, 0.551 mmol) was dissolved in acetonitrile (10 ml). 2-Bromomethylbenzoic acid methyl ester (126 mg, 0.551 mmol) was added followed by potassium carbonate anhydrous (114 mg, 0.826 mmol). The mixture was heated to reflux overnight and then evaporated to dry. Water and ethyl acetate were added and two phases were separated. The organic phase was dried (magnesium sulphate) and evaporated. Column chromatography of the residue on silica gel using ethyl acetate/heptane (40:60) as eluant gave 135 mg the desired product, yield 57%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:16]2[C:17](=[O:23])[NH:18][C:19]3=[CH:20][CH:21]=[CH:22][C:14](=[C:15]23)[O:13][CH2:12]1)[CH3:10]>C(#N)C.C(O)(=O)C>[Br:1][C:22]1[C:14]2[O:13][CH2:12][C:11]([CH2:9][CH3:10])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:16]3[C:17](=[O:23])[NH:18][C:19]([C:15]=23)=[CH:20][CH:21]=1
Reactant: CCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: CCC1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
N-Bromosuccinimide (70 mg, 0.4 mmol) was added to a solution of 4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (80 mg, 0.4 mmol) in acetonitrile (5 mL) and acetic acid (10 mL) cooled to 0° C. The reaction was stirred for 30 min, was concentrated to remove residual acetic acid, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.07 g. 80%). LCMS calculated for C16H15BrN3O2 (M+H)+: m/z=360.1, 362.1. found: 359.8, 361.8.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][CH2:19][C:20]1([CH2:23][OH:24])[CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1([CH:23]=[O:24])[CH2:21][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC1(C=O)CC1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
To a stirred solution of DMSO (6.9 mL, 0.097 mol) in anhydrous DCM (90 mL) at −70° C. was added oxalyl chloride (4.20 mL, 0.0486 mol). After stirring for 10 min. at −70° C., a solution of [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopropyl]methanol (7.011 g, 0.03240 mol) in anhydrous DCM (30 mL) was added via cannula. The resulting milky mixture was slowly warmed to −55° C. over 45 min. DIPEA (34.0 mL, 0.194 mol) was added. The resulting mixture was stirred for 5 min. at −55° C., and then the cooling bath was removed and the reaction mixture was allowed to warm to RT. The reaction was then quenched with saturated aqueous NaHCO3 (150 mL) and extracted with DCM (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by Combiflash chromatography eluting with 0-10% EtOAc/hexanes to afford the desired product as a colorless oil (4.558 g, 66% yield).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]3[N:16]=[CH:17][S:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])=[CH:13][C:12]([Br:28])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:28][C:12]1[CH:13]=[C:14]([C:15]2[N:16]=[CH:17][S:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[Cl:27])[C:9]([NH2:8])=[N:10][CH:11]=1
Reactant: COc1ccc(CNc2ncc(Br)cc2-c2ncsc2-c2cccc(Cl)c2Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(Br)cc1-c1ncsc1-c1cccc(Cl)c1Cl
Yield: 2 %

Procedure:
A solution of N-(4-methoxybenzyl)-5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine (110 mg) and TFA (100 μL) in methylene chloride (2 mL) was stirred at 40° C. overnight. The reaction was concentrated and purified by reversed-phase HPLC to give 5-bromo-3-(5-(2,3-dichlorophenyl)thiazol-4-yl)pyridin-2-amine as a white solid [1.1 mg, 2% yield; LC-MS M+H=519.9; 1H-NMR (300 MHz, methanol-d4) 9.17 (1H, d), 7.95 (1H, d), 7.60-7.63 (2H, m), 7.34-7.35 (1H, m), 7.27 (1H, dd)].