Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N=[CH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:15][CH3:16])CCC.[OH:17]S(O)(=O)=O>O.CCOC(C)=O>[CH2:15]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:7]=1[CH:6]=[O:17])[CH3:16]
Reactant: O=S(=O)(O)O
Reactant: CCCCN=Cc1c(CC)cccc1CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1C=O
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a solution of butyl-(2,6-diethyl-benzylidene)-amine (1.10 g; 5.06 mmol) in water (20 mL) was added H2SO4 (5.00 ml; 93.80 mmol), and the resulting mixture was heated under reflux for 2 hours. After cooling to RT the mixture was diluted with EtOAc, and washed with water, a 5% aqueous NaHCO3-solution and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to afford 2,6-diethyl-benzaldehyde (0.72 g).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:32])=[C:24]([N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:32][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:31])[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CN(C)C=CC(=O)c1ccc(F)c(N(C)S(C)(=O)=O)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F)S(C)(=O)=O
Yield: 78.1 %

Procedure:
A mixture of 0.064 g (0.33 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.1 g (0.33 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 111 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulfonamide as a solid (yield 77%).
Reaction SMILES: Br[C:2]1[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:23][O-:24].[Na+]>C(OCC)(=O)C.[Cu]Br>[CH2:8]([C:7]1[N:6]=[CH:5][N:4]=[C:3]([NH:10][C@H:11]2[CH2:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[C:2]=1[O:24][CH3:23])[CH3:9]
Reactant: C[O-]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br
Agent: [Cu]Br
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCc1ncnc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1OC

Procedure:
7.20 g (20 mmol) of 5-bromo-6-ethyl-4-(cis-4-phenylcyclohexylamino)pyrimidine (DE-A-42 08 254) and 0.44 g (3 mmol) of copper(I) bromide were heated under reflux for 12 hours in 10 ml of 30% methanolic sodium methylate solution, to which 0.70 g of ethyl acetate have been added. For working up, the solvent is stripped off, the residue is taken up in ethyl acetate, this mixture is subjected to extraction by stirring with water, and the organic phase is dried and concentrated. For purification, the crude product is chromatographed on silica gel using ethyl acetate/petroleum ether (8:2). 3.7 g (60% of theory) of a colorless oil were obtained which gradually solidified.
Reaction SMILES: [NH2:1][CH:2]=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6]CC)=O.CO[C:16](OC)([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:17].C1(OC2C=CC=CC=2)C=CC=CC=1>O>[CH3:17][C:16]1[N:1]=[CH:2][CH:3]([C:4](=[O:6])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: COC(C)(Cc1ccccc1)OC
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C1C=NC(C)=C(c2ccccc2)C1=O

Procedure:
25 g. of diethyl aminomethylenemalonate, 18 g. of phenylacetone dimethylketal, 300 ml. of dry diphenyl ether and 1.0 g. of TSA.H2O were mixed and heated under a nitrogen atmosphere at 135°-145° C. for three hours. The mixture was then brought to reflux. After 30 minutes the solution was cooled and extracted with 200 ml. of 21/2 aqueous NaOH solution. The basic extracts were acidified yielding a precipitate of ethyl 6-methyl-5-phenyl-4-oxonicotinate. Recrystallization of this material from methylene chloride/ether provided 12.3 g. of white solid, m.p.=178°-180° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(CCO)cc2)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol (2.94 g) and 1-fluoro-4-nitrobenzene (3.0 g) in dimethylformamide (21 mL) was added potassium carbonate (4.41 g) and the solution was stirred at 120° C. for 4 hours. After cooling to room temperature, water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give the title compound having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O.[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24]>O1CCOCC1>[CH2:23]([N:25]([CH2:26][CH3:27])[CH2:4][C:3]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:2]=1[F:1])[CH3:24]
Reactant: CCNCC
Reactant: Cc1ccc(S(=O)(=O)OCc2cc([N+](=O)[O-])ccc2F)cc1
Solvent: C1COCCO1
Product: CCN(CC)Cc1cc([N+](=O)[O-])ccc1F
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-fluoro-5-nitro-benzyl ester (0.696 g, 2.13 mmoles) in 1,4-dioxane (4 mL) was added TEA (0.45 mL, 3.20 mmoles) and diethylamine (0.33 mL, 3.21 mmoles). The reaction mixture was stirred for 8 h at 55° C., concentrated and purified by TLC (petroleum ether/AcOEt/NH4OH//8/2/0.2). The expected compound was obtained as a yellow oil (0.365 g, 76% yield). MALDI-TOF: m/z 227.1 [M+H]+. 1H NMR (300 MHz, CDCl3) δ8.44; (dd, J=6.3 Hz and 2.9 Hz, 1H), 8.12; (ddd, 4-CH, J=8.9 Hz, 2.9 Hz and 4.4 Hz, 1H), 7.15; (dd, J=8.9 Hz and 8.9 Hz, 1H), 3.67; (s, 2H), 2.58; (q, J=7.1 Hz, 4H), 1.08; (t, J=7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ126.7; (CH, d, J=6.9 Hz), 124.1; (CH, d, J=10.2 Hz), 115.9; (CH, d, J=24.6 Hz), 49.6; (CH2), 47.1; (CH2), 11.8; (CH3).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32]Br>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][N:22]([CH2:32][C:31]5[CH:34]=[CH:35][CH:36]=[C:29]([C:28]([F:27])([F:37])[F:38])[CH:30]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(Cc3cccc(C(F)(F)F)c3)C2=O)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 17, from 8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 1), sodium hydride and 3-(trifluoromethyl)benzyl bromide, to give the desired product as a white solid (74%).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(CC)CC.[CH3:12][N:13]1[C:17]([CH3:18])=[C:16]([C:19]([NH:21][C:22]2[CH:44]=[CH:43][C:25]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:24][CH:23]=2)=[O:20])[C:15](=[O:45])[N:14]1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN1C(=O)CCC1>[CH2:2]([NH:4][C:34](=[O:35])[NH:33][C:29]1[CH:28]=[C:27]([O:26][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:19]([C:16]3[C:15](=[O:45])[N:14]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[N:13]([CH3:12])[C:17]=3[CH3:18])=[O:20])=[CH:44][CH:43]=2)[CH:32]=[CH:31][N:30]=1)[CH3:3]
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Reactant: CCN
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cc(Oc2ccc(NC(=O)c3c(C)n(C)n(-c4ccccc4)c3=O)cc2)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.6 %

Procedure:
To a solution of ethylamine hydrochloride (29 mg, 0.356 mmol) was in NMP (3 mL) was added Et3N (0.1 mL). The solution was stirred at rt for 10 minutes, followed by the addition of phenyl (4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)pyridin-2-yl)carbamate (100 mg, 0.187 mmol). The reaction was stirred at 40° C. overnight, then concentrated in vacuo at 40° C., and diluted with water (10 mL). The precipitate was collected by filtration, and then purified by a silica gel column chromatography (DCM/EtOAc/MeOH (v/v/v)=80/40/1) to give the title compound as a white solid (46 mg, 50%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:8]([O:10][CH3:11])=[O:9])([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O>C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:16][CH2:15][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(OC(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Yield: 64.6 %

Procedure:
To a solution of methyl 3-isopropoxy-4-methylbenzoate (1.0 g, 4.8 mmol) in ethyl acetate (20 mL) were added N-bromosuccinimide (0.92 g, 5.19 mmol) and 2,2′-azobis(isobutyronitrile) (3 mg), and the mixture was heated under reflux for 6 hr. The reaction mixture was cooled, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (0.89 g, yield 64%) as a colorless oil. MS (ESI+): 287 (M+H), 289.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[CH:6]=O)([O-])=O.[SH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CS(C)=O>[N+:12]([C:8]1[C:5]2[CH:6]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[S:15][C:4]=2[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COC(=O)CS
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c([N+](=O)[O-])cccc2s1
Temperature: 0 °C

Procedure:
1.0 g (5.10 mmol) of 2,6-dinitrobenzaldehyde, 0.54 g (5.10 mmol) of methyl mercaptoacetate and 1.42 ml (10.20 mmol) of triethylamine in 3 ml of DMSO are heated at 80° C. for 3.5 h. The reaction solution is poured into 100 ml of ice-water. The resulting precipitate is filtered off with suction, washed with water and dried at 50° C. under reduced pressure overnight. This gives 1.10 g (88.7% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:31][C:15]1[CH:16]=[C:17]([N:20]2[CH2:24][CH:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][O:13][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: CC(=O)NCC1CN(c2ccc(C(CO)Cn3cc([N+](=O)[O-])nc3Br)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NCC1CN(c2ccc(C3COc4nc([N+](=O)[O-])cn4C3)c(F)c2)C(=O)O1
Temperature: 50 °C
Reaction time: 4 h
Yield: 9.1 %

Procedure:
To a solution of crude N-(3-{4-[2-(2-Bromo-4-nitro-imidazol-1-yl)-1-hydroxymethyl-ethyl]-3-fluoro-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide (9 mg, 0.018 mmol) in DMF (1 mL) was added Cs2CO3 (18 mg, 0.054 mmol) at rt, and stirred for 4 h at 50° C. The reaction mixture was cooled to rt, diluted with EtOAc, washed with brine & water. The organic layers were separated, dried (MgSO4) and concentrated. Prep TLC (5% MeOH/CH2Cl2) provided 690 μg of pale yellow solid. ESI MS m/z 420 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]([C:18]3[N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:20]([S:29]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)(=[O:31])=[O:30])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)[OH:17])=[CH:8]2)=[CH:4][CH:3]=1>ClCCl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[N:19]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[C:20]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:31])=[O:30])=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[N:22]=3)=[O:17])=[CH:8]2)=[CH:47][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)nc(C(O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)n2COCC[Si](C)(C)C)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2c(-c3ccccn3)nc(C(=O)c3cn(Cc4ccc(Cl)cc4)c4ccccc34)n2COCC[Si](C)(C)C)cc1

Procedure:
Combined dichloromethane solution was washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the crude material was separated by silica gel chromatography (2:1 hexane/ethyl acetate to 2:1 ethyl acetate/hexane) to afford the desired intermediate [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol as an oil (65 mg, 30%). 1H NMR (CDCl3) δ−0.05 (s, 9H), 0.70 (t, 2h, J=6), 2.55 (s, 3H), 3.2-3.35 (m, 2H), 4.02 (d, 1H, J=7), 5.2-5.4 (m, 2H), 5.41 (s,2H), 6.4 (d, 1H), 7.0-8.0 (m, 16 H), 8.8 (d,1H, J=5). ESMS calcd for (C37H39ClN4O4SSi): 698.6; found: 699.6 (M+H)+. A solution of [1-(4-chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol (35 mg, 50.1 mmol) in dichloromethane was treated with excess of MnO2 (0.2 g, 2.3 mmol) at room temperature for 1 hour. MnO2 was then filtered off and the filtrate was concentrated under reduced pressure. Product [1-(4-Chloro-benzyl)-1H-indol-3-yl]-[4-pyridin-2-yl-5-(toluene-4-sulfonyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone was obtained as an oil (34.2 mg, 98%). 1H NMR (CDCl3) δ0.21 (s, 9H), 0.85 (t, 2H, J=6), 2.50 (s, 3H), 3.55 (t, 2H, J=6), 5.54 (s, 2H), 6.13 (s, 2H), 7.25-7.55 (m, 11H), 7.91 (d, 2H, J=7), 8.05 (t, 1H, J=7), 8.65 (d, 1H, J=7), 8.85 (s, 1H), 8.95 (d, 1H, J=7). ESMS calcd for (C37H37ClN4O4Ssi): 696.6; found: 697.6 (M+H)+.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:13]([N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:10](=[O:12])[CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)CNCC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(CC(C)C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of N-Boc-glycine (1.0 g, 5.7 mmol) in DMF (10 ml) were added diisobutylamine (0.10 ml, 11.4 mmol), DIPEA (1.9 ml, 11.4 mmol) and TBTU (2.7 g, 8.5 mmol). The mixture was stirred for 1 hr at room temperature, quenched with saturated aqueous sodium bicarbonate (15 ml), and extracted with EtOAc (20 ml). The organic phase was washed with brine (15 ml), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (30% EtOAc in hexanes) to provide tert-butyl 2-(diisobutylamino)-2-oxoethylcarbamate (1.6 g, 98%) as a colorless oil. [M+H]+ 287.3, HPLC purity: 90%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][O:5][C:4](=[O:7])[NH:3]1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].CC1C=CC(S(O[C:29]2[CH:34]=[CH:33][N:32]3[N:35]=[CH:36][C:37]([C:38]4[CH:43]=[CH:42][C:41]([C:44]5[N:45](COCC[Si](C)(C)C)[CH:46]=[CH:47][N:48]=5)=[CH:40][CH:39]=4)=[C:31]3[N:30]=2)(=O)=O)=CC=1.[NH4+].[Cl-].FC(F)(F)C(O)=O>CN(C=O)C.ClCCl>[NH:45]1[CH:46]=[CH:47][N:48]=[C:44]1[C:41]1[CH:42]=[CH:43][C:38]([C:37]2[CH:36]=[N:35][N:32]3[CH:33]=[CH:34][C:29]([N:3]4[C@@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[N:30][C:31]=23)=[CH:39][CH:40]=1
Reactant: C[C@H]1COC(=O)N1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccn3ncc(-c4ccc(-c5nccn5COCC[Si](C)(C)C)cc4)c3n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncc[nH]4)cc3)c2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 7.8 %

Procedure:
A solution of (S)-4-methyloxazolidin-2-one (9.0 mg, 0.089 mmol) in dry DMF (0.5 mL) was cooled to 0° C. Sodium hexamethyldisilazide (0.089 mL, 0.089 mmol) was added and the resulting yellow solution stirred for 10 minutes before addition of a solution of 3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl 4-methylbenzenesulfonate (20.0 mg, 0.0356 mmol) in DMF (0.5 mL). The mixture was then brought to ambient temperature prior to heating at 80° C. for 1 hour. The cooled reaction mixture was poured into saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification of the crude material by column chromatography, eluting with 1-2% MeOH/dichloromethane afforded the protected intermediate which was taken up in dichloromethane (1 mL). Trifluoroacetic acid (3 mL) was added and the mixture stirred at ambient temperature for 12 hours. The reaction mixture was concentrated, washed with saturated aqueous NaHCO3, extracted into ethyl acetate, dried over sodium sulfate, filtered and concentrated. Purification of the crude material by column chromatography, eluting with 2-4% MeOH/dichloromethane, afforded (S)-3-(3-(4-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-methyloxazolidin-2-one as a light yellow solid (1 mg, 8%). LCMS (APCI+) m/z 361 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=7.8 Hz, 1H), 8.54 (s, 1H), 8.17 (d, J=8.6 Hz, 2H), 7.97 (d, J=7.8 Hz, 1H), 7.91 (d, J=8.6 Hz, 2H), 7.14 (s, 2H), 5.06-5.13 (m, 1H), 4.65 (t, J=8.2 Hz, 1H), 4.21-4.24 (m, 1H), 1.66 (d, J=6.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[N:18][CH:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1cncc(F)c1
Product: COC(=O)c1cc(Cl)ccc1Oc1cncc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 5-chloro-2-fluorobenzoate and 5-fluoropyridin-3-ol: MS (ESI) m/z 282 (M+H)+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12]([C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][NH:20]2)=[C:16]([O:23][CH2:24][CH3:25])[CH:15]=1)=O>O=[Mn]=O>[CH2:24]([O:23][C:16]1[CH:15]=[C:14]([CH:12]=[O:11])[CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2)[CH3:25]
Reactant: CCOc1cc(C(=O)OC)cc2[nH]ccc12
Agent: O=[Mn]=O
Agent: CC(C)C[AlH]CC(C)C
Product: CCOc1cc(C=O)cc2[nH]ccc12

Procedure:
The necessary intermediate 4-Ethoxy-1H-indole-6-carbaldehyde was synthesized following the procedure described in J. Org. Chem. 2004, 69, 6945 and ensuing DIBAL-H—reduction and MnO2—oxidation of the resultant 4-ethoxy-1H-indole-6-carboxylic acid methyl ester, as yellow solid.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[NH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([Cl:33])[CH:28]=1)N>>[Cl:33][C:29]1[CH:28]=[C:27]([N:25]2[C:17]([C:12]3[C:13](=[O:16])[CH:14]=[CH:15][N:10]([C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:24])[F:1])[CH:5]=4)[N:11]=3)=[CH:18][CH:19]=[N:20]2)[CH:32]=[CH:31][N:30]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1ccnc(Cl)c1
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccnc(Cl)c1

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 4-hydrazino-2-chloropyridine according to the method described for example 91. MS: M=416.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](O)=[O:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29](=[O:30])[NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(=O)O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2C(=O)NS(C)(=O)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-carboxyphenyl)-L-phenylalanine methyl ester (57.0 mg) was dissolved in anhydrous THF (1 mL), carbonyldiimidazole (23.5 mg) was added and the mixture was stirred at room temperature under N2 for 2 h. Methanesulfonamide (17.2 mg) and DBU (27 μL) were added and the mixture was stirred for an additional 18 h. The mixture was then heated to 40° C., stirred for 7 h at the same temperature, cooled to room temperature, diluted with EtOAc, washed with 1N HCl and then brine, dried (MgSO4) and evaporated. The residue was purified by preparative TLC (silica gel) using CH2Cl2/MeOH (100:1 to 10:1) as an eluent to give N-(2,6-dichlorobenzoyl)-4-[2-[N-(methanesulfonyl)carbamoyl]phenyl]-L-phenylalanine methyl ester (37.0 mg). ESMS: m/z 549 (MH+).