Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[F:16][C:17]([O:22][CH2:23][CH:24]1[O:26][CH2:25]1)([F:21])[CH:18]([F:20])[F:19]>>[F:16][C:17]([F:21])([O:22][CH2:23][CH:24]([OH:26])[CH2:25][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=1)[CH:18]([F:19])[F:20]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: FC(F)C(F)(F)OCC1CO1
Product: CC(C)(C)CC(C)(C)c1ccc(OCC(O)COC(F)(F)C(F)F)cc1
Temperature: 100 °C
Yield: 107.8 %

Procedure:
A 250 mL 2-neck flask was charged with 20.6 g (0.10 mol) of 4-tert-octylphenol obtained from Aldrich Chemical Co., a catalytic amount of dry, ground potassium carbonate obtained from EM Science, Inc. (1.38 g, 0.010 mol), a stir bar, and 95% ethanol (75 mL) under argon. The side arm was then stoppered with a rubber septum, and a condenser with an argon inlet was attached to the center neck. The system was evacuated and backflushed with argon three times. Stirring was commenced to dissolve the phenol, then glycidyl 1,1,2,2-tetrafluoroethyl ether (27.0 mL, 19.15 g, 0.11 mol) obtained from Aldrich Chemical Co., was added through the septum in two portions using a 20 mL glass syringe. The reaction was monitored by thin layer chromatography (TLC) while it refluxed for 24 hours in an oil bath at 100° C. The mixture was then allowed to cool and the ethanol removed by rotary evaporation. The product was obtained by dissolving the reaction mixture in 100 mL hexanes and extracting with 1×50 mL 5% NaOH in 15:85 v/v water/methanol followed by 2×50 mL deionized water washes. The methanol-water layers were back-extracted with 50 mL hexanes. After drying over anhydrous MgSO4, the combined hexanes were evaporated off to give 41.0 g (108% yield) of a pale yellow oil. The product was purified by fractional distillation under vacuum with 31.96 g (84%) of spectroscopically pure product being collected at 145-153° C. (0.2 mm Hg). The structure and purity of the compound were corroborated by proton (1H) and carbon-13 NMR spectrometry.
Reaction SMILES: C([O:3][C:4](=[O:51])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[C:16]2=[NH:50])[CH:6]=1)C.[OH-].[Na+]>CO>[C:39]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:17]3[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:7]4[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=4)[C:4]([OH:51])=[O:3])[C:16]3=[NH:50])=[CH:30][CH:29]=2)[CH2:36][CH2:35]1
Reactant: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(N4CCN(Cc5ccccc5-c5ccccc5)CC4)cc3)c3ccccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=c1n(CCCOc2cccc(C(=O)O)c2)c2ccccc2n1Cc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
To a solution of 3-(3-{3-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid ethyl ester (20 mg, 0.03 mmol) in MeOH (2 ml) at rt was added 1M NaOH (2 ml). The reaction was heated at to 80° C. for 5 h and then concentrated under reduced pressure. The material that remained was partitioned between EtOAc and H2O and the organic layer was separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give 3-(3-{3-[4-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-benzyl]-2-imino-2,3-dihydro-benzoimidazol-1-yl}-propoxy)-benzoic acid (10 mg, 52%). HPLC-MS [M+1]+ 327. 1H NMR (500 MHz, CHLOROFORM-d) □ ppm 2.13 (2 H, br s), 2.36 (4 H, br s), 2.87 (4 H, br. s.), 3.39 (2 H, s), 3.99 (2 H, br s), 4.39 (2 H, br s), 5.24-5.55 (2 H, m), 6.37-6.87 (3 H, m), 7.09 (7 H, br s), 7.29-7.67 (11 H, m).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](SC)[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[NH:13]([C:4]1[N:3]=[C:2]([OH:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CSc1ncc([N+](=O)[O-])c(O)n1
Reactant: Nc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cnc(Nc2ccccc2)nc1O

Procedure:
4.65 gm of 4-hydroxy-2-methylmercapto-5-nitropyrimidine (0.025 mol) are dissolved with heating in 150 ml of ethanol and refluxed for 5 hours with 4.68 gm of aniline (0.05 mol). The precipitated product is extracted in the cold, washed with ethanol and dried.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@:9]1([CH2:22][OH:23])[CH3:21])=O)(C)(C)C.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25].C(Cl)Cl>>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[Si:14]([O:13][C@@H:10]1[CH2:11][CH2:12][NH:8][C@@:9]1([CH2:22][OH:23])[CH3:21])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@]1(C)CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN[C@]1(C)CO

Procedure:
(2R,3R)-3-(tert-Butyldimethyl-silanyloxy)-2-hydroxymethyl-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester (58B) (269 mg, 0.78 mmol) was stirred in 17% TFA/CH2Cl2 (6 mL) for 30 min. The reaction was concentrated to provide a brown oil (334 mg). LC/MS m/z 246 [M+H]+
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:12].C(Cl)(Cl)Cl>O1CCCC1>[C:1]1([C:7]2[CH:11]=[CH:10][SH:9]([CH:6]([OH:12])[CH2:1][CH2:2][CH3:3])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: c1ccc(-c2ccsn2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCC(O)[SH]1C=CC(c2ccccc2)=N1
Reaction time: 1 h

Procedure:
Dissolved in 60 ml of anhydrous tetrahydrofuran were 3.1 g (19.1 mmol) of 3-phenylisothiazole, followed by the addition 18.2 ml of an n-butyl lithium-hexane solution (1.57 mol/l) under a nitrogen gas stream at -78° C. over a dry ice-acetone bath. After the resulting mixture was stirred for 1 hour, 1.51 g (21 mmol) of butylaldehyde were added dropwise. The solution was stirred for 1 hour at the same temperature, whereby the reaction was completed. Water and chloroform were added. The reaction product was extracted into an organic layer. The organic layer was concentrated and the concentrate was purified by silica gel chromatography (eluent: 20:1 n-hexane/ethyl acetate), so that 3-phenyl-5-(1-hydroxybutyl)isothiazole was obtained as yellow oil.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][C@H:28]([C:30]([F:33])([F:32])[F:31])[CH2:27][C@H:26]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N:19][CH:20]=1)([O-:14])=[O:13].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][C@H:28]([C:30]([F:33])([F:32])[F:31])[CH2:27][C@H:26]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:40])[CH3:39])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N+:19]([O-:9])[CH:20]=1)([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
mCPBA (0.16 g, 0.93 mmol) was added to a solution of tert-butyl [(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.16 g, 0.37 mmol) (second peak, pure product resolved on chiral HPLC from previous step) in DCM (2.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The mixture was treated with aq. Na2S2O3, then 1 M NaOH, and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using CombiFlash® apparatus (20 g column) eluting with 0-100% EtOAc in hexanes followed by MeOH/EtOAc (0-30%) to give 0.10 g (60%) of the sub-title compound as a reddish solid. 0.033 g of unreacted starting material was recovered. LCMS calc. for C19H26F3N4O5 (M+H)+ m/z=447.2. found: 446.9.
Reaction SMILES: C1SCC(C(O)=O)NC1C(O)=O.[Li]C(CC)C.[CH:18]1([C:21]2[CH:22]=[C:23]([CH:27]=[C:28]([F:30])[CH:29]=2)[C:24]([OH:26])=[O:25])[CH2:20][CH2:19]1.[Br:31]C(Cl)(Cl)C(Cl)(Cl)Br>C1COCC1>[Br:31][C:27]1[C:28]([F:30])=[CH:29][C:21]([CH:18]2[CH2:19][CH2:20]2)=[CH:22][C:23]=1[C:24]([OH:26])=[O:25]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1cc(F)cc(C2CC2)c1
Agent: O=C(O)C1CSCC(C(=O)O)N1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: O=C(O)c1cc(C2CC2)cc(F)c1Br
Reaction time: 1 h

Procedure:
To a solution of TMDA (1.3 ml, 8.61 mmol) in dry THF (9 mL) under inert atmosphere at −65° C., a 1.4M solution of sec-BuLi (8 ml, 11.20 mmol) was added dropwise. Then a solution of 3-cyclopropyl-5-fluorobenzoic acid (0.69 g, 3.83 mmol) in dry THF (3 mL) was added dropwise and stirred for 1 h. Then a solution of 1,2-dibromotetrachloroethane (5 g, 15.48 mmol) in dry THF (11 mL) was added dropwise for 1 h and stirred for additional 20 min. A white suspension was obtained. The cooling bath was removed and at −20° C. water (30 mL) and diethyl ether (30 mL) were added. The organic layer was separated and the aqueous phase was acidified (until pH: 1) using a 2N aqueous solution of HCl (13 mL needed) and extracted with diethyl ether. The organic phase was washed with water and brine, dried, filtered and concentrated in vacuo to afford a mixture 1:1 of the expected compound and starting material (38% yield), which was used without further purification
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[N:11][CH:12]=1.[B:20](OC)([O:23]C)[O:21]C.Cl>O.C(OCC)C>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([B:20]([OH:23])[OH:21])=[CH:12][N:11]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COB(OC)OC
Reactant: CCCCCCOc1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CCCCCCOc1ccc(B(O)O)cn1
Reaction time: 1 h

Procedure:
250 mmol of n-butyllithium (1.6M solution in n-hexane) are added dropwise at 0° C. with exclusion of moisture and under a protective-gas atmosphere to a solution of 250 mmol of 5bromo-2-hexyloxypyridine in 500 ml of abs. diethyl ether. The mixture is stirred at this temperature for a further 1 hour, and 275 mmol of trimethyl borate are subsequently added slowly. After the mixture has been stirred at 0° C. for a further hour, a solution of 175 ml of water and 25 ml of 37 percent hydrochloric acid is added dropwise. The mixture is stirred at room temperature for 1 hour, the phases are then separated, the aqueous phase is extracted a number of times with dichloromethane, and the combined organic extracts are dried using magnesium sulfate. The solvents are removed in vacuo. After drying in a high vacuum, the red-brown, high-viscosity crude product is reacted further without additional purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]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+]>C(#N)C>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([N:1]2[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:2]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
A mixture of ethyl 1H-imidazole-4-carboxylate (8 g, 57.1 mmol), 4-fluoro-1-nitrobenzene (8.05 g, 57.1 mmol) and potassium carbonate (8.68 g, 62.8 mmol) in acetonitrile (100 mL) was stirred at 60° C. for 16 h then cooled to room temperature and most the solvent was removed in vacuo. The residue was partitioned between AcOEt (200 mL) and water (150 mL) and the layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave ethyl 1-(4-nitrophenyl)-1H-imidazole-4-carboxylate (12.53 g, 48.0 mmol, 84%) as a yellow oil.
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].C(NC(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([C:54]23[C:67]4[C:62](=[C:63]([F:69])[CH:64]=[CH:65][C:66]=4[F:68])[O:61][CH2:60][CH:59]2[NH:58][CH2:57][CH2:56][CH2:55]3)(=[O:53])=[O:52])=[CH:47][CH:46]=1>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][CH2:9][C:10]([N:58]1[CH:59]2[C:54]([S:51]([C:48]3[CH:49]=[CH:50][C:45]([Cl:44])=[CH:46][CH:47]=3)(=[O:53])=[O:52])([C:67]3[C:62]([O:61][CH2:60]2)=[C:63]([F:69])[CH:64]=[CH:65][C:66]=3[F:68])[CH2:55][CH2:56][CH2:57]1)=[O:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCCNC1COc1c(F)ccc(F)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N1CCCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
BOC-Glycine was dissolved in 150 ml of DMF. 0.5 ml of diisopropylamine was added followed by HATU (2.54 g, 6.68 mmol). The solution was stirred at room temperature for 25 minutes then 4a-(4-Chloro-benzenesulfonyl)-5,8-difluoro-2,3,4,4a,10,10a-hexahydro-1H-9-oxa-1-aza-phenanthrene (541 mg, 1.35 mmol) was added and the reaction was stirred overnight. The reaction was quenched with water and washed with 1:1 mixture of ethyl acetate and hexanes solution. The organic layer was dried over sodium sulfate and concentrated. The product was purified by column using EtOAc/Hex. as the eluent (0/100 to 25/75 in 35 minutes). Yield: 594.6 mg, 79%. 1H NMR (CDCl3 400 MHz) δ 7.57 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.03 (td, J=8.8, 4.4 Hz, 1H), 6.57-6.49 (m, 1H), 5.60-5.55 (m, 1H), 5.35 (bs, 1H), 4.49 (dd, J=11.7, 3.7 Hz, 1H), 4.18 (dd, J=11.7, 5.9 Hz, 1H), 4.00 (s, 1H), 3.90 (d, J=5.1 Hz, 1H), 3.54 (bs, 1H), 2.95-2.80 (m, 1H), 2.65-2.56 (m, 1H), 2.52-2.41 (m, 1H), 2.13-1.98 (m, 1H), 1.51-1.40 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)([CH3:4])([CH3:3])[CH3:2].[CH:20]([Mg]Br)=[CH2:21].[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:10]=1[NH:15][CH:21]=[CH:20]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccccc1[N+](=O)[O-]
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCc1cccc2cc[nH]c12
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 30 %

Procedure:
A solution of tert-butyl-dimethyl-[2-(2-nitro-phenyl)-ethoxy]-silane (5.0 g, 17.76 mmol) in THF (74 mL) was cooled to −65° C. and a 1.0 M solution of vinyl magnesium bromide in THF (53 mL, 53 mmol) was introduced while maintaining a temperature of <−40° C. The reaction was stirred for 15 minutes at −40° C., additional vinyl magnesium bromide (9 mL, 9 mmol) was added and the reaction was stirred at −45 to −40° C. for 25 minutes. The reaction was poured into saturated aq ammonium chloride and diluted with EtOAc (300 mL). The two layers were separated and the organic layer was dried (MgSO4), filtered and concentrated. Flash chromatography (95%hexane/EtOAc) gave the title compound (1.47 g, 30%) as a transparent oil. 1H NMR (400 MHz, DMSO-d6) −0.11 (s, 6H), 0.80 (s, 9H), 3.03 (t, J=6.8 Hz, 2H), 3.85 (t, J=6.8 Hz, 2H), 6.39 (dd, J=1.2, 3.2 Hz, 1H), 6.86–6.92 (m, 2H), 7.28 (dd, J=3, 3 Hz, 1H), 7.36 (dd, J=4.8, 4.8 Hz, 1H), 11.02 (br s, 1H). MS (electrospray, m/z) 276 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)C(C)C)(C)C.[CH3:32][O:33][CH2:34][CH2:35][O:36][C:37]1[CH:38]=[C:39]([NH:47][C:48](=O)[O:49]C2C=CC=CC=2)[CH:40]=[CH:41][C:42]=1[C:43]([F:46])([F:45])[F:44]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:48]([NH:47][C:39]2[CH:40]=[CH:41][C:42]([C:43]([F:45])([F:46])[F:44])=[C:37]([O:36][CH2:35][CH2:34][O:33][CH3:32])[CH:38]=2)=[O:49])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: COCCOc1cc(NC(=O)Oc2ccccc2)ccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)ccc1C(F)(F)F
Temperature: 50 °C
Yield: 65.4 %

Procedure:
As described in Example 113C, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (90 mg, 0.3 mmol) in THF (5 mL) was treated with N,N-diisopropylethylamine (78 μl, 0.45 mmol), 4-(dimethylamino)pyridine (4 mg, 0.03 mmol) and phenyl 3-(2-methoxyethoxy)-4-(trifluoromethyl)phenylcarbamate (161 mg, 0.45 mmol). The reaction mixture was heated to 50° C. for 3 h. After removal of the solvent, the crude material was purified by silica gel chromatography (ethyl acetate/dichloromethane 1:1) to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-methoxyethoxy)-4-(trifluoromethyl)phenyl)urea (109.5 mg, 65%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.14 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 7.59 (d, 2H), 7.50-7.38 (m, 2H), 7.43-7.38 (m, 2H), 7.27 (d, 1H), 7.04 (d, 1H), 6.96 (d, 1H), 4.17-4.14 (m, 2H), 4.04 (s, 6H), 3.69-3.67 (m, 2H), 3.34 (s, 3H); LC-MS (ESI) m/z 559 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]([CH2:22][C:23]1[CH:31]=[C:26]2[CH:27]=[N:28][CH2:29][CH2:30][N:25]2[N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:28]2[CH2:29][CH2:30][N:25]3[N:24]=[C:23]([CH2:22][O:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:31]=[C:26]3[CH2:27]2)=[O:38])=[CH:35][CH:34]=1
Reactant: C1=NCCn2nc(COc3ccccc3)cc21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
Sodium triacetoxyborohydride (20.8 mg, 0.093 mmol) was added to a stirred solution of 2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine (15 mg, 0.062 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 16 hours and then, 4-fluorobenzoyl chloride (0.011 mL, 0.093 mmol) was added and the mixture stirred at room temperature for 1 hour. The mixture was diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield rac-(4-fluoro-phenyl)-(2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (19 mg, 84% yield) as a colourless oil that precipitated upon standing. 1H NMR (500 MHz, CDCl3) δ ppm 1.56 (d, J=6.9 Hz, 3H), 3.59 (br. s., 1H), 4.34 (br. s., 1H), 4.05-4.22 (m, 1H), 4.22-4.32 (m, 1H), 5.04 (s, 2H), 5.58 (br. s., 1H), 6.15 (br. s., 1H), 6.96 (t, J=7.4 Hz, 1H), 7.00 (d, J=7.8 Hz, 2H), 7.10-7.20 (m, 2H), 7.27-7.34 (m, 2H), 7.40-7.49 (m, 2H).
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1O
Temperature: 25 °C
Yield: 57.2 %

Procedure:
4-Benzyloxy-5-methoxy-2-nitrobenzamide (26 g, 91 mmol), (J. Med. Chem. 1977, vol 20, 146-149), was dissolved in TFA and heated at reflux for 2 hours. After cooling the TFA was removed by evaporation and the residue was stirred with 2M sodium hydroxide and insoluble material was removed by filtration. The red aqueous solution was acified to pHl with concentrated hydrochloric acid and allowed to cool back to ambient temperature before collecting the product by filtration. The obtained solid was washed with water and ether and dried in a vacuum oven at 60° C. to give 4-hydroxy-5-methoxy-2-nitrobenzamide (11.04 g, 62%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:10]=1)[N:7](COCC[Si](C)(C)C)[N:6]=[CH:5]2>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][O:12][CH2:13][C:14]3([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Brc1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 4-(((5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (40 mg, 0.064 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 3 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. Column chromatography (90:8:4 dichloromethane/methanol/2 M ammonia in methanol) gave 19 mg (75%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.47 (m, 2H), 7.38 (m, 3H), 7.14 (d, J=1.2 Hz, 1H), 4.65 (s, 2H), 3.56 (s, 2H), 2.95 (m, 2H), 2.78 (m, 2H), 2.28 (bs, 1H), 2.22 (m, 2H), 1.88 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 143.8, 137.4, 133.6, 129.0, 127.0, 126.8, 125.2, 122.6, 122.5, 113.3, 80.7, 71.7, 42.5, 41.7, 33.5. Mass spec.: 400.01 (MH)+. Accurate mass spec.: m/z 400.1035 [MH]+, Δ=2.6 ppm.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[S:13][C:14]([CH3:21])=[CH:15][C:16]=1[C:17]([O:19][CH3:20])=[O:18].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:22][CH2:21][C:14]1[S:13][C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)sc1N1C(=O)c2ccccc2C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)sc1N1C(=O)c2ccccc2C1=O
Yield: 60 %

Procedure:
To a solution of protected 2-aminothiophene 14 (2.5 g; 8.33 mmol), N-bromosuccinimide (1.55 g; 8.74 mmol) and benzoyl peroxide (20 mg) in CCl4 (50 ml) was heated at reflux temperature for 20 h under argon atmosphere. The CCl4 was evaporated under reduced pressure and the residue was extracted with dichloromethane (3×50 ml). The combined organic phases were washed with a saturated solution of NaHCO3, dried over magnesium sulfate and the solvent was evaporated under reduced pressure Purification by column chromatography (silica, eluent CH2Cl2) afforded 15 (1.9 g, 60%) as an off-white solid. 1H NMR (300 MHz, CDCl3) δH 3.72 (s, 3H); 4.66 (s, 2H); 7.51 (s, 1H); 7.84 (m, 2H); 7.97 (m, 2H).