Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])(C)(C)C.[CH3:14][C:15]1([CH3:48])[CH:24]=[C:23](OS(C(F)(F)F)(=O)=O)[C:22]2[C:17](=[CH:18][C:19]([O:46][CH3:47])=[C:20]([C:33]#[C:34][C:35]3[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH:21]=2)[S:16]1>C1COCC1.CCCCC.[Cl-].[Cl-].[Zn+2].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>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]2[C:22]3[C:17](=[CH:18][C:19]([O:46][CH3:47])=[C:20]([C:33]#[C:34][C:35]4[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=4)[CH:21]=3)[S:16][C:15]([CH3:14])([CH3:48])[CH:24]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2cc3c(cc2OC)SC(C)(C)C=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2OC)SC(C)(C)C=C3c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-methylbromobenzene (499.0 mg, 2.92 mmol) in 2.0 mL of THF was cooled to -78° C. and tert-butyllithium (374.2 mg, 5.84 mmol, 3.4 ml of a 1.7M solution in pentane) was added to give a yellow solution. After 30 minutes a solution of ZnCl2 (613.0 mg, 4.50 mmol) in 4.0 mL THF was slowly added via cannula. The resulting solution was warmed to room temperature and transferred via cannula to a solution of ethyl 4-(2,2-dimethyl-4-trifluoromethanesulfonyloxy-7-methoxy-(2H)-thiochromen-6-ylethynyl)-benzoate (Compound 212, 285.0 mg, 0.54 mmol) and tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 0.02 mmol) in 2.0 mL THF. This solution was heated to 50° C. for 2 hours, cooled to room temperature, and the reaction quenched by the addition of saturated aqueous NH4Cl. The solution was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound, 200.0 mg (79%), was isolated by column chromatography (2-5% EtOAc/hexanes) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ: 7.98 (2H, d, J=8.3 Hz), 7.54 (2H, d, J=8.3 Hz), 7.23-7.21 (5H, m), 5.71 (1H, s), 4.38 (2H, q, J=7.1 Hz), 3.95 (3H, s), 2.41 (3H, s), 1.49 (6H, s), 1.40 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH2:6].Cl[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(N(CC)CC)C>CN(C)C=O.CCOCC>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:6][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: COC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)CNCc1cc(F)cc(F)c1
Temperature: 60 °C
Yield: 41 %

Procedure:
A solution of 3,5-difluorobenzylamine prepared as above (12.3 g, 0.0863 mole), methyl chloroacetate (7.6 ml, 0.0863 mole) and triethylamine (12.0 ml, 0.0863 mole) in dry dimethylformamide (85 ml) was heated at 60° C. for 3 hours. The mixture was diluted with an equal volume of ether and the triethylamine hydrochloride filtered. The filtrate was concentrated under vacuum, the resultant oil triturated with ethyl acetate, and the solution decanted from a small amount of residual oil. The solvent was removed and the product was purified by flash chromatography (silica) by eluting with hexane-ethyl acetate (70:30) to give N-(3,5-difluorobenzyl)glycine methyl ester as an oil (7.61 g, 41%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:21]N1C(=O)CCC1=O>C(#N)C.CCOC(C)=O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (1.25 g, 4.35 mmol) in acetonitrile (40 mL) was treated with N-bromosuccinimide (0.852 g, 4.79 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (200 mL), washed with saturated aqueous sodium bisulfite (100 mL) and brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 1.55 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.34 (s, 1 H), 6.65 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 3.55 (m, 1.3 H), 3.37 (m, 0.7 H), 3.2−2.9 (bm, 4 H), 1.30 (m, 3 H). MS calculated for C14H15BrF3NO2+H: 366, observed: 366.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[N:21][C:22]=3[NH2:24])[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[N:16]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:23]=12
Reactant: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)nn2C1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2C1CCCC1
Temperature: 80 °C
Yield: 99.8 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.47 g, 6.41 mmol, 1 equiv), Pd black (0.341 g, 3.20 mmol, 0.5 equiv), and ammonium formate (2.02 g, 32 mmol, 5 equiv) in ethanol (50 mL) was heated at 80° C. for 4 h. The reaction mixture was allowed to cool to ambient temperature and the resulting solids were removed by filtration through a pad of Celite with the aid of EtOH (300 mL). The filtrate was concentrated to give a pale yellow solid which was purified by washing with CH2Cl2 (200 mL) to afford 4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol as a white solid (1.89 g, 6.4 mmol): 1H NMR (d6 DMSO, 400 MHz): δH 8.22 (1H, s), 7.45 (2H, d, J=8.5 Hz), 6.92 (2H, d, J=8.5 Hz), 5.17-5.24 (1H, m), 2.01-2.10 (4H, m), 1.87-1.90 (2H, m), 1.67-1.70 (2H, m). RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 13.13 min. MS: MH+ 296.
Reaction SMILES: [C:1]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Br)(Br)[Br:28]>C1(C)C=CC=CC=1>[Br:28][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(OCc2cccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1ccc(OCc2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A suspension of sodium ethoxide (924 mg, 13.6 mmol) in DMF was stirred at 0° C. for 10 min. Ethyl 4-hydroxy benzoate (2.26 g, 13.6 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h, then allowed to reach room temp. To this mixture 1-(bromomethyl)naphthalene (2.0 g, 9.0 mmol) was added dropwise [(predissolved in DMF (5 mL)]. Resulting mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue taken up in EtOAc, and washed with brine, water and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and the solvent evaporated off in-vacuo to yield ethyl 4-(naphthalene-1-ylmethoxy)benzoate (1.7 g, 5.55 mmol). This was then dissolved in THF and LiAlH4 (211 mg, 5.55 mmol) was added portionwise, with vigorous stirring. The suspension was stirred at room temperature for 3 h. THF was evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). EtOAc was evaporated off in-vacuo to obtain (4-(naphthalene-1-ylmethoxy)phenyl)methanol (1.3 g, 4.9 mmol) as a crude product. This was used in the next reaction step without further purification. (4-(naphthalen-1-ylmethoxy)phenyl)methanol (1.0 g, 3.8 mmol) was dissolved in toluene (30 mL) and pyridine (305 uL, 3.8 mmol) was added. The solution was cooled to 0° C. PBr3 (359 uL, 3.8 mmol) was added dropwise over 15 min. The mixture was brought up to room temperature and stirred for 1 h. It was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to obtain 1-((4-(bromomethyl)phenoxy)methyl)naphthalene (660 mg, 53%). This intermediate was used in the following reaction.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:22]1[CH:35]=[C:34]2[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]([C:41]4[CH:42]=[N:43][CH:44]=[N:45][CH:46]=4)=[CH:31][C:32]=3[C@:33]32[CH2:39][O:38][C:37]([NH2:40])=[N:36]3)=[CH:24][C:23]=1[F:47])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[O:1]1[CH2:2][CH:3]=[C:4]([C:22]2[C:23]([F:47])=[CH:24][C:25]3[O:26][C:27]4[C:32](=[CH:31][C:30]([C:41]5[CH:46]=[N:45][CH:44]=[N:43][CH:42]=5)=[CH:29][CH:28]=4)[C@@:33]4([CH2:39][O:38][C:37]([NH2:40])=[N:36]4)[C:34]=3[CH:35]=2)[CH2:5][CH2:6]1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1cc(F)c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1cc(F)c(C3=CCOCC3)cc12
Temperature: 85 °C

Procedure:
A 0.5-2 ml microwave vial was charged with tetrakis(triphenylphosphine)palladium(0) (27.9 mg, 0.024 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (86 mg, 0.411 mmol). A solution of (S)-2-amino-6′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (120 mg, 0.242 mmol) in DMF (1612 μL) was added followed by sodium carbonate (2M solution) (363 μL, 0.725 mmol). The vial was sealed and heated in microwave reactor at 85° C. for 1 hr. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, filtered through celite and concentrated to leve brown oil. The crude material was purified by silica gel chromatography on 12 g RediSep column using (15-60% DCM/MeOH/NH4OH 90:10:1 in DCM) to afford (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine Found MS: MH+=431.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[C:19]#[N:20].[H][H].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O>[CH:12]12[CH2:18][CH:15]([CH:16]=[CH:17]1)[CH2:14][CH:13]2[CH2:19][NH2:20]
Reactant: [H][H]
Reactant: N#CC1CC2C=CC1C2
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: NCC1CC2C=CC1C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A three-neck flask is equipped with mechanical stirrer, reflux condenser and dropping funnel. The flask is charged under N2, with 42 ml of a 1.0 M solution of lithium aluminum hydride in anhydrous ether (42 mmol). A solution of 5 g of 5-Norbornene-2-carbonitrile (bicyclo[2.2.1]hept-5-ene-2-carbonitrile) in 45 ml of ether (42 mmol, 1.0 M) is added dropwise through the addition funnel at a rate that allows a gentle reflux. After one hour, the mixture is cooled to 0° C. and water is added dropwise until hydrogen gas liberation is no longer observed. To this, 100 ml of 20% sodium potassium tartrate is added and produces a clear solution. The reaction solution is transferred to a separatory funnel, and the aqueous phase is collected and washed with 3×50 ml portions of ether. The combined ether fractions are dried with calcium sulfate and solvent is removed by rotary evaporation yielding a yellow oil. This product is further distilled under reduced pressure to yield a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH2:24].[BH4-].[Na+]>CO>[CH3:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH2:23][NH:24][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1
Reactant: CC(C)(C)CCN
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCNCc1ccc(Oc2cnc(C(N)=O)cn2)c(F)c1
Reaction time: 8 h
Yield: 57 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.350 g, 1.14 mmol), 3,3-dimethylbutylamine (0.19 g, 1.41 mmol) and 3 Å molecular sieves in a vial. Add methanol (9.7 mL), cap and stir overnight. Add NaBH4 (0.053 g, 1.41 mmol) and stir until the gasses stop evolving. Filter the reaction mixture, then concentrate. Purify by eluting through a 40 g ISCO® column with 6% to 30% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.225 g, 49%): TOF MS ES+ 347.2 (M+H)+, HRMS calcd for C18H24N4O2F 347.1883 (M+H)+, found 347.1883, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 min, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=10.9 min, 100% purity.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:39](=[CH:40][C:41]=3[C:42]3[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[CH:44][CH:43]=3)[N:38](COCC[Si](C)(C)C)[N:37]=[C:36]4[NH:64][C:65](=[O:69])[CH2:66][CH2:67][CH3:68])=[CH:29][CH:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:34]=[C:35]4[C:39](=[CH:40][C:41]=3[C:42]3[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)=[CH:44][CH:43]=3)[NH:38][N:37]=[C:36]4[NH:64][C:65](=[O:69])[CH2:66][CH2:67][CH3:68])=[CH:29][CH:28]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(OCc4ccccc4)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3ccc(OCc4ccccc4)cc3)cc12

Procedure:
16.3 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.9 g of N-[5,6-bis[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]-methyl]-1H-indazol-3-yl]butanamide, described previously, in 100 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and is then allowed to return to room temperature and 100 cm3 of ethyl acetate are added; the organic phase is washed with 2×100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 25 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed with 2×20 cm 3 of diisopropyl ether. After drying under reduced pressure (90 Pa; 50° C.), 700 mg of N-[5,6-bis[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide are obtained in the form of white crystals melting at 140° C.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br-].[CH3:13][C:14]([CH3:16])=[O:15].Cl>CCOCC>[OH:15][C:14]([CH3:16])([CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: BrCCCc1ccccc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Br-]
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of magnesium turnings 13.16 g (0.541 mol) in 200 ml of anhydrous Et2O was added 100.0 g (0.492 mol) of 1-bromo-3-phenyl propane as a solution in 100 ml of Et2O. After of 5-10 ml of the solution had been added, the addition was stopped until the formation of the Grignard reagent was in progress. The remaining bromide was then added over 1 hour. The Grignard reagent was stirred for 20 minutes at 35° C. and then 31.64 g (0.541 mol) of acetone was added over a 45 minute period. The reaction was stirred overnight at room temperature before being cooled to 0° C. and acidified by the careful addition of 20% HCl. The aqueous layer was extracted with Et2O (3×200 ml) and the combined organic layers washed with water, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvent under reduced pressure and distillation of the residue afforded 63.0 g (72%) of the product as a pale-yellow oil, bp 99-102° C./0.5 mm Hg. 1H NMR (CDCl3): δ 7.28-7.18 (5H, m), 2.63 (2H, t, J=7.5 Hz), 1.68 (2H, m), 1.52 (2H, m), 1.20 (6H, s).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13]C)[CH:10]=[C:9]2[C:4]=1[C:5](=[S:23])[N:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=1)[CH:7]=[N:8]2.B(Br)(Br)Br.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[OH:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[C:5](=[S:23])[N:6]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH:7]=[N:8]2
Reactant: COc1ccc(-n2cnc3cc(OC)cc(OC)c3c2=S)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: Oc1ccc(-n2cnc3cc(O)cc(O)c3c2=S)cc1
Temperature: 0 °C
Yield: 60 %

Procedure:
5,7-Dimethoxy-3-(4-methoxyphenyl)-4(3H)-quinazolinethione (6.5 g, 19.8 mmol), as prepared in Example 33, was dissolved in 75 ml of CH2Cl2. The solution was cooled to 0° C. and 37 ml of BBr3 (396 mmol) was added dropwise for 1 h 30 min. The reaction mixture was then stirred at room temperature until complete transformation of the starting material as monitored by HPLC. The reaction mixture was evaporated to dryness. A cold saturated solution of NaHCO3 was added and the resulting solid filtered and dried. This solid was mixed with pyridine hydrochloride salt (46 g, 396 mmol). The mixture was heated to 189° C. for 3.5 hours. Subsequently, the reaction was cooled to room temperature. Methanol was added to dissolve the mixture. The obtained dark solution was poured to a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic phases were washed with brine and dried over MgSO4 to yield a brownish solid that was purified by chromatography on silica gel (loaded with CH2Cl2 and a slight amount of MeOH, eluted with 2%, 2.5%, 3% of MeOH in CH2Cl2) to provide 5,7-dihydroxy-3-(4-hydroxyphenyl)-4(3H)-quinazolinethione (3.4 g, 60%) as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=O)[C:3]1=[O:13].[CH2:14]([NH2:17])[CH2:15][NH2:16]>>[NH2:16][CH2:15][CH2:14][NH:17][C:8](=[O:10])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: NCCN
Product: NCCNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3.5 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate and 11.2 g of 1,2-ethylenediamine is left to stand at room temperature for 20 hours. The excess 1,2-ethylenediamine is evaporated in vacuo. The residue is dissolved in 40 ml of hot acetonitrile and stirred at room temperature for 2 hours and then in an ice-bath for 1 hour. By filtration there is isolated N-[2-(amino)ethyl]-2-(3-hydroxy-2oxo-1-pyrrolidinyl)acetamide of melting point 110°-112°.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.[F:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][NH:22][CH:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:18][CH:17]=1.CCCCCCC>CC#N.CC(O)=O>[F:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][N:22]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH:23]2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:18][CH:17]=1
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccc2c(c1)C(c1ccccc1)NCC2
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(O)CCC(=O)N1CCc2ccc(F)cc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.3 %

Procedure:
5.0 g (49.7 mmol) of succinic anhydride and 4.0 ml (28.4 mmol) of NEt3 were added in succession to a solution of the crude product 7-fluoro-1-phenyl-1,2,3,4-tetrahydroisoquinoline (max. 14.2 mmol) in MeCN (200 ml) and the mixture was stirred for 16 h at RT. It was then concentrated to small volume under vacuum and the residue was taken up with a saturated aqueous NaHCO3 solution (300 ml). It was extracted with DCM (2×200 ml). The combined organic phases were washed with a 1M aqueous hydrochloric acid (200 ml), dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (heptane/EE 1:1+1% AcOH) of the residue produced 1.72 g (5.3 mmol, 10% over 3 stages) of 4-(7-fluoro-1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl)-4-oxobutyric acid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C@H:19]([NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=2)=[O:30])[C:20](=[O:27])[N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.C(OCC)(=O)C>[CH2:12]([C@H:19]([NH:28][C:29]([C:31]1[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([Cl:40])=[CH:35][CH:34]=2)=[O:30])[C:20](=[O:27])[N:21]1[CH2:22][CH2:23][S:24](=[O:6])[CH2:25][CH2:26]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSCC1)c1cc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCS(=O)CC1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 76 %

Procedure:
m-Chloroperoxybenzoic acid (80 mg of 50%, 0.23 mmol) was added at 25° C. to a solution of 5chloro-1H-indole-2-carboxylic acid ((1S)-benzyl-2-oxo-2-thiomorpholin-4-yl-ethyl)-amide (100 mg, 0.23 mmol) in dichloromethane (2 mL). After 1 hour, the mixture diluted with ethyl acetate and washed three times with a 50/50 mixture of saturated aqueous sodium bicarbonate and 10% aqueous sodium thiosulfate, once with saturated aqueous sodium bicarbonate, brine, and dried. The crude product was purified by column chromatography on silica gel eluted with 0.5-8% ethanol in dichloromethane to give the title compound. Yield 76%; HPLC (60/40) 3.97 minutes (97%); mp 230-234° C.; TSPMS 444/446 (MH+, 100%);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2ccnc2)cc1
Yield: 49.9 %

Procedure:
A mixture of 37.4 g (0.2 mole) of 4-bromoanisole, 170 g (0.25 mole) of imidazole, 26 g (0.2 mole) of potassium carbonate, and 1.2 g of cuprous bromide in 150 ml of N-methylpyrrolidinone was heated at reflux under a blanket of nitrogen for 4 hr. The mixture was filtered and concentrated to remove the solvent. The residue was partitioned between dilute sodium hydroxide solution and methylene chloride. After filtration, the organic fraction was chromatographed. The desired fractions were concentrated and the crystalline residue was recrystallized from toluene/cyclohexane to give 17.4 g (50%) of the title compound as white plates, mp 63.0°-64.0° C.