Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:49])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:53][CH:54]1[CH2:57][NH:56][CH2:55]1.CCN(C(C)C)C(C)C>C1COCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[S:30][C:29]([C:31]5[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=5[CH3:40])=[N:28][C:27]=4[C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:24][N:23]=[C:22]([N:56]4[CH2:57][CH:54]([F:53])[CH2:55]4)[N:21]=3)[C@H:14]2[CH3:49])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:50])[CH:8]=1
Reactant: FC1CNC1
Reactant: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(S(C)(=O)=O)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1-c1nc(C(C)(C)C)c(-c2cnc(N3CC(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-4-tert-butyl-1,3-thiazol-2-yl}-3-methylbenzoic acid (INTERMEDIATE 52, 180 mg, 0.106 mmol) in THF (5 mL) was added 3-fluoroazetidine hydrochloride (35.4 mg, 0.317 mmol) and DIEA (0.092 mL, 0.529 mmol). It was stirred at 60° C. for 15 minutes to see complete conversion by LCMS. The solvent was evaporated, and the residue was purified on reverse phase HPLC, eluting with water and acetonitrile (10% to 100%), to give the title compound as a yellowish solid after lyophilization (74 mg, 93% yield). LCMS (M+H)+: 752.05. 1H NMR (CDCl3, 500 MHz): δ8.36 (s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.87 (m, 1H), 7.79 (s, 2H), 5.80 (d, 9.0 Hz, 1H), 4.75 (m, 4H), 4.61-4.53 (m, 4H), 4.47 (m, 1H), 4.09 (m, 1H), 3.76 (s, 3H), 1.33 (s, 9H), 0.82 (d, 7.0 Hz, 3H). RTA IC50: 197 nM.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>>[CH2:13]([O:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Yield: 96.5 %

Procedure:
As in the case of Reference Example 3 ,ethyl 4-hydroxybenzoate (2.50 g) was benzylated with benzyl bromide (2.57 g) followed by hydrolysis with potassium hydroxide, thereby yielding 3.31 g of 4-benzyloxybenzoic acid as a crystal. In tetrahydrofuran (50 ml), this compound (1.18 g) was suspended together with N,N'-dicyclohexylcarbodiimide (1.14 g) and 4-hydroxybenzotriazole (0.81 g) and then, with 1-isobutylpiperazine (0.71 g) added thereto, stirred at room temperature for 24 hours. The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) and the resulting solid was recrystallized (from n-hexane/ethyl acetate), thereby yielding 1.03 g of the aimed compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]1[O:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14](F)=[C:13]([F:18])[CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[C:19](=[O:22])([O-])[O-].[K+].[K+]>N1CCOCC1.C(Cl)Cl>[F:18][C:13]1[CH:12]=[C:11]([C:8]2[CH2:7][CH:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[O:10][N:9]=2)[CH:16]=[CH:15][C:14]=1[N:4]1[CH2:5][CH2:19][O:22][CH2:2][CH2:1]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Agent: [K+]
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC(=O)NCC1CC(c2ccc(N3CCOCC3)c(F)c2)=NO1
Temperature: 140 °C

Procedure:
To a resealable tube containing (+/-)-N-[[4,5-dihydro-3-(3,4-difluorophenyl)-5-isoxazolyl]methyl]acetamide (Step 3, Example 3) (1.70 g) in morpholine (5.83 mL) is added potassium carbonate (1.16 g) and heated to 140° C. for 48 hours. The reaction is diluted with CH2Cl2 (50 mL) and washed with H2O (3×50 mL) and saline (50 mL). The organic phase is dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh), eluting with methylene chloride/methanol (98.5/1.5). The appropriate fractions are combined (Rf =0.30, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound. The racemic material is separated on chiral HPLC (Chiralpak AD column, eluting with 8:2:1.5 heptane/isopropanol/chloroform) to give the individual enantiomers, the title compound having mp 179-180° C., [α]25D -71° (DMSO).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5](Br)=[N:4][C:3]=1[C:8]([NH:10][C:11]1[CH:12]=[N:13][N:14]([CH3:34])[C:15]=1[N:16]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OCC2C=CC=CC=2)[CH2:18][CH2:17]1)=[O:9].[F:35][C:36]1[CH:37]=[CH:38][C:39]([OH:45])=[C:40](B(O)O)[CH:41]=1>>[NH2:1][C:2]1[S:6][C:5]([C:38]2[CH:37]=[C:36]([F:35])[CH:41]=[CH:40][C:39]=2[OH:45])=[N:4][C:3]=1[C:8]([NH:10][C:11]1[CH:12]=[N:13][N:14]([CH3:34])[C:15]=1[N:16]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1cc(F)ccc1O
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2N)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3O)sc2N)c1N1CCC[C@@H](N)CC1
Yield: 21 %

Procedure:
Following Example 278, Suzuki coupling of (R)-benzyl 1-(4-(5-amino-2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)azepan-4-ylcarbamate and 5-fluoro-2-hydroxyphenylboronic acid gave 357 as a yellow solid (12 mg, 21% over two steps). 1H NMR (400 MHz, d6-DMSO with D2O) δ 7.80 (dd, J=10.1, 3.3 Hz, 1H), 7.42 (s, 1H), 6.94 (td, J=8.5, 3.4 Hz, 1H), 6.77 (dd, J=9.0, 4.9 Hz, 1H), 3.63 (s, 3H), 3.23-3.04 (m, 6H), 1.93-1.76 (m, 3H), 1.68-1.51 (m, 3H). LCMS (ES+) m/z 446 (M+1)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CO>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
The (1α,3β)-1,3-bis((tert-butyl(dimethyl)silyl)oxy)pregna-5,7,16-trien-20-one synthesized in Example 24 (45.0 g) was dissolved in toluene (240 ml) and then cooled to −20° C., followed by stirring for 30 minutes. Borane-dimethylsulfide complex (22.9 ml) was added to the resulting solution at −20° C. and stirred for 5 minutes. A 1M toluene solution of (R)-2-methyl-CBS-oxazaborolidine (22.9 ml) was further added to the solution at −20° C. and stirred for 1 hour. Methanol was added to the reaction mixture, which was then extracted with ethyl acetate. The extracted solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (liquid phase: hexane/ethyl acetate=9/1) to give the titled compound (23.3 g, yield 89%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.CI.[C:14]([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([O:11][CH3:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1scc(Br)c1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)c1scc(Br)c1OC
Reaction time: 2 h
Yield: 95.6 %

Procedure:
To a solution of 36 g (0.15 mole) of methyl 4-bromo-3-hydroxy-2-thiophenecarboxylate in 300 mL of dimethyl sulfoxide (DMSO) was added 32 g (0.23 mole) of methyl iodide and then 32 g of powdered K2CO3. After 2 hr, the reaction mixture was poured into water and extracted with ether. The organic phase was washed with water (4×200 mL), dried over MgSO4, filtered and concentrated to give 36 g of a colorless solid. 1H NMR (300 MHz, CDCl3): δ 7.4 (s, 1H); 4.0 (s, 3H); 3.9 (s, 3H). Anal. Calc'd for C7H7BrO3S: C, 33.48; H, 2.81; S, 12.77. Found: C, 33.18; H, 2.70; S, 12.49.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.C([O-])=O.[NH4+]>>[CH3:16][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[CH:2][N:7]=2)=[C:9]([C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[N:10]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 26 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (75 mg, 0.135 mmol) and ammonium formate (85 mg, 1.347 mmol), the title compound was obtained as a yellow solid (21 mg, 29% yield). MS (ESI): 523 [M+H]+.
Reaction SMILES: [C:1]([C:9]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH:10]1[CH:12]=[CH2:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC.C1(C(C2CC2)=O)CC1>>[C:14]([C:9]1[CH2:11][CH:10]([CH:12]=[CH2:13])[O:8][C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CC1CC1(C(=O)OCC)C(=O)c1ccccc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: O=C(C1CC1)C1CC1
Agent: [Cl-]
Product: C=CC1CC(C(=O)OCC)=C(c2ccccc2)O1

Procedure:
4-Carbethoxy-5-phenyl-2-vinyl-2,3-dihydrofuran was obtained in the usual manner by isomerizing ethyl 1-benzoyl-2-vinylcyclopropane-1-carboxylate. To catalyze the isomerization, tricaprylylmethylammonium chloride was employed at a 20 percent weight level. The mixture was heated at 150° C. for about two hours after which time only about 7 percent of the cyclopropyl ketone remained. After two distillations, essentially pure 4-carbethoxy-5-phenyl-2-vinyl-2,3-dihydrofuran was obtained. The product (B.P. 110° C. @ 0.1 mm Hg; nD25° 1.5570) had a pleasing aroma that was somewhat coumarin-like in odor character. Nuclear magnetic resonance and infrared spectroscopic analysis confirmed the structure ##STR16##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][OH:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=[O:21].N.O>C1COCC1>[C:20]([O:19][CH2:18][C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])(=[O:21])[NH2:22]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](COC(N)=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
In a 250 mL flask equipped with magnetic stirrer, N-(t-butyloxycarbonyl)-o-fluorophenylalaninol (0.096 mole, 2.15 g) was dissolved in 200 ml of THF and was added with 1,1'-carbonyl diimidazole (0.010 mol, 1.62 g) at 0° C. The reaction mixture was stirred at room temperature for 2 hours, followed by the injection of ammonia at 0° C. for 30 min. Following elevating to room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a solid. This was recrystallized in a solution mixture of n-hexane and diethyl ether, to produce 1.93 g of O-carbamoyl-N-(t-butyloxycarbonyl)-o-fluorophenylalaninol: Yield 75%.
Reaction SMILES: [Cl-].C([Al+]CC)C.[F:7][C:8]([F:32])([F:31])[C:9]1[CH:10]=[C:11]([S:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=2[CH:25]=[O:26])[CH:12]=[CH:13][CH:14]=1.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>O1CCCC1.CCCCCC.[Zn].[Cu]Br>[OH:26][CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][S:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:8]([F:31])([F:7])[F:32])[CH:10]=1)[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Agent: [Cu]Br
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCSc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a suspension of zinc dust (0.25 g, 3 mmoles) and copper (I) bromide (0.02 g, 0.129 mmoles) in distilled tetrahydrofuran (20 ml) was added a solution of diethylaluminum chloride (2.8 ml, 2.8 mmoles) in hexane while stirring under argon at 25° C. The resulting mixture was cooled to -20° C, and a solution of 2-[7-(3-trifluoromethylphenylthio)heptyl]benzaldehyde (1.08 g, 2.8 mmoles) and t-butyl bromoacetate (0.42 ml, 2.8 mmoles) in tetrahydrofuran (6 ml) was added slowly at -20° C. The reaction mixture was permitted to warm to room temperature. After 2 hours the zinc was filtered off and washed with ether. The solvents were evaporated and the residue flash chromatographed on silica gel, eluted with 10% ethyl acetate in hexane, to provide the desired product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([O:30][CH2:31][CH2:32][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[C:27]([NH2:29])[CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:23]3[CH:24]=[CH:25][C:26]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)=[C:27]([NH:29][C:1](=[O:3])[CH3:2])[CH:28]=3)=[N:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16 μL (170 μmol) acetic anhydride are added to a solution of 35 mg (84 μmol) 5-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-(2-pyrrolidin-1-yl-ethoxy)-phenylamine in 2 mL DCM and the reaction mixture is stirred overnight at RT and then purified by chromatography on silica gel (gradient: EtOAc to EtOAc/MeOH/NH3 7:3:0.3) without any further working up
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.[NH:38]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]1.C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:8][C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([N:38]2[CH2:44][CH2:43][C:42](=[O:45])[NH:41][CH2:40][CH2:39]2)[CH:7]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: O=C1CCNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCNC(=O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 185 °C
Yield: 96.2 %

Procedure:
A mixture of 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)-pyrazolo-[1,5-a]pyrimidin-7-amine (50 mg, 0.09 mmoL), 1,4-diazepan-5-one (36 mg, 0.32 mmoL), EtN(iPr)2 (110 uL, 0.63 mmoL) in NMP (0.8 mL) was heated at 185° C. under microwave condition for 45 min. Purification by prep-LC afforded titled compound (32.3 mg, 85%) as its formic acid salt. LCMS tR=2.49 Min. Mass calculated for, M+ 373.1, observed LC/MS m/z 374.1 (M+H).
Reaction SMILES: O1C2(CCC(C3C4C(=CC=CC=4)NC=3)CC2)OCC1.[O:20]1[C:24]2([CH2:29][CH2:28][C:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:39])[NH:32][CH:31]=3)=[CH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[O:23]1[C:24]2([CH2:25][CH2:26][CH:27]([C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:39])[NH:32][CH:31]=3)[CH2:28][CH2:29]2)[O:20][CH2:21][CH2:22]1
Reactant: Fc1cccc2[nH]cc(C3=CCC4(CC3)OCCO4)c12
Agent: c1ccc2c(C3CCC4(CC3)OCCO4)c[nH]c2c1
Product: Fc1cccc2[nH]cc(C3CCC4(CC3)OCCO4)c12
Yield: 70 %

Procedure:
This compound was prepared in the manner described above for intermediate 2a by replacing 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-7-en-8-yl)-4-fluoro-1H-indole (6.3 g)) to afford 4.44 g (70%) of the title compound as a white solid: mp 161-162° C.
Reaction SMILES: [CH:1]([C:3]1[N:7]=[C:6]([CH3:8])[O:5][N:4]=1)=[CH2:2].[N:9]1([C:20](=[O:21])[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH3:10]>CN(C)C=O>[CH3:8][C:6]1[O:5][N:4]=[C:3]([CH2:1][CH2:2][N:18]2[C:19]3[C:20](=[O:21])[N:9]([CH3:10])[C:11](=[O:12])[N:13]([CH3:14])[C:15]=3[N:16]=[CH:17]2)[N:7]=1
Reactant: C=Cc1noc(C)n1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Solvent: CN(C)C=O
Product: Cc1nc(CCn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Yield: 72 %

Procedure:
2.2 g. of 3-vinyl-5-methyl-1,2,4-oxadiazole, 30 cm3 dimethylformamide and 0.2 cm3Triton-B catalyst are boiled with 3.6 g. of theophylline for 1 hour. The solvent is distilled off and the residue is crystallized from ethanol. 4.2 g. (72% yield) of 7-[2-(5-methyl-1,2,4-oxadiazol-3-yl)-ethan-1-yl]-theophylline are obtained. m.p.: 112°-114° C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([N:23]1[C:27](=[O:28])[CH:26]=[CH:25][C:24]1=[O:29])(=[O:22])[NH2:21]>>[C:27]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:28])/[CH:26]=[CH:25]\[C:24](=[O:29])[NH:23][C:20](=[O:22])[NH2:21]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: NC(=O)N1C(=O)C=CC1=O
Product: CCCCCCCCCCCCCCCCCCOC(=O)/C=C\C(=O)NC(N)=O
Yield: 97 %

Procedure:
The addition of octadecanol to N-carbamylmaleimide under the conditions of Example G afforded a 97% yield of octadecyl maleurate. M.P.: 109°-11° C. (dec.); 1H NMR (CDCl3): δ10.5 (brs, 1H), 8.2 (br s, 1H), 6.3 (m, 2H), 5.4 (br s, 1H), 4.2 (t, 2H), 1.6 (m, 2H), 1.2 (m, 30H), 0.9 (t, 3H); HPLC (80% CH3CN/H2O, C18): Rt=12.8 minutes.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2C=CC(F)=CC=2)=O)=O)=[CH:4][CH:3]=1.C(C1C=CC=C(C(C)C)C=1N)(C)C>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[CH2:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:10][CH3:12]
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC(C)c1cccc(C(C)C)c1N
Solvent: c1ccccc1
Product: CCCc1ccccc1
Temperature: 2 °C
Reaction time: 72 h

Procedure:
In a 250--mL RB flask fitted with pressure equalizing addition funnel, thermometer, magnetic stirrer, and N2 inlet was placed 0.75 g (3.0 mmol) of 4,4'-difluorobenzil, 13.8 mL (80 mmol) of 2,6-diisopropylaniline (DIPA), and 100 mL dry benzene. In the addition funnel was placed 50 mL of dry benzene and 210 mL (3.5 g; 18 mmol) of titanium tetrachloride. The reaction flask was cooled to 2° C. with ice and the TiCl4 solution was added dropwise over 45 min, keeping the reaction temperature below 5° C. The ice bath was removed after addition was complete and the mixture was stirred at RT for 72 h. The reaction mixture was partitioned between water and ethyl ether, and the ether phase was rotovapped and the concentrated oil was washed with 800 mL 1N HCl to remove the excess diisopropylaniline. The mixture was extracted with 100 mL of ether, and the ether layer was washed with water and rotovapped. Addition of 15 mL hexane plus 30 mL of methanol to the concentrate resulted in the formation of fine yellow crystals which were filtered, methanol-washed, and dried under suction to yield 0.4 g of (2,6--i--PrPh)2DAB(4--F--Ph)2, mp: 155°-158° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(F)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: OCc1cncc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a 0° C. solution of 5-fluoropyridine-3-carbaldehyde (500 mg, 4.0 mmol) in anhydrous methanol (20 mL) was added sodium borohydride (150 mg, 4.0 mmol). The reaction mixture was stirred at room temperature for 3 hours. Saturated ammonium chloride solution (20 mL) was added. The resultant mixture was extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (5-fluoropyridin-3-yl)methanol (430 mg, 85% yield). The product was used without further purification.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:27]([O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[C:27]([O:31][C:32](=[O:37])[C:33]([CH3:35])([S:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][N:10]2[C:11](=[O:20])[C:12]3=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]3[C:14]2=[O:15])[N:6]=1)[CH3:34])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: O=C1c2ccccc2C(=O)N1CCCc1csc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCCN2C(=O)c3ccccc3C2=O)cs1
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.5 %

Procedure:
2-Mercapto-4-(3-phthalimidopropyl)-1,3-thiazole (22.6 g) obtained in Example 31 was dissolved in N,N-dimethylformamide (200 mL), potassium carbonate (11.3 g) and 2-bromo-2-methylpropionic acid tert-butyl ester (17.4 g) were added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added, and the mixture was stirred. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:3) to give the title compound (32.0 g) as a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[N:15]2)=[O:7])C.Cl>C(O)C>[C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[N:15]2)([OH:7])=[O:5]
Reactant: CCOC(=O)CCCOc1ccc2[nH]c(=O)cnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1ccc2[nH]c(=O)cnc2c1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
2N-NaOH 6 ml was added to compound 914 (1 g, 3.6 mM, as the starting material) dissolved in 50% aqueous ethanol 50 ml and the mixture was stirred at room temperature for 1-1.5 hour. Dilute HCl was added to the reaction mixture to adjust it to an acidic pH, and the solvent was distilled off in vacuo. The residue was dried in vacuo to obtain crude 6-(3-carboxypropoxy)-2-oxo-1,2-dihydroquinoxaline (compound 938).