Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)=[O:23])=[O:10])=[N:6][CH:7]=1.S>CCN(CC)CC.N1C=CC=CC=1>[CH3:20][O:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:10])=[C:12]([NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[N:6]([CH3:7])[CH2:5][CH2:4][N:31]=3)=[CH:28][CH:29]=2)=[O:23])[CH:13]=1
Reactant: COc1cc(NC(=O)c2ccc(C#N)cc2)c(C(=O)Nc2ccc(Br)cn2)cc1OC
Agent: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)c2ccc(C3=NCCN3C)cc2)c(C(=O)Nc2ccc(Br)cn2)cc1OC
Reaction time: 8 h

Procedure:
To a solution of compound obtained in Example 259 (100 mg, 0.20 mmol) in 10% Et3N/pyridine (10 mL) at 0° C. was bubbled dry H2S gas to saturation. The mixture was stirred at ambient temperatures overnight, and the conversion was complete. The solvent was removed to dryness, and the residue was suspended in anhydrous acetone. (10 mL), followed by addition of MeI (1 mL). The reaction mixture was refluxed for 1 hour. The solvent was removed by rotary evaporation. To the residue was added anhydrous MeOH (10 mL) and N-methylethylenediamine (1 mL). The resulting mixture was refluxed for 1 hour, concentrated and subjected to RP-HPLC purification to give the title compound. MS found for C25H24BrN5O4 (M+H)+: 538.1, 540.1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>C1COCC1>[CH2:1]([O:8][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][C:17]=1[C:25]([F:26])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of benzyl alcohol (10.9 mL; 104.98 mmol) and KOtBu (12.96 g; 115.5 mmol) in THF (500 mL) was heated under reflux for 10 minutes. Subsequently, 4′-fluoro-3′-(trifluoromethyl)acetophenone (21.64 g; 105 mmol) was added and the mixture heated under reflux for another 2 hours. After cooling to RT, the mixture was partitioned between EtOAc and a 5% aqueous NaHCO3 solution. The organic layer was separated, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:2.5) to afford 1-(4-Benzyloxy-3-trifluoromethyl-phenyl)-ethanone (22.37 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]([CH3:23])[CH3:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:35][C:36]1[CH:41]=[C:40]([C:19]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]([CH3:23])[CH3:22])[CH:39]=[CH:38][CH:37]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)C=C(c1cccc(F)c1)c1cc2cccnc2n1S(=O)(=O)c1ccccc1
Yield: 102.2 %

Procedure:
A suspension of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 130, 3.0 g, 6.05 mmol), 3-fluoro-phenylboronic acid (2.1 g, 15 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.42 g, 0.6 mmol) in dioxane (30 mL) and an aqueous sodium carbonate solution (2N, 15 mL) was heated at 90° C. in a microwave for 2 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a saturated aqueous sodium bicarbonate solution (2×50 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (40 g, 17% ethyl acetate/petroleum ether) afforded 2-(1-(3-fluoro-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.6 g, 88%) as an off-white solid: 1H NMR (300 MHz, CDCl3) δ ppm 8.50 (dd, 1H, J1=5.1 Hz, J2=1.8 Hz), 7.89 (dd, 1H, J1=7.5 Hz, J2=1.5 Hz), 7.69 (dd, 2H, J1=8.4 Hz, J2=1.2 Hz), 7.46-7.40 (m, 1H), 7.27-7.13 (m, 5H), 7.01-6.89 (m, 2H), 6.85-6.80 (m, 1H), 6.53 (s, 1H), 6.14 (d, 1H J=10.2 Hz), 2.71-2.59 (m, 1H), 1.15-1.10 (m, 6H).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]([CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:24][CH:23]=1)[CH3:18].ClC(OC)=O.CNC>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]([CH2:19][CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([N:3]([CH3:4])[CH3:1])=[O:31])=[CH:26][CH:27]=1)[CH3:18]
Reactant: CCN(CC)CC
Reactant: CN(CCOc1ccc(CCC(=O)O)cc1)c1nc2ccccc2o1
Agent: CNC
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)CCc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (0.4 mL) was added to an ice-cooled solution of 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]propanoic acid (1.00 g) in dry tetrahydrofuran (20 mL). The mixture was stirred at 0° C. during the addition of freshly distilled methyl chloroformate (0.25 mL), and stirring continued at this temperature for 45 minutes prior to the addition of a solution of dimethylamine in industrial methylated spirit (30% w/v; 20 mL). The mixture was stirred at room temperature for 20 hrs then evaporated. The residue was suspended in water (100 mL). Ethyl acetate (200 mL) and brine (100 mL) were added, the layers were separated and the aqueous layer extracted with ethyl acetate (2×200 mL). The combined ethyl acetate solutions were washed with brine (500 mL), dried (MgSO4) and evaporated. The resulting gum was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford a gum which crystallised on standing to afford the title compound, mp 103°-5° C.
Reaction SMILES: [CH3:1][C:2]1([C:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH2:28][NH:29]C(OC(C)(C)C)=O)[C:15]([NH:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[CH:24]=[N:23][CH:22]=[CH:21]4)=[O:16])=[CH:10][CH:9]=2)=[O:6])[CH2:4][CH2:3]1.[ClH:37]>C(Cl)Cl>[ClH:37].[ClH:37].[CH3:1][C:2]1([C:5]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]([CH2:28][NH2:29])[C:15]([NH:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[CH:24]=[N:23][CH:22]=[CH:21]4)=[O:16])=[CH:12][CH:13]=2)=[O:6])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OC(=O)C2(C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CC1(C(=O)Oc2ccc(C(CN)C(=O)Nc3ccc4cnccc4c3)cc2)CC1
Reaction time: 9 h

Procedure:
To 4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenyl 1-methylcyclopropanecarboxylate (E11) in CH2Cl2 was added HCl (4N in dioxane) and the solution was stirred for 8-10 h. The solvents were evaporated to give pure 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenyl 1-methylcyclopropanecarboxylate dihydrochloride (E12).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Product: O=C(Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12)c1ccccc1

Procedure:
The title compound, MS m/e (%): 391 (M+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and benzoylchloride.
Reaction SMILES: B.C1COCC1.[CH3:7][NH:8][S:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C1COCC1.Cl>[OH:17][CH2:16][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][CH3:7])(=[O:11])=[O:10])=[CH:20][CH:19]=1
Reactant: CNS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(CO)cc1
Yield: 48.5 %

Procedure:
At 0° C., borane-THF complex (66.8 mL, 1 M in THF) is carefully added to a solution of 4-methylsulfamoyl-benzoic acid (3.56 g, 16.5 mmol) in THF (90 mL). The mixture is refluxed for 1.5 h, cooled to it and diluted with 1 N aq. HCl (175 mL). The mixture is extracted with EA and the organic extract is washed with sat. aq. NaHCO3, dried over MgSO4 and filtered. The filtrate is concentrated and the crude product is purified by CC on silica gel eluting with DCM containing 5% of methanol to give 4-hydroxymethyl-N-methyl-benzenesulfonamide (1.61 g) as a colourless oil; LC-MS: tR=0.56 min, [M+1+CH3CN]+=243.14.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[S:23][CH2:22]1)[C:17]([OH:19])=[O:18])=O)C1C=CC=CC=1.[BrH:37].C(O)(=O)C>C(O)(=O)C.C(OCC)C>[BrH:37].[BrH:37].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:20][C@@H:21]1[C:27](=[O:28])[N:26]([CH2:29][C:30]([OH:32])=[O:31])[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[S:23][CH2:22]1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)CN1C(=O)[C@@H](NC(CCCCNC(=O)OCc2ccccc2)C(=O)O)CSc2ccccc21
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NCCCCC(N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 1 h

Procedure:
To a solution of 3(R)-(5-benzyloxycarbonylamino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (40 mg) obtained in Example 52-(2) in acetic acid (1 ml) is added 30% hydrogen bromide-acetic acid solution (1 ml). The resulting mixture is allowed to stand for 1 hour at room temperature and diluted with a mixture ethyl ether (80 ml) and petroleum ether (20 ml), followed by stirring. The supernatant layer is removed by decantation, and precipitate is collected and dried to provide 3(R)-(5-amino-1-carboxypentyl)amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide (33 mg) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[O:13])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[C:18]1([Li])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O.C1(C)C=CC=CC=1>O1CCCC1.C1CCCCC1.CCOCC>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]([OH:13])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(c2ccccc2C(O)c2ccccc2)C(C)=C1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (2.0 g, 8.80 mmol) in tetrahydrofuran (34.0 mL) was added dropwise a 1.05 M solution of phenyllithium in cyclohexane and ether (17.7 mL) at −78° C. The temperature of the mixture was raised to room temperature and the mixture was stirred for 4 hrs. To the reaction mixture solution were added deionized water (20.0 mL) and toluene (20.0 mL) to separate an organic layer and an aqueous layer. The organic layer was dried over sodium sulfate, then distilled to remove the solvent, and purified by a silica gel column (hexane/ethyl acetate=9/1) to give {2-(2,3,4,5-tetramethylcyclopentadienyl)phenyl}phenylmethylalcohol (2.83 g, yield 87.0%) as a pale yellow oily substance.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[N:4]([CH3:25])[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:25][N:4]1[C:5]2[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)=[CH:3]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(Br)c2ncnc(NC3CCN(C(=O)OC(C)(C)C)CC3)c21
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: C1COCCO1
Product: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(NC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
tert-butyl 4-(7-bromo-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl amino)piperidin-1-carboxylate, 73 mg of 4-methanesulfonyl-phenylboronic acid, 17 mg of Pd(PPh3)4 and 0.73 ml of 2N Na2CO3 were added in 3 ml of 1,4-dioxane and stirred in a closed reactor at 100° C. for 12 hr. The resulting mixture was cooled to room temperature, extracted with ethylacetate and distilled water. The organic layer was washed with water and saline solution, dried over anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 15 mg of the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:13])([F:12])[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]([CH2:5][C:4]([F:3])([F:12])[F:13])[CH2:11][CH2:10]1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: FC(F)(F)CN1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(CC(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To as stirred solution of 1-(2,2,2-trifluoroethyl)piperazine dihydrochloride (181.6 mg, 753 μmol) and triethylamine (182 mg, 250 μL, 1.79 mmol) in dichloromethane (5 mL) cooled to 0° C., 2-chloroacetyl chloride (85.1 mg, 60.0 μL, 753 μmol) was added drop-wise over 2 min then stirred for 10 min. The reaction mixture was warmed to 25° C. over 3 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (25 mL) and dichloromethane (25 mL). The organic layer was separated, washed with water (25 mL) and brine (50 mL), dried over sodium sulfate, and concentrated to give 2-chloro-1-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)ethanone (123.3 mg, 504 μmol, 67%) as an orange oil. 1H NMR (DMSO-d6) δ: 4.73 (br. s, 2H), 3.45 (br. s, 4H), 3.23 (q, J=10.3 Hz, 2H), 2.61 (d, J=20.8 Hz, 4H).
Reaction SMILES: C1(C[O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([NH2:23])[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)C=CC=CC=1.[H][H].[ClH:26]>CO.[Pd]>[ClH:26].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([NH2:23])[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1
Reactant: NC(Cc1ccccc1)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(Cc1ccccc1)c1ccc(O)cc1

Procedure:
To a solution of 1-[4-(phenylmethoxy)phenyl]-2-phenylethylamine (4.5 g, 0.013 mol) in methanol (200 mL) and 1N hydrochloric acid (50 mL) was added 5% palladium on carbon (0.8 g). The mixture was shaken on a Parr apparatus under a pressure of 35-40 psi of hydrogen for 3 h. The catalyst was removed by filtration, and the filtrate concentrated under vacuum to give a white solid. This solid was recrystallized from 2-propanol (75 mL) and ether (50 mL) and vacuum dried at 80° C. for 48 h to give 2.31 g of 1-(4-hydroxyphenyl)-2-phenylethylamine hydrochloride; mp 203°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(Cc2ccc(Cl)nc2)CC1
Yield: 74 %

Procedure:
To a suspension of 2-chloro-5-(chloromethyl)pyridine (971 mg, 5.99 mmol) in acetonitrile (50 mL) was added a solution of N-methylpiperazine (1.20 g, 12.0 mmol) in acetonitrile (3 mL) followed by potassium carbonate (0.83 g, 5.99 mmol). The obtained yellow solution was heated at reflux for 40 min. The mixture was allowed to cool for 10 min and the solvent was removed in vacuo. The residue was partitioned between water, NaCl (s), and ethyl acetate. The aqueous layer was extracted with another portion of ethyl acetate. The combined organic layers were dried (Na2SO4) and the solvent was removed in vacuo affording 1.0 g (74% yield) of the title compound as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.31 (d, J=2 Hz, 1 H), 7.65 (dd, J=8, 2 Hz, 1 H), 7.29 (d, J=8 Hz, 1 H), 3.49 (s, 2 H), 2.46 (br s, 8 H), 2.28 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 150.2, 150.1, 139.5, 132.8, 124.0, 59.2, 55.0, 53.0,46.0; MS (ESP) m/z 226 (M++1).
Reaction SMILES: C(O)(=O)CCCCCCCCCCC.S(Cl)(Cl)=O.Cl.[Br:20]Br.[CH3:22][O:23][C:24](=[O:58])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]C1C(=CC=C(O)C=1CCCCCCCCCCCC(O)=O)O>>[CH3:22][O:23][C:24](=[O:58])[CH:25]([Br:20])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: BrBr
Reactant: COC(=O)CCCCCCCCCCCc1c(O)ccc(O)c1CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCC(Br)C(=O)OC
Reaction time: 2.5 h

Procedure:
Initially, α-bromolauric acid methyl ester was prepared as follows. Pure lauric acid (100 gm 0.5 mol) was dissolved in thionyl chloride (89 gm, 0.75 mol) at 55° C. under nitrogen. A large amount of hydrogen chloride gas was generated. When all the lauric acid was converted to acid chloride and there was no more HCl gas being generated after stirring for 2.5 hours, bromine (89.25 gm, 0.65 mol) was slowly added to the solution at room temperature. The reaction mixture was stirred for another 8 hours at 45° C. The reaction was then stopped by evaporating additional bromine at 80° C. by bubbling in nitrogen. The crude product, α-bromolauric acid chloride, was cooled to 0° under nitrogen. Pure methanol was then added very slowly to the acid chloride solution at 0° C. The temperature was not allowed to exceed 15° C. during this process. The final crude product, α-bromolauric acid methyl ester, was washed with water several times. The final product was extracted twice with hexane. The NMR results showed that the product was completely pure. The yield of the reaction was about 98% and may be summarized as follows: ##STR7## B. Preparation of Hydroquinone Bislauric Acid Methyl Ester (2)
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[N:8][C:7]([OH:10])=[N:6]1)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:18]Cl>C(O)C>[CH2:1]([N:5]1[C:9]([Cl:18])=[N:8][C:7]([OH:10])=[N:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cn1cnc(O)n1
Reactant: ClCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)Cn1nc(O)nc1Cl
Temperature: 25 °C

Procedure:
241 g of 1-isobutyl-3-hydroxy-1,2,4-triazole and 475 ml of triethylamine are dissolved in 2100 ml of absolute ethanol, and 182 g of chlorine are passed in while cooling at 20°-30°C. The solution is stirred for 1 1/4 hours at room temperature, after which the triethylamine hydrochloride is filtered off. The filtrate is concentrated in a rotary evaporator, the residue dissolved in 1000 ml of ether and 1000 ml of water are added. The phases are separated and the aqueous phase is extracted 3 times with 300 ml of ether each time. The ether phase is dried and concentrated. The residue is recrystallised from ligroin/xylene. Yield: 104.7 g (34 % of theory); m.p. 84°-86°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:20])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH:5]=[O:6].[CH:21]([Mg]Br)=[CH2:22]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH:21]=[CH2:22])[CH:7]=[C:8]([Br:20])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(COc2c(Br)cc(C=O)cc2Br)cc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1cc(Br)c(OCc2ccc(OC)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 75.3 %

Procedure:
To a stirred solution of 3,5-dibromo-4-(4-methoxybenzyloxy)benzaldehyde (C) (3.04 g, 7.60 mmol) in anhydrous THF (40 mL) under nitrogen, cooled to −76° C., was added dropwise over 15 min vinylmagnesium bromide (1.0 M solution in THF, 11.4 mL, 11.4 mmol), keeping the internal temperature below −70° C. The mixture was stirred at <−70° C. for 65 min, and then quenched with saturated aqueous ammonium chloride solution (6 mL). The stirred mixture was allowed to warm to room temperature, and then partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with saturated aqueous sodium chloride (80 mL), dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (silica gel, 15% EtOAc/pet. ether) to give 2.45 g (75%) of the title compound as a colourless oil. 1H NMR δ (ppm) (CDCl3): 1.96 (1 H, d, J=3.75 Hz), 3.83 (3 H, s), 4.96 (2 H, s), 5.14 (1 H, t, J=4.58 Hz), 5.27 (1 H, d, J=10.29 Hz), 5.35-5.42 (1 H, m), 5.98 (1 H, ddd, J=17.08, 10.28, 6.28 Hz), 6.90-6.96 (2 H, m), 7.50-7.57 (4 H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C@:20]1([CH2:31][F:32])[CH2:25][C@@H:24]([C:26]([F:29])([F:28])[F:27])[O:23][C:22]([NH2:30])=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:11]1[N:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:20]3([CH2:31][F:32])[CH2:25][C@@H:24]([C:26]([F:27])([F:28])[F:29])[O:23][C:22]([NH2:30])=[N:21]3)[CH:4]=2)=[CH:13][CH:12]=1)#[CH:15]
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93 %

Procedure:
A mixture of (4S,6S)-4-(2-fluoro-5-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.2034 g, 0.435 mmol, Example 111), potassium carbonate (0.301 g, 2.175 mmol), and MeOH (3 mL) was stirred at room temperature for 1.25 h. The reaction mixture was concentrated in vacuo, diluted with water and extracted with DCM three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography: 0-100% EtOAc/hexane in 12 min. The product was obtained as a white solid (0.16 g, 93% yield). MS m/z=396 [M+H]+. Calculated for C19H14F5N3O: 395.3.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5](Cl)=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH3:2].[NH3:12]>C(O)C>[CH2:1]([NH:3][C:4]1[C:5]([NH2:12])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH3:2]
Reactant: N
Reactant: CCNc1c(Cl)ncnc1Cl
Solvent: CCO
Product: CCNc1c(N)ncnc1Cl
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of ethyl(4,6-dichloropyrimidin-5-yl)amine (0.31 g, 1.61 mmol) and concentrated aqueous ammonia (10 mL) in ethanol (3 mL) was heated to 100° C. in a sealed tube for 16 hours. The solution was cooled and evaporated to dryness. The residue was partitioned between ethyl acetate (20 mL) and dilute brine (10 mL). The organic layer was dried, filtered and concentrated to give N5-ethyl-6-chloropyrimidine-4,5-diamine (0.214 g, 1.24 mmol, 77%) as a waxy solid. LC-MS (LCT2) m/z 173, 175 [M+H+], Rt 3.97.