Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][CH2:12][C@@:11]([NH:34]C(=O)OC(C)(C)C)([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[N:18]=2)[C:10]1=[O:42]>C(Cl)Cl>[NH2:34][C@@:11]1([CH2:14][C:15]#[C:16][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[N:18]=2)[CH2:12][CH2:13][N:9]([CH3:8])[C:10]1=[O:42]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(NC(=O)OC(C)(C)C)CCN(C)C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(C#CC[C@]2(N)CCN(C)C2=O)n1
Reaction time: 8 h
Yield: 89 %

Procedure:
Trifluoroacetic acid (5 mL, 67.31 mmol) was added to a solution of tert-butyl N-[(3S)-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]-2-oxo-pyrrolidin-3-yl]carbamate (3.83 g, 7.84 mmol) (which may be prepared as described in Description 13a) in DCM (50 mL) at 20° C. and the reaction was stirred overnight. The reaction was concentrated and a further portion of trifluoroacetic acid (2 ml) added. Stirring was continued for 3 hrs then solid K2CO3 was added (care: gas evolved) and the mixture was diluted with water. The phases were separated and the organic layer was dried (Na2SO4). The solvent was evaporated to give (3S)-3-amino-1-methyl-3-[3-[4-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl]prop-2-ynyl]pyrrolidin-2-one (D14a) (2.71 g, 6.9775 mmol, 89% yield) as a yellow oil. The NMR was the same as that produced by the R isomer in Description 14 but with some impurities present.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1>C(N)(C)C.O>[CH:6]([NH:5][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1)([CH3:11])[CH3:7]
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Solvent: CC(C)N
Solvent: O
Product: Cc1nc(NC(C)C)c2cccc([N+](=O)[O-])c2n1
Yield: 108.3 %

Procedure:
A solution of 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 100 mg, 0.45 mmol) in isopropylamine (1 mL) was heated at reflux for 30 mins. Then the reaction mixture was diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 60 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.54-8.51 (d, J=8.4 Hz, 1H), 8.23-8.21 (d, J=7.5 Hz, 1H), 8.17-8.14 (d, J=7.8 Hz, 1H), 7.56-7.51 (t, J=7.8 Hz, 1H), 4.58-4.51 (m, 1H), 2.44 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][C:19](=O)[CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[ClH:37]>O1CCCC1.B>[ClH:37].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:18][CH2:19][CH2:20][CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH3:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CC(c1ccccc1)c1ccccc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCCC(c1ccccc1)c1ccccc1

Procedure:
To the suspension of 11.2 g of dl-1-(p-benzyloxyphenyl)-2-(3,3-diphenylpropionamido)-propane in 200 ml of tetrahydrofuran, 150 ml of 1 molar borane in tetrahydrofuran are added dropwise while stirring under nitrogen at 0°. The mixture is refluxed overnight, cooled to 0° and treated dropwise with 150 ml of methanol, followed by 30 ml of concentrated hydrochloric acid. The mixture is evaporated, again treated with 150 ml of methanol, warmed to 50° and evaporated. The resulting white solid is recrystallized from isopropanol containing a little methanol to afford the dl-1-(p-benzyloxyphenyl)-2-(3,3-diphenylpropylamino)-propane hydrochloride, melting at 187°-190°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@H:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:19][CH:18]=1)[CH3:9]>ClCCl>[CH2:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:35])[C@@H:25]([CH3:26])[NH2:27])=[CH:19][CH:18]=1)[CH3:9]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Temperature: 25 °C

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl [(1R)-2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1-methyl-2-oxoethyl]carbamate (Intermediate 47, 251.1 mg) was dissolved in dichloromethane (2 mL) to give a pale orange solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes the solvent was evaporated under vacuum affording a yellow oil which was charged on a 5 g SCX cartridge and flushed with 25 mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (170.0 mg).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[C:7]([C:10](OCC)=[O:11])[N:6]=[CH:5][C:4]=2[CH2:3][O:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:1]1[C:9]2[CH:8]=[C:7]([CH2:10][OH:11])[N:6]=[CH:5][C:4]=2[CH2:3][O:2]1
Reactant: CCOC(=O)c1cc2c(cn1)COC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc2c(cn1)COC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.7 %

Procedure:
A solution of ethyl 1,3-dihydrofuro[3,4-c]pyridine-6-carboxylate (0.871 g, 4.51 mmol) in THF (20 ml) at −78° C. under argon was treated with LiAlH4 (1M in THF) (4.51 ml, 4.51 mmol) and allowed warm to rt. After 10 min at rt, water (1 ml), 2M aq NaOH (1 ml) and water (1 ml) were sequentially added and the mixture stirred at rt for 0.5 h. The mixture was then filtered through a short pad of Kieselguhr, eluting with THF (50 ml), organic extracts were then evaporated, chromatographed (0-20% methanol/DCM) to give product as an orange oil (66 mg, 10%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.[F:14][C:15]1([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:21][CH:20]2[NH:22][CH:17]([CH2:18][CH2:19]2)[CH2:16]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:14][C:15]1([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][N:24]=2)[CH2:16][CH:17]2[N:22]([C:11]([C:8]3[CH:7]=[C:6]([C:4]4[CH:5]=[N:1][NH:2][CH:3]=4)[S:10][CH:9]=3)=[O:13])[CH:20]([CH2:19][CH2:18]2)[CH2:21]1
Reactant: Cc1cccnc1C1(F)CC2CCC(C1)N2
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1(F)CC2CCC(C1)N2C(=O)c1csc(-c2cn[nH]c2)c1
Reaction time: 1 h

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.04 g, 0.2 mmol) and 3-fluoro-3-(3-methyl-pyridin-2-yl)-8-aza-bicyclo[3.2.1]octane (PA Mixture) (0.058 g, 0.2 mmol) were dissolved in DMF (3 mL). HATU (0.093 g, 0.24 mmol) and diisopropylethylamine (0.144 mL, 0.89 mmol) were added and the resulting mixture was stirred for 1 hour. Aqueous sodium hydroxide (1 N, 3 mL) was added and the mixture stirred for 0.5 hours. The mixture was diluted with ethyl acetate and washed with brine, dried over magnesium sulphate, filtered and the solvent evaporated under vacuum. The residues were purified by HPLC on a C18 cartridge, eluting with 40%-70% methanol/water with 0.1% formic acid. The fractions containing the desired products were concentrated under vacuum and further lyophilised from methanol and water to give the title compounds.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:7]([C@H:20]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:6]([CH3:31])=[CH:5]2.[C:32]([Sn](CCCC)(CCCC)CCCC)#[C:33][CH3:34].C([O-])(O)=O.[Na+].C(N(CC)CC)C>[Pd+2]>[C:27]([O:26][C@@H:20]([C:7]1[C:6]([CH3:31])=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:32]#[C:33][CH3:34])[CH:3]=2)[C:8]=1[O:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:15])=[O:14])[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:28])([CH3:29])[CH3:30]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(Br)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC#Cc1ccc2c(OS(=O)(=O)C(F)(F)F)c([C@H](OC(C)(C)C)C(=O)OCC)c(C)cc2c1
Temperature: 120 °C

Procedure:
A Smith process vial was charged (S)-ethyl 2-(6-bromo-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (55 mg, 0.104 mmol), (1-Propynyl)tributylstannane (35 μL, 0.115 mmol), Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (8 mg, 0.01 mmol), NaHCO3 (4 mg, 0.05 mmol), triethylamine (44 μL, 0.3 mmol) and flushed with nitrogen. DMF (2.0 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 120° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give (S)-ethyl 2-tert-butoxy-2-(3-methyl-6-(prop-1-ynyl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)acetate. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J=4.4 Hz, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.50 (d, J=4.6 Hz, 1H), 5.63 (s, 1H), 4.08 (m, 2H), 2.52 (s, 3H), 2.08 (s, 3H), 1.21 (s, 9H), 1.18 (t, 3H).
Reaction SMILES: C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O.[CH3:15][N:16]([CH3:33])[CH:17]1[C:26]2[CH2:25][O:24][C:23]([CH:27]=[N:28]O)=[CH:22][C:21]3=[CH:30][NH:31][CH:32]=[C:19]([C:20]=23)[CH2:18]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:15][N:16]([CH3:33])[CH:17]1[C:26]2[CH2:25][O:24][C:23]([C:27]#[N:28])=[CH:22][C:21]3=[CH:30][NH:31][CH:32]=[C:19]([C:20]=23)[CH2:18]1
Reactant: CN(C)C1CC2=CNC=C3C=C(C=NO)OCC1=C32
Agent: O=C(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C1CC2=CNC=C3C=C(C#N)OCC1=C32
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Triethylamine 33 μl and trichloroacetyl chloride 13 μl were added to a solution of compound (47) 28.9 mg in dichloromethane 2 ml with cooling ice and the mixture was stirred with cooling in ice and at room temperature for 18 h. A saturated sodium hydrogencarbonate solution was added thereto for alkalinization. The mixture was extracted with chloroform. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in chloroform:methanol (97:3) to give the titled compound 26.3 mg as colorless crystals. Yield 98%. Furthermore, the titled compound was recrystallized from methanol-isopropyl ether to give colorless crystals, m.p. 205-207° C.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([O:12]C)[CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].COC1C=C(OC)C=CC=1C(Cl)=O.F[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41](N)[CH3:42].C(N(CC)CC)C>>[F:34][C:32]1[CH:33]=[CH:28][C:29]2[C:35]3[C:36]([CH:41]([CH3:42])[N:7]([C:5]([C:4]4[CH:8]=[CH:9][C:10]([OH:12])=[CH:11][C:3]=4[OH:2])=[O:6])[C:30]=2[CH:31]=1)=[CH:37][CH:38]=[CH:39][CH:40]=3
Reactant: CC(N)c1ccccc1-c1ccc(F)cc1F
Reactant: COc1ccc(C(N)=O)c(OC)c1
Agent: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: CCN(CC)CC
Product: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1O

Procedure:
N-1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-2,4-dimethoxybenzamide—The title compound was prepared from 2,4-dimethoxybenzoyl chloride (860 mg, 4.28 mmol), 1-(-2′,4′-difluoro-biphenyl-2-yl)-ethylamine (1 g, 4.28 mmol), and triethylamine (717 uL, 5.1 mmol) according to the procedure and in the same manner as described in Example 33, step c resulting in the isolation of 1.47 g (86%) of a white solid. mp 134.8-135.2° C.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=5.95 Hz, 3 H) 3.81 (s, 3 H) 3.92 (s, 3 H) 4.93 (d, J=6.73 Hz, 1 H) 6.59 (dd, J=8.79, 2.33 Hz, 1 H) 6.64 (d, J=2.33 Hz, 1 H) 7.18 (m, 2 H) 7.49 (m, 6 H) 8.29 (s, 1 H); MS (ESI) m/z 398 ([M+H]+); Anal. calcd for C23H21F2NO3: C:69.51 H:5.33 N:3.52 Found: C:69.27 H:5.30 N:3.39
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([CH3:19])[S:17][CH:18]=2)=[CH:10][CH:9]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>O1CCCC1.[NH4+].[Cl-].[Cl-].[Na+].O>[Si:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:19][C:16]1[S:17][CH:18]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)[N:15]=1)([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29]
Reactant: COc1ccc(-c2csc(C)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2csc(CCCCCCCO[Si](C)(C)C(C)(C)C)n2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 61.2 %

Procedure:
Add a solution of tert-butyllithium (26.35 mmol, 15.5 mL, 1.7 M in hexanes) dropwise to a solution of 4-(4-methoxyphenyl)-2-methylthiazole (6.15 g, 29.9 mmol) in degassed anhydrous tetrahydrofuran (THF) (100 mL) at −78° C. under nitrogen and stir the solution for 45 minutes. To this solution, add a solution of (6-bromohexyloxy)-tert-butyldimethylsilane (7.20 g, 24.4 mmol) over 5 min and stir the mixture for 2 hours. Warm the mixture to 0° C., dilute with NH4Cl (200 mL) and brine (250 mL) and extract with methylene chloride (3×150 mL). Dry the combined organic extracts over magnesium sulfate and remove the solvent under reduced pressure. Purify the crude product by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (5:1), to provide 2-[7-(tert-butyldimethylsilanyloxy)heptyl]-4-(4-methoxyphenyl)thiazole (6.27 g, 50%).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][O:9]2.[OH-].[Na+]>O>[Br:3][C:4]1[C:13]([S:14](=[O:16])(=[O:15])[NH:2][CH3:1])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][O:9]2
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Br)c2c1OCCC2
Reactant: CN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNS(=O)(=O)c1cc(C(=O)O)c2c(c1Br)CCCO2
Temperature: 0 °C

Procedure:
70 g of methylamine in a 40% aqueous solution and 70 ml of water were introduced into a 1-liter round-bottomed flask. The contents were cooled to 0° C. and 160 g of 5-bromo-6-chlorosulphonylchroman-8-carboxylic acid were added in 16 g portions, the introduction of each portion of acid being followed by the addition of 18 ml of a solution containing 90 ml of 30% sodium hydroxide in 90 ml of water. The temperature was maintained between 0° and 5° C. during the entire period of introduction and for a further period of one hour. The temperature was then allowed to rise. The solution obtained was taken up with 1 liter of water, filtered with charcoal and acidified with concentrated hydrochloric acid until a color change of Congo red was observed.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]2([OH:24])C(=O)NC(=O)NC2=O)=[CH:9][C:8]=1[O:25][CH3:26]>O>[NH2:6][C:7]1[C:8]([O:25][CH3:26])=[CH:9][C:10]([CH:15]=[O:24])=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1cc(C2(O)C(=O)NC(=O)NC2=O)cc(OC)c1N
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(C=O)cc(OC)c1N
Temperature: 0 °C

Procedure:
28 ml of sulfuric acid (d=1.8; 0.45 mol) were heated to 120° while stirring and treated in one portion with 11.25 g of 5-(4-amino-3,5-dimethoxyphenyl)-5-hydroxybarbituric acid (0.038 mol). The mixture was stirred until evolution of gas was no longer observed (about 15-20 minutes) and then poured into a mixture of 140 g of ice and 140 g of water while stirring. Resinous polymerization products were separated by a filtration over a pad of 15 g of celite. While stirring and cooling, the filtrate was treated with 63.6 g of potassium carbonate powder until neutral. The aqueous suspension was extracted three times with 50 ml of ethyl acetate each time, the combined organic phases were dried over sodium sulfate and concentrated in water-jet vacuum. The residue was dried up to constant weight in a high vacuum. There was obtained 6.36 of crude 4-amino-3,5-dimethoxybenzaldehyde as a yellow oil which solidified on standing (mp=94°-96° C.). The purity determined by gas chromatography was 96%. 4-amino-3,5-dimethoxybenzaldehyde was converted into 2,4diamino-5-(4-amino-3,5-dimethoxybenzyl)pyrimidine as follows:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=2)=[CH:12][N:11]=1.Br[CH2:32][CH3:33]>>[CH2:32]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=3)=[CH:12][N:11]=2)=[C:2]([F:1])[C:7]=1[F:8])[CH3:33]
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Reactant: CCBr
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCC)c(F)c3F)nc2)cn1
Yield: 51 %

Procedure:
The etherification of 2.8 mmol of 2-(2,3-difluoro-4-hydroxyphenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine using 3.0 mmol of 1-bromoethane is carried out analogously to the procedure indicated for Example 3. Corresponding purification gives 0.62 g (51%) of colorless crystals, X 111 SC 122.5 SA 185 I.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([N+:22]([O-])=O)([CH2:20][OH:21])[CH2:18][OH:19])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C.[C].[Pd]>[NH2:22][C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=1)([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: CCCCCCCCCCc1ccc(C(CO)(CO)[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCc1ccc(C(N)(CO)CO)cc1
Reaction time: 8 h
Yield: 5.7 %

Procedure:
2-(4-Decylphenyl)-2-nitro-1,3-propanediol (170 mg) was dissolved in ethanol (30 ml) and the mixture was subjected to catalytic reduction in the presence of 5% palladium carbon (40 mg) under hydrogen pressure of 20 atm. After stirring the mixture for 8 hours, the insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (silica gel) to give 8.9 mg of the subject compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[O-]S([O-])(=O)=O.[Mg+2].[CH:17](=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CCN(CC)CC.[BH4-].[Na+]>CO.C1COCC1>[CH2:17]([NH:6][C@@H:5]([CH:7]([CH3:9])[CH3:8])[C:4]([O:3][CH3:2])=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC=O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCN[C@H](C(=O)OC)C(C)C
Yield: 50.5 %

Procedure:
Synthesized according to the general procedure as described in Example 1a using L-valine methyl ester hydrochloride (1.5 gm, 8.9 mmol), THF (25 mL), MgSO4 (1.81 gm, 15.13 mmol), decanal (3.36 mL, 17.89 mmol), Et3N (1.24 mL, 8.9 mmol), sodium borohydride (677 mg, 17.89 mmol), and methanol (25 mL) to give 11i (1.22 gm, 50%) in FIG. 2. 1H NMR (500 MHz, CDCl3): δ 0.87 (3H, t, J=7.07 Hz), 0.92 (3H, d, J=7.37 Hz), 0.94 (3H, d, J=6.83 Hz), 1.2-1.5 (17H, m), 1.88 (1H, sextet), 2.37-2.44 (1H, m), 2.5-2.8 (1H, m), 2.97 (1H, d, J=6.34 Hz), 3.74 (3H, s). ESI-MS: 294.3 (M+23).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[F:21][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[CH2:14][S:15]([C:16]1[O:17][CH:18]=[CH:19][N:20]=1)=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Solvent: ClCCl
Product: Cn1nc(C(F)(F)F)c(CS(=O)c2ncco2)c1OC(F)F

Procedure:
Under an atmosphere of argon, 2-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (2.00 g, 6 mmol) is initially charged in 333 ml of dichloromethane. With stirring and ice-cooling, 3-chloroperbenzoic acid (1.362 g, 6 mmol, 77% pure) is then added a little at a time, and the mixture is stirred at 0° C. for a further 6 hours. For work-up, the reaction mixture is extracted twice with 2-molar sodium hydroxide solution and then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 6:4). This gives 1.98 g of product (89.7% of theory).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9]O)[CH2:5][CH2:4]1.P(Br)(Br)[Br:12]>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]1
Reactant: BrP(Br)Br
Reactant: COC1CCC(CO)CC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC1CCC(CBr)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methoxycyclohexylmethanol (10.5 g) was dissolved in carbon tetrachloride (45 g) and cooled with ice. Phosphorus tribromide (2.8 ml) was added dropwise to the above solution and stirred at ambient temperature overnight. The carbon tetrachloride layer was decanted and dried over magnesium sulfate. After filtering, the carbon tetrachloride from the filtrate was evaporated to yield pale yellow colored liquid of bromomethyl-4-methoxycyclohexane.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>C(Cl)(Cl)(Cl)Cl.ClCCl.O>[CH3:21][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:10][C@@H:2]2[CH2:1][O:5][C@@H:4]3[C@H:6]([OH:9])[CH2:7][O:8][C@H:3]23)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)cc1
Temperature: 0 °C

Procedure:
Isomannide (40) (10 g, 68.49 mmol) and p-toluenesulphonyl chloride (6.53 g, 34.25 mmol) were dissolved in a mixture of carbon tetrachloride (50 mL), dichloromethane (5 mL) and water (40 mL). The flask was cooled to 0° C. and a solution of potassium hydroxide (1.92 g, 34.25 mmol) in water (5 mL) added dropwise over 30 minutes with stirring. The resulting biphasic mixture was stirred at 0° C. for 7 hours. Then off-white precipitate was collected by filtration in vacuo then partitioned between dichloromethane (30 mL) and water (10 mL). The organic phase was washed with brine (2×10 mL) then dried (Na2SO4), filtered and reduced in vacuo to leave a colourless solid. Recrystallisation from carbon tetrachloride gave monotosylate (50) as colourless granules (3.92 g, 38%). TLC (Rf=0.11, EtOAc:heptane 1:1); analytical HPLC main peak, Rt=10.692 min; HPLC-MS 318.2, 323.1 [M+Na]+, 623.2 [2M+Na]+; [α]D18 +72.2° (c=5.4, CHCl3); δH (500 MHz, CDCl3) 2.44 (3H, s, CH3), 3.54 (1H, dd, J=9.31 and 7.23 Hz, OCH2CHOH), 3.78 (1H, dd, J=9.18 and 7.59 Hz, OCH2CHOTs), 3.95 (1H, dd, J=9.36 and 6.45 Hz, OCH2CHOH), 4.01 (1H, dd, J=9.33 and 6.64 Hz, OCH2CHOTs), 4.26 (1H, m, CHOH), 4.42 and 4.48 (each 1H, brt, J=5.03 and 5.00 Hz respectively, CHCHCHOH and CHCHCHOTs), 4.90 (1H, dd, J=12.15 and 6.84 Hz, CHOTs), 7.37 (2H, d, J=8.13 Hz, aromatic CH3CCH), 7.82 (2H, d, J=8.20 Hz, aromatic OSO2CCH); δC (125 MHz, CDCl3) 21.69 (CH3), 70.03 (CH2CHOTs), 72.29 (CHOTs), 74.02 (CH2CHOH), 80.00 (CH2CHOH), 81.36 (CHCHOTs), 81.76 (CHCHOH), 128.00 and 129.89 (aromatic CH), 133.04 (CHOSO2C quaternary), 145.26 (CH3C quaternary).