Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[O:21][CH2:35][CH2:34][C:24]1[N:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:27][C:23]=1[CH3:22])[CH:2]=[CH2:3]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1OCCc1nc(-c2ccccc2)oc1C
Yield: 83.8 %

Procedure:
A mixture of 2,6-diallyl-4-benzyloxy-phenol (520 mg, 1.85 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO 9518125) (828 mg, 2.32 mmol), and Cs2CO3 (604 mg, 1.85 mmol) was heated at 55° C. in DMF (5 mL) for 20 h. Additional toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (300 mg, 0.839 mmol) and CS2CO3 (200 mg, 0.614 mmol) were added, and the mixture was heated for 18 h. The reaction mixture was cooled and partitioned between EtOAc (40 mL) and H2O (10 mL). The organic layer was washed with brine (15 mL), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography using hexanes:ethyl acetate (8:1) to give a colorless oil (722 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.95 (t, 2H, J=6.3 Hz), 3.33 (d, 2H, J=6.3 Hz), 4.01 (t, 2H, J=6.3 Hz), 4.96 (s, 2H), 4.97-5.02 (m, 2H), 5.03 (s, 2H), 5.84-5.94 (m, 1H), 6.65 (s, 2H), 7.28-7.45 (m, 8H), 7.99 (dd, 2H, J=2.0, 7.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[C:8]=1[C:17]([O:19][CH3:20])=[O:18])([O-])=O.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:1][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=2[C:8]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: [H][H]
Reactant: COC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2ccc(C)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Nc2ccccc2N)sc2ccc(C)cc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using methyl 2-(2-nitroanilino)-5-methylbenzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), methyl 2-(2-aminoanilino)-5-methylbenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>CCOCC.C1COCC1.O.CCCCCC>[Cl:13][C:14]1[N:19]=[C:18]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ncccn1
Reactant: Brc1cccnc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nccc(-c2cccnc2)n1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of butyllithium (1.6M in hexanes, 9.7 ml, 16 mmol) in 25 ml of anhydrous ether at −78° C. was added 3-bromopyridine (1.5 ml, 16 mmol) over 5 min. The resulting mixture was stirred at −75° C. for 1 h. A suspension of 2-chloropyrimidine (1.8 g, 16 mmol) in 15 ml of ether was then added in portions over 8 min. The resulting suspension was stirred for 30 min at −30° C. and allowed to warm to 0° C. for 1 h. The reaction was quenched with water (0.5 ml, 1.5 eq.) in THF (5 ml) and then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (3.8 g, 17 mmol) in THF (12 ml) was added. The resulting suspension was stirred at RT for 15 min, then cooled to 0° C. Hexane (13 mL) was added followed by 0° C. solution of NaOH (12 ml, 3N). The suspension was stirred at 0° C. for 5 min, 50 ml of water was added and the layers were separated. The organic layer was dried (Na2SO4) and concentrated in vacuo. The crude product was dissolved in DCM and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 20% to 65% EtOAc in hexane, to provide 2-chloro-4-(pyridin-3-yl)pyrimidine as off-white solid. Found M+H+=192, 194
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:19](=[O:21])[CH3:20])[CH2:12][CH2:11][N:10]([CH3:15])[C:9]2=[O:16])=[N:5][N:4]=1
Reactant: CN1CCC(O)N(c2nnc(C(F)(F)F)s2)C1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: CC(=O)OC1CCN(C)C(=O)N1c1nnc(C(F)(F)F)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.1mole), acetic anhydride (0.11 mole), toluenesulfonic acid (0.05 gram) and benzene (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is heated on a steam bath with stirring for a period of about 2 hours. After this time the reaction mixture is cooled to room temperature and is stripped of solvent under reduced pressure leaving a residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acetyloxy-2(1H)-pyrimidinone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:19])=[O:18])=[CH:13][N:12]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])(=[O:18])=[O:19])=[CH:13][N:12]=1
Reactant: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2O)nc1)c1ccccc1F
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(CCc2ccc(F)cc2O)nc1)c1ccccc1F
Reaction time: 8 h
Yield: 14.2 %

Procedure:
2-[(E)-2-(2-Hydroxy-4-fluorophenyl)vinyl]-5-[(2-fluorophenyl)sulfonyl]pyridine (Example 9, 55 mg, 0.15 mmol) was dissolved in ethyl acetate (3 mL) and degassed. Palladium (10% wt. on activated carbon, 15 mg) was added and the reaction stirred under a balloon of hydrogen overnight, then under a fresh balloon for 3 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica eluting with 2:1 isohexane:ethyl acetate to give the title compound (8 mg, 14%). δH (400 MHz, CDCl3): 9.67 (1H, s), 9.08 (1H, s), 8.25–8.22 (1H, m), 8.11–8.07 (1H, m), 7.63–7.58 (1H, m), 7.37–7.32 (2H, m), 7.15–7.09 (1H, m), 7.05–7.00 (1H, m), 6.58–6.50 (2H, m), 3.32 (2H, t, J=5.8 Hz), 3.07 (2H, t, J=6.0 Hz); m/z (ES+) 376 [MH+].
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[C:19]([CH2:20][N:21]([CH2:32][CH3:33])[C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:18][C:17]([CH3:34])=[CH:16][N:15]=2)[CH:7]=1)C.[Li+].[OH-]>>[CH2:25]([NH:24][C:22](=[O:23])[N:21]([CH2:20][C:19]1[C:14]([C:8]2[CH:7]=[C:6]([CH2:5][C:4]([OH:35])=[O:3])[CH:11]=[CH:10][C:9]=2[O:12][CH3:13])=[N:15][CH:16]=[C:17]([CH3:34])[CH:18]=1)[CH2:32][CH3:33])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ncc(C)cc2CN(CC)C(=O)NCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Product: CCN(Cc1cc(C)cnc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccccc1

Procedure:
{3-[3-(3-Benzyl-1-ethyl-ureidomethyl)-5-methyl-pyridin-2-yl]-4-methoxy-phenyl}-acetic acid ethyl ester was hydrolyzed with 1N aqueous LiOH to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([NH:21][C:22]1[CH:23]=[N:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:56]([O:58][C:59](=[O:63])[CH2:60][CH2:61][NH2:62])[CH3:57].C(N(CC)CC)C>ClCCl>[CH2:56]([O:58][C:59](=[O:63])[CH2:60][CH2:61][NH:62][C:28]([C:25]1[N:26]=[CH:27][C:22]([NH:21][CH:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH:2]([CH3:31])[CH3:1])=[CH:23][N:24]=1)=[O:29])[CH3:57]
Reactant: CC(C)CC(Nc1cnc(C(=O)O)nc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ncc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.5 %

Procedure:
(+/−)-5-[3-Methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carboxylic acid (636 mg, theoretical 596 mg, 1.39 mmol) was combined with N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (399 mg, 2.08 mmol), 1-hydroxybenzotriazole hydrate (319 mg, 2.08 mmol), and anhydrous dichloromethane (10 mL). Beta-alanine ethyl ester hydrochloride (256 mg, 1.67 mmol) was added followed by triethylamine (0.386 mL, 2.78 mmol). This was stirred at room temperature as a solution for 17 h before the reaction was partitioned between ethyl acetate and sat. NH4Cl. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptanes followed by methanol/ethyl acetate) gave impure material. The residue was partitioned between ethyl acetate and sat. NaHCO3. The aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4 and concentrated in vacuo to give (+/−)-3-({5-[3-methyl-1-(4′-trifluoromethyl-biphenyl-4-yl)-butylamino]-pyrimidine-2-carbonyl}-amino)-propionic acid ethyl ester (0.687 g, 94%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 8.17 (t, J=6.2 Hz, 1 H) 8.09 (s, 2 H) 7.62-7.73 (m, 4 H) 7.56 (d, J=8.2 Hz, 2 H) 7.40 (d, J=8.2 Hz, 2 H) 4.53-4.58 (m, 1 H) 4.44-4.52 (m, 1 H) 4.11-4.19 (m, 2 H) 3.72 (q, J=6.2 Hz, 2 H) 2.61 (t, J=6.0 Hz, 2 H) 1.66-1.87 (m, 3 H) 1.21-1.29 (m, 3 H) 1.04 (d, J=6.0 Hz, 3 H) 0.99 (d, J=5.9 Hz, 3 H); MS (M+1): 529.7.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:12])[C@:4]1([CH3:11])[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>CCOCC>[CH3:10][C:6]1([CH3:9])[O:5][C@:4]([CH3:11])([C:3]([Cl:12])=[N:2][O:1][S:14]([CH3:13])(=[O:16])=[O:15])[CH2:8][O:7]1
Reactant: CC1(C)OC[C@@](C)(C(Cl)=NO)O1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@](C)(C(Cl)=NOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
(S)—N-hydroxy-2,2,4-trimethyl-1,3-dioxolane-4-carbimidoyl chloride (5.5 g, 28.4 mmol) was dissolved in Et2O (150 mL) and methanesulfonyl chloride (2.21 ml, 28.4 mmol) was added. Triethylamine (3.96 ml, 28.4 mmol) was added dropwise and the reaction was stirred at ambient temperature for 1 hour. The resulting solids were filtered and the filtrate concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (S)-2,2,4-trimethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (4.7 g, 17.3 mmol, 60.9% yield) as an amber oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[CH:13]=[N:14][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:16]=1[CH3:17])=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:17][C:16]1[N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:14]=[CH:13][C:12]=1[CH2:10][OH:9]
Reactant: CCOC(=O)c1cnn(-c2ccccn2)c1C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(CO)cnn1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
Add lithium aluminum hydride (0.225 g, 5.92 mmol) to tetrahydrofuran (15 mL) at 0° C. then slowly add 5-methyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester (0.685 g, 2.96 mmol) in tetrahydrofuran (5 mL) dropwise. Warm the mixture to room temperature and stir for 2 hr. then cool the solution to 0° C. Add saturated aqueous sodium sulfate (0.5 mL), warm to room temperature then stir for 2 hr. Filter off the solid materials then dry the solution (sodium sulfate), filter and concentrate to give (5-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-methanol as a white solid (0.501 g, 89%).
Reaction SMILES: [ClH:1].O1CCOCC1.[OH:8][C@H:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)[C:12]=2[C@H:11]([CH3:31])[CH2:10]1>O1CCOCC1>[ClH:1].[ClH:1].[CH3:31][C@H:11]1[C:12]2[C:17]([N:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]3)=[N:16][CH:15]=[N:14][C:13]=2[C@H:9]([OH:8])[CH2:10]1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
4M HCl/dioxane (11.2 mL, 44.9 mmol) was added to a solution of tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.600 g, 1.79 mmol) in dioxane (15 mL). The reaction mixture was stirred at room temperature under nitrogen overnight (20 hours). The mixture was concentrated to dryness and dried on high vacuum line. The crude product was suspended in ether, sonicated, and stirred for 5 minutes. The solids were isolated by filtration through a medium frit funnel under nitrogen pressure, rinsed with ether, dried under nitrogen pressure, and dried further on a high vacuum line to give (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.440 g, 79.8% yield) as a powder. LC/MS (APCI+) m/z 235. The (5R,7S)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride was prepared using an analogous method.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([CH:28](OC)[O:29]C)[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(O)C.Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([CH:28]=[O:29])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(OC)OC)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: Cl
Solvent: CCO
Product: CCCCc1nc(C=O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
A 92 mg sample of 5-[4′-[[5-butyl-3-(dimethoxymethyl)-1H-1,2,4-triazol-1-yl]methyl][1,1′-biphenyl]-2-yl]-1H-tetrazole from Example 24 was dissolved in 20 ml of ethanol and 2 ml of 3N HCl. The reaction was stirred at ambient temperature for 3 days. The solvent was removed in vacuo. Lyophilization from acetonitrile/water gave 70 mg (81%) of 5-butyl-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-ylmethyl]-1H-1,2,4-triazole-3-carboxaldehyde as the colorless hydrochloride salt: NMR (CDCl3) δ 0.89 (t, J=8 Hz, 3H), 1.30–1.44 (m, 2H), 1.66–1.78 (m, 2H), 2.78 (t, J=8 Hz, 2H), 5.38 (s, 2H), 7.17 (q, J=8 Hz, 4H), 7.40 (d, J=8 Hz, 1H), 7.50–7.64 (m, 2H), 8.02 (d, J=8 Hz, 1H); MS (FAB) m/e (rel intensity) 388 (36), 235 (42), 207 (100), 192 (50); HRMS. Calc'd for M+Li: 395.2046. Found: 395.2049.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]([F:13])([F:12])[F:11])=[CH2:9])[CH:5]=[C:4]([Cl:14])[CH:3]=1.[CH2:15]([N:22]([CH2:28]OC)[CH2:23][Si](C)(C)C)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([N:22]1[CH2:28][CH2:9][C:8]([C:6]2[CH:5]=[C:4]([Cl:14])[CH:3]=[C:2]([Cl:1])[CH:7]=2)([C:10]([F:11])([F:13])[F:12])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 48.3 %

Procedure:
To a stirred solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (10 g, 41.49 mmol) in DCM (150 mL) was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (Preparation 29, 39.33 g, 165.97 mmol) at room temperature. Resulting reaction mixture was cooled to 0° C. and TFA (0.32 mL, 0.41) was added slowly and stirred at room temperature for 5 hours. After complete consumption of starting material, reaction mixture was basified by aqueous Na2CO3 and extracted with DCM (3×100 mL). Combined organic layer was dried over Na2SO4, and concentrated under vacuum to afford brown oil (9.5 g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 2% ethyl acetate in hexane to afford product as brown solid (7.5 g, 48.29%). 1H-NMR (400 MHz, CDCl3) δ: 2.28-2.35 (m, 1H), 2.53-2.60 (m, 1H), 2.69-2.81 (m, 2H), 3.03-3.11 (m, 2H), 3.66 (s, 2H), 7.26-7.35 (m, 8H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH2:23](O)[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: CCO
Reactant: O=C(O)c1ccccc1Oc1cccc(F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1Oc1cccc(F)c1

Procedure:
2-(3-Fluorophenoxy)benzoic acid (10 g.) and 100 ml of ethanol containing 1 ml. of concentrated H2SO4 were heated at reflux through molecular sieves overnight. The solvent was evaporated, and the residue poured into 50 ml. of 7% NaHCO3. The resulting ester was extracted with ether. ##STR10##
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCOCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCOCCO

Procedure:
3.73 g (14.8 mmol) ethyl 3-(2-benzyloxy-ethoxy)-propionate are hydrogenated together with 665 mg 10% palladium charcoal in 70 ml of ethanol for 44 minutes at ambient temperature under a hydrogen atmosphere at 3 bar. Then the mixture is suction filtered and the filtrate is evaporated down i. vac.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:38]=[CH:37][C:27]([CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[C:26]([F:39])[C:25]=1[O:40][CH3:41]>>[F:39][C:26]1[C:25]([O:40][CH3:41])=[C:24]([NH:23][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)[CH:38]=[CH:37][C:27]=1[CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1F)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1F)OCC

Procedure:
The title compound was prepared according to the procedure from Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A) and Diethyl (4-amino-2-fluoro-3-methoxybenzyl)phosphonate (Compound 147A). 1H NMR (CD3OD, 400 MHz): δ=1.26-1.36 (m, 6 H), 1.44 (t, J=6.95 Hz, 3 H), 3.32-3.39 (m, 2 H), 4.04-4.15 (m, 4 H), 4.22 (q, J=7.07 Hz, 2 H), 7.00 (dd, J=8.34, 1.77 Hz, 1 H), 7.21 (d, J=1.77 Hz, 1 H), 7.75 (d, J=8.34 Hz, 1 H). MS (ES+): m/z 586.14 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10](=[O:14])[N:11]([CH3:13])[N:12]=1.OO.C(=O)([O-])[O-].[K+].[K+].[Cl:24]CCl>C(O)(=O)C>[Cl:24][C:3]1[C:2]([CH3:1])=[C:7]([C:8]2[O:9][C:10](=[O:14])[N:11]([CH3:13])[N:12]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c[n+]([O-])ccc1-c1nn(C)c(=O)o1
Reactant: ClCCl
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1c(-c2nn(C)c(=O)o2)ccnc1Cl
Temperature: 80 °C
Yield: 88 %

Procedure:
Step-3: 3-Methyl-4-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyridine-1-oxide: To a stirred solution of step-2 intermediate (1.0 g, 5.23 mmol) in acetic acid (30 mL) was added hydrogen peroxide (0.321 mL, 10.46 mmol) drop-wise at RT and the reaction was heated to 80° C. and maintained for 12 h. The resulting mixture was cooled to RT and basified with solid potassium carbonate. The resulting slurry was diluted with dichloromethane (50 mL) and filtered. The filtrate was concentrated under vacuum to afford 800 mg (88%) of title compound as white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.19 (d, J=5.0 Hz, 1H), 7.67 (d, J=5.0 Hz, 1H), 3.43 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][OH:14])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: NCCCO
Reactant: Fc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCCNc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.5 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (15.0 g, 89.8 mmol) in ethanol (300 mL) were added 3-amino-1-propanol (8.23 mL, 107.8 mmol) and sodium carbonate (47.6 g, 449 mmol). The reaction mixture was vigorously stirred at rt for 72 h. Then the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (100% EtOAc) to give the title compound as a white solid (9.5 g, 51%). LC/MS m/z 206.3 (M+H)+; 1H NMR (300 MHz, CD2Cl2) δ 1.85 (quintet, 2H), 3.55 (t, 2H), 3.65 (t, 2H), 4.85-4.98 (br, 2H), 7.85 (d, 1H).
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[CH:6]=[CH:5][C:4]=1[CH2:22]N(C)C.[BH4-].[Na+].Cl>C(O)C>[OH:2][C:3]1[C:8]2[C:9]([CH3:21])=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[O:11][C:7]=2[C:6]([Cl:1])=[CH:5][C:4]=1[CH3:22]
Reactant: COc1ccc(Cc2oc3ccc(CN(C)C)c(O)c3c2C)cc1
Reactant: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cc2oc3c(Cl)cc(C)c(O)c3c2C)cc1

Procedure:
To a solution of (177) (Example 45) (0.106 g, 0.3 mmol) in 5 mL ethanol was added sodium borohydride (0.111 g, 3 mmol). The mixture was refluxed for 1 h, cooled and poured into cold dilute HCl (1N). Extraction with ethyl acetate, followed by chromatography of the concentrated organic extract gave the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13].CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:6][C:7]1[CH:16]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:9]([CH:8]=1)[C:17]([O:19][CH3:20])=[O:18])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OS(C)(=O)=O)cc(C(=O)OC)c1
Yield: 100.5 %

Procedure:
MsCl (0.16 mL, 0.234 g, 2.06 mmol, 1.1 eq) was added to a stirred solution of dimethyl 5-hydroxyisophthalate (0.40 g, 1.86 mmol, 1 eq) and Et3N (0.78 mL, 0.56 g, 5.6 mmol, 3 eq) in 5 mL anhydrous CH2Cl2 at 0° C. under Ar. The reaction was stirred at 0° C. to room temperature over the weekend. The reaction was quenched with water, and the layers were separated. The organic layer was washed with water (×2), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo yielding 0.54 g (1.87 mmol, 100% yield) of dimethyl 5-(methylsulfonyloxy)isophthalate.