Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].O1CCCC1>[Pt]=O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)/C=C/c1ccc(OC)cc1F
Agent: O=[Pt]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A mixture of ethyl (2E)-3-(2-fluoro-4-methoxyphenyl)acrylate (7.07 g, 31.5 mmol), tetrahydrofuran (50 mL), ethanol (5 mL) and platinum oxide (300 mg) was stirred overnight at room temperature under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (5.97 g, yield 84%) as a colorless oil. 1H NMR (CDCl3) δ: 1.23 (3H, t, J=7.2 Hz), 2.58 (2H, t, J=7.6 Hz), 2.90 (2H, t, J=7.6 Hz), 3.77 (3H, s), 4.12 (2H, q, J=7.2 Hz), 6.57-6.63 (2H, m), 7.07-7.13 (1H, m).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=3)=[CH:17][N:16]=2)=[C:11]([F:36])[C:10]=1[F:37])C1C=CC=CC=1>C1COCC1>[F:36][C:11]1[C:10]([F:37])=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:26]=2)=[CH:17][N:16]=1
Reactant: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCc4ccccc4)c(F)c3F)nc2)cn1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(O)c(F)c3F)nc2)cn1
Yield: 94.4 %

Procedure:
The hydrogenation of 21 mmol of 2-(4-benzyloxy-2,3-difluorophenyl)-5-(6-octyloxypyridin-3-yl)pyrimidine in 200 ml of THF is carried out analogously to the procedure indicated for precursor 14, giving 8.2 g (93%) of a colorless solid, m.p. 130-132° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:14]1([C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](C(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added pyrrolidine (9.2 g), 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (24.7 g) and triethylamine (13.6 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, and dried over sodium sulfate. The solvent is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=20/1) to give methyl trans-4-(pyrrolidin-1-ylcarbonyl)-cyclohexanecarboxylate (11.8 g). APCI-MS M/Z:240[M+H]+
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=1)(=O)=O.C([Sn](CCCC)(CCCC)[CH:34]1[CH2:36][CH2:35]1)CCC>>[Cl:13][C:11]1[CH:10]=[C:9]([C:14]2[N:19]=[N:18][C:17]([NH2:20])=[N:16][C:15]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([CH:34]2[CH2:36][CH2:35]2)[CH:12]=1
Reactant: Nc1nnc(-c2cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c2)c(-c2ccccc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)C1CC1
Product: Nc1nnc(-c2cc(Cl)cc(C3CC3)c2)c(-c2ccccc2)n1
Yield: 6.7 %

Procedure:
6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazin-3-amine (20 mg, 7%) was prepared from 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (0.40 g, 0.93 mmol) and tri-n-butyl(cyclopropyl) tin (0.37 g, 1.11 mmol) according to the general procedure for Example 4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][C:17]([OH:19])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[N:5]2.C(C1NC=CN=1)(C1[NH:23]C=CN=1)=O.N>Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([CH2:16][C:17]([NH2:23])=[O:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH2:12][N:13]([CH3:15])[CH3:14])=[N:5]2
Reactant: CN(C)Cc1cnc2ccc(Cl)c(CC(=O)O)c2n1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: CN(C)Cc1cnc2ccc(Cl)c(CC(N)=O)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
Hydrochloric acid (4 M in dioxane, 8 drops) was added to a solution of the above (6-chloro-3-dimethylaminomethyl-quinoxalin-5-yl)-acetic acid in N,N-dimethylformamide (3 ml). A solution of carbonyl diimidazole (188 mg, 1.16 mmol, 1.2 equiv) in N,N-dimethylformamide (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Concentrated aqueous ammonia (25%, 10 ml) was added, and after 10 minutes at room temperature, volatiles were removed in vacuo. The residue was purified via flash chromatorgraphy (gradient of CH2Cl2/MeOH 95:5 to 70:30) to afford the title compound (180 mg, 67%) as a foam. 1H NMR (400 MHz, d6-DMSO): δ=9.02 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.94 (d, J=9.2 Hz, 1H), 7.54 (br s, 1H), 6.98 (br s, 1H), 4.7-4.5 (br, 2H), 4.32 (s, 2H), 2.78 (br s, 6H). MS (ES+): 279.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([CH2:11][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(Oc2ccc(Cl)cc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(Cl)cc4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-chlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.34-7.19 (m, 7H), 6.98-6.87 (m, 5H), 3.50 (s, 2H), 2.98 (d, 2H, J=11.8 Hz), 2.58-2.44 (m, 2H), 2.10-1.98 (m, 2H), 1.83-1.76 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: [CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[OH-].[Cu+2:11].[OH-].CO.C(Cl)(Cl)Cl>O>[CH:1]1[CH:8]=[CH:7][C:5](=[O:6])[C:4]([OH:9])=[CH:3][CH:2]=1.[Cu:11]
Reactant: [Cu+2]
Agent: O=c1cccccc1O
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: [Cu]
Temperature: 80 °C

Procedure:
To a solution of tropolone (244 mg) in water is added a suspension of copper (II) hydroxide (98 mg) in water. The mixture is heated at 80° C. and methanol-chloroform is added thereto until the mixture becomes homogeneous. The solution is concentrated under reduced pressure. The depositing green crystals are collected by filtration and dissolved in hot chloroform. After removing impurities by filtration, to the filtrate is added methanol. The solution is cooled with ice. The precipitating green needles are recovered by filtration to give tropolone copper complex (203 mg).
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C=O)C>[CH2:21]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: CCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Cytidine (10.1 g, 0.0415 mol), sodium hydride (2.0 g, 1.2 eq), iodononane (9.8 ml, 1.2 eq.) in DMF (100 ml) were reacted as per the procedure of Example 71, Step 1 to yield the 2' and 3' isomers as a sticky foam (11.6 g).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[NH:8][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])=[O:21]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Cl
Yield: 47.1 %

Procedure:
The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2-chlorophenylisocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.29 g, 47%). EI-MS m/z 308(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=1.[C:29]([Cu])#[N:30]>CN(C=O)C.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>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:29]#[N:30])[CH:22]=1
Reactant: N#C[Cu]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C#N)c2)c1N
Temperature: 100 °C
Yield: 33.8 %

Procedure:
To a solution of 3-[5-amino-4-(3-iodobenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (110 mg, 0.23 mmol) in DMF (5 mL) was added CuCN (40 mg, 0.45 mmol) and tetrakis(triphenylphosphine)palladium (catalytic) and the mixture was heated at 100° C. over night under N2. The solvent was removed and the residue was suspended in EtOAc, and solids were filtered off. The filtrate was washed by water, brine, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc). Product was obtained as a beige solid (30 mg, 34%). HPLC (4 minute 10-90 gradient) tR 2.02 min; MS m/z 386.13 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15].[Li+].CC([N-]C(C)C)C.[I:24]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[F:1][C:2]1[C:7]([I:24])=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15]
Reactant: N#Cc1c(F)cccc1-c1ccccc1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccccc2)ccc(I)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 243A (6.8 g, 34.5 mmol) in THF (110 mL) at −78° C. under nitrogen atmosphere was treated dropwise with LDA (2.0 M solution in THF) and stirred for 1 h, then a solution of iodine in THF (30 mL) was added via cannula over about 10 min. The thick mixture was allowed to warm to rt and stirred for 1 h, then treated with saturated aqueous Na2S2O3 solution (10 mL). The mixture was concentrated to remove the THF, then H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel, eluting with EtOAc/hexanes (1:7), and the resulting solid was triturated with hexanes and EtOAc to give the desired product (6.8 g). Rf=0.44 (7:1 hexane:EtOAc)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[C:13](O)=[N:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:13]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1cc(Cc2ccc(F)c(F)c2)cnc1O
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(Cc2ccc(F)c(F)c2)cnc1Cl
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[(3,4-difluorophenyl)methyl]-3-nitro-2-pyridinol (10.49 g, 39.40 mmol) and phosphorous oxychloride (18 ml) was heated at 110° C. for 4 h and allowed to stir at room temperature overnight. The reaction was quenched by diluting with EtOAc and carefully adding water. The organic layer was washed three times with a saturated solution of NaHCO3 in water, dried and concentrated in vacuo to afford the product as an amber oil. 1H NMR (CDCl3) δ 8.46 (1H, s), 7.95 (1H, s), 7.19-7.14 (1H, m), 7.00-6.96 (1H, m), 6.91-6.88 (1H, m), 4.03 (2H, s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].Cl.[CH3:14]O>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH3:14])=[O:8])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cccc(C(C)=O)c1
Reaction time: 48 h

Procedure:
A solution of 5 g of 3-acetylbenzoic acid in dry MeOH was saturated with hydrogen chloride gas. The reaction vessel was stoppered and kept at room temperature for 2 days. The MeOH was evaporated and the residue extracted into diethylether and clarified by filtration. The ether was evaporated and the dark oil was chromatographed through a short column of silica gel eluting with methylene chloride. The combined fractions were evaporated to dryness giving 4.25 g of a yellow oil that solidified on standing. The solid ester was used as obtained.
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:35]=[CH:34][C:26]([C:27]([O:29]C(C)(C)C)=[O:28])=[CH:25][CH:24]=5)[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.C(O)(C(F)(F)F)=O>>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:35]=[CH:34][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=5)[C:20]([CH3:36])=[CH:19][N:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 4-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate (68 mg, 0.13 mmol) DCM (1.42 mL) and TFA (1.00 mL) were added and stirred at room temperature for one hour. The DCM and TFA were evaporated under reduced pressure. The crude product was dissolved in DMSO (1 mL), filtered and purified by reverse phase preparative HPLC to yield 4-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoic acid. ESI-MS m/z calc. 453.1, found 454.3 (M+1)+. Retention time 1.62 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])=[C:4]([O:19][CH3:20])[CH:3]=1.C(O)CC#C.[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)#[CH:27]>>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:27]#[C:26][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:3][C:4]=1[O:19][CH3:20]
Reactant: C#Cc1ccccn1
Reactant: COc1cc(Br)ccc1Oc1ccc([N+](=O)[O-])cc1F
Agent: C#CCCO
Product: COc1cc(C#Cc2ccccn2)ccc1Oc1ccc([N+](=O)[O-])cc1F

Procedure:
According to the procedure of example 11 (a) except substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by 4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (0.29 mmol; 100 mg) and 3-butyn-1-ol by 2-ethynylpyridine (0.73 mmol; 73 μL), the title compound was prepared as a yellow solid (81%; mg) after purification on preparative TLC (cyclohexane/ethyl acetate: 7/3).
Reaction SMILES: CN(C)C=O.S(Cl)(Cl)=O.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20](=[O:24])[C:21]([OH:23])=[O:22])([O-:12])=[O:11]>>[OH:24][CH:20]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N+:10]([O-:12])=[O:11])[C:21]([OH:23])=[O:22]
Reactant: O=C(O)C(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(O)C(O)Cc1ccccc1[N+](=O)[O-]
Yield: 95 %

Procedure:
To magnetically stirred N,N-dimethylformamide (23 ml., 297.3 mmol) cooled in ice was slowly added dropwise thionyl chloride (139 ml., ca. 1.91 mol). A solution of (+)-α-hydroxy-2-nitrobenzenepropanoic acid [11.60 g., 54.9 mmol, [α]D25 +49.94° (c 2.465, 95% EtOH)], obtained from the chiral reduction of 2-nitro-α-oxobenzenepropanoic acid described in Example 1, in dichloromethane (133 ml.) was then added dropwise to the cold Vilsmeier reagent. The ice bath was removed and the solution, protected from moisture, was left at room temperature (25° C.) for 18 hours. The resulting yellow solution was evaporated to syrup. The syrup was dissolved in dichloromethane and the solution was poured cautiously onto stirred ice. The mixture was stirred for one hour during which time it warmed to room temperature. The organic phase was separated, washed (×3) with water and dried (MgSO4). Evaporation gave a syrup which was subjected to an oil pump vacuum for 0.5 hour. The syrup was dissolved in ether and 2,6-dimethylpiperidine was added to approximate neutrality (ca. pH 8 by pH paper). The crude titled compound (12.40 g., 66%) crystallized readily, m.p. 148°-153° C. Three crystallizations (with decolorization) from methanol-ether gave 6.01 g. (32% of pure product, m.p. 164°-167° C. dec., [α]D25 -41.49° (c 1.005, 95% EtOH).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[NH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30]O)[CH2:25][CH2:24]1.N1C=CN=C1>ClCCl>[NH2:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH2:30][Br:20])[CH2:25][CH2:24]1
Reactant: BrBr
Reactant: N[C@H]1CC[C@H](CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCBr)CC1
Reaction time: 18 h

Procedure:
The freshly prepared mixture of 1.45 g (5 eq.) triphenylphosphine and 0.28 ml (5 eq.) Br2 in 20 ml of dichloromethane was added to 1 g of the polymer-bound trans-2-(4-amino-cyclohexyl)-ethanol and 0.38 g (5 eq.) 1-H-imidazole. The suspension was shaken for 18 hours, filtered and the resin was washed in sequence with the following solvents (20 ml, twice with each): dichloromethane, methanol, 10% triethylamine in dimethylformamide, methanol, dimethylformamide, tetrahydrofuran, diethylether.
Reaction SMILES: [CH2:1]([CH:4]([C@H:12]([O:14]C(=O)CCCCCCCCCCC)[CH3:13])[C:5]([O:7][C:8](C)(C)C)=[O:6])[CH2:2][CH3:3].S(=O)(=O)(O)O.O>CO>[CH2:1]([CH:4]([C@H:12]([OH:14])[CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:2][CH3:3]
Reactant: CCCCCCCCCCCC(=O)O[C@H](C)C(CCC)C(=O)OC(C)(C)C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCCC(C(=O)OC)[C@@H](C)O
Yield: 64 %

Procedure:
A mixture of 4.5 g of t-butyl (3R)-2-propyl-3-dodecanoyloxybutanoate obtained in (1) above 45 ml of methanol and 0.5 ml of concentrated sulfuric acid was refluxed for 40 hours and 50 ml of water was added thereto followed by ether extraction. The ether phase was dried over anhydrous sodium sulfate, and ether was distilled away, and the residue was distilled and 1.2 g of methyl (3R)-2-propyl-3-hydroxybutanoate of the following formula was obtained. b.p. 76°-81° C. (5.0 mm Hg), [α]D26 =2.9°(C-1.37, CHCl3) ##STR79##
Reaction SMILES: [C:1]([Si:5]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C@H:7]1[CH2:12][C@H:11]2[CH2:13][C@@H:8]1[CH2:9][C@@H:10]2[OH:14])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Si:5]([O:6][C@H:7]1[CH2:12][C@H:11]2[CH2:13][C@@H:8]1[CH2:9][C:10]2=[O:14])([C:1]([CH3:4])([CH3:2])[CH3:3])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2O)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1CC2=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Silica gel 60 (particle size, 0.040-0.063 mm, CAS # 63231-67-4, from EMD Chemical Inc., 21 g) was added to a solution of (1R,2S,4R,5S)-5-(tert butyldiphenylsilyloxy)-bicyclo[2.2.1]heptan-2-ol (6.75 g, 18.4 mmol) in anhydrous dichloromethane (100 mL). The mixture was cooled to 0° C. Pyridinium chlorochromate (6.35 g, 29.5 mmol) was added to the mixture. The reaction mixture was gradually warmed to ambient temperature and stirred at this temperature for 16 h. The mixture was diluted with dichloromethane, and filtered through a pad of silica gel. Removal of the solvents gave the title compound as a colorless viscous oil.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.P(=O)(O)(O)O.[N+]([O-])(O)=O.N([O-])=O.[Na+].[BrH:29]>O>[Br:29][C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: CCOC(=O)c1sc(N)nc1C(F)(F)F
Reactant: Br
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CCOC(=O)c1sc(Br)nc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
To a solution of 4.5 g (0.0187 mole) of ethyl 2-amino-4-trifluoromethyl-5-thiazolecarboxylate in 50 ml. of 85% phosphoric acid at -10° C. was added 25 ml. of nitric acid. To this mixture was added dropwise at -10° C. to -5° C. a solution of 4.0 g (0.0579 mole) of sodium nitrite in 20 ml. of water in 30 minutes. This mixture was stirred for 10 minutes at -10° C. to -5° C. and poured into a solution of 2.70 g (0.0187 mole) of freshly prepared cuprous bromide in 20 ml. of hydrobromic acid. A vigorous evolution of gas occurred. The reaction mixture was stirred for 5 minutes and diluted with water. The solid suspension was filtered and air-dried to give 4.8 g of solid which was chromatographed on silica gel using ether/petroleum ether (1:4) as eluant. The first 1 liter of eluate gave 3.7 g of solid which was recrystallized from petroleum ether to give 2.9 g (51%) of the desired product as white needles, m.p. 75.5°-76.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14].N1CCCCC1.Cl>O.N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cc(C=O)ccc1O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C=CC(=O)O)ccc1O
Temperature: 60 °C
Reaction time: 22 h
Yield: 83.9 %

Procedure:
3-Methyl-4-hydroxybenzaldehyde (794 mg, 5.83 mmol), malonic acid (911 mg, 8.75 mmol) and piperidine (144 μl) were added to pyridine (5 ml), and the mixture was stirred at 60° C. for 22 hours under an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and water (20 ml) was added. 6N Hydrochloric acid was added to allow precipitation of a solid. The precipitated solid was collected by filtration, and the filtrate was washed with water and dried under reduced pressure. The obtained solid was recrystallized from diethylether-n-hexane to give 3-methyl-4-hydroxycinnamic acid (872 mg, yield 84.0%) as crystals.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CON(C)C(=O)c1nc2ccccn2c1Br
Product: CON(C)C(=O)c1nc2ccccn2c1-c1cccc(F)c1
Yield: 80 %

Procedure:
The desired compound was prepared according to the procedure of Example 1, step E, using 3-bromo-N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide and (3-fluorophenyl)boronic acid as the starting materials in 80% yield. LCMS for C16H15FN3O2 (M+H)+: m/z=300.1.