Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C@@H:6]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH2:7][N+:8]([O-])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O.Cl>O1CCCC1.C(OC(C)C)(C)C>[NH2:8][CH2:7][C@H:6]([C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[OH:17])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=1
Reactant: O=C1CCCCC1[C@@H](C[N+](=O)[O-])c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](c1ccc(F)cc1)[C@H]1CCCC[C@H]1O
Reaction time: 15 h

Procedure:
A solution of 105 g (0.4 mol) of rac-(2S*)-2-[(R*)-4-fluoro-α-(nitromethyl)benzyl]cyclohexanone in 1 l of dry tetrahydrofuran is added dropwise while stirring to a suspension of 38 g (1 mol) of lithium aluminum hydride in 500 ml of dry tetrahydrofuran under argon so that the temperature does not exceed 50°. The reaction mixture is stirred at 50° for 15 hours, cooled and then treated with tetrahydrofuran/water (1:1). The separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is distilled. The oil obtained is treated with 3N hydrochloric acid, extracted twice with 500 ml of ether each time, the aqueous phase is made alkaline with ammonia and extracted with ether. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The oil obtained is dissolved in 250 ml of isopropyl ether, whereupon the solution is left to stand in a refrigerator overnight for crystallization. There is obtained rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-4-fluorobenzyl]cyclohexanol in the form of colourless crystals of m.p. 75°-76°. The rac-(1S*)-cis-2-[(R*)-α-(aminomethyl)-4-fluorobenzyl]cyclohexanol hydrochloride prepared in the usual manner is recrystallized from ethanol/ether; there are obtained colourless crystals of m.p. 233°-234°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ncccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Temperature: 25 °C
Yield: 52.9 %

Procedure:
A stirring solution of 240 mg (1.03 mmol) of 3-Methyl-1 tert-butoxycarbonyl-pyrazolo[3,4-b]pyridine, prepared as in Part B, in 10 mL of CCl4 is heated to reflux, and then a mixture of 220 mg (1.23 mmol, 1.2 equiv) of N-bromosuccinimide and 25 mg (0.10 mmol, 0.1 equiv) of benzoyl peroxide is added all at once as a solid. The resulting solution is heated at reflux for 3.5 h, then cooled to RT. The reaction mixture is filtered through a pad of Celite to remove the precipitated succinimide, and the solvent is removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 3/1 as eluent afforded 170 mg of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) δ8.75 (dd, 1H, J=1.4, 4.6), 8.21 (dd, 1H, J=1.4, 8.0), 7.32 (dd, 1H, J=4.6, 8.0), 4.74 (s, 2H), 1.70 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1[CH:8]=O.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[OH:1][CH2:2][CH:3]([CH2:21][OH:22])[CH2:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][C:7]=1/[CH:8]=[CH:24]/[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[O:25]
Reactant: COc1cc(OCC(CO)CO)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OCC(CO)CO)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Yield: 61 %

Procedure:
The title compound was prepared by condensing 2-(3-hydroxy-2-hydroxymethyl-propoxy)-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-64B) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Light orange solid, mp 219–220° C., 61% yield. 1H-NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.20 (d, 2H, J=7.5 Hz), 8.05–8.11 (m, 3H), 7.93 (d, 1H, J=16.2 Hz), 7.67 (d, 1H, J=3.0 Hz), 7.52 (d, 1H, J=5.1 Hz), 7.13 (dd, 1H, J=5.1, 3.0 Hz), 6.88 (s, 1H), 4.66 (brs, 2H), 4.23 (d, 2H, J=6.3 Hz), 4.01 (s, 3H), 3.55–3.66 (m, 4H), 2.09–2.14 (m, 1H). MS (ESI) m/z=469 ([M+H]+, 100%). Anal. Calcd. for C25H24O7S.H2O: C, 61.72; H, 5.39; S, 6.59. Found: C, 61.93; H, 5.30; S, 7.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([C:15](=O)[CH2:16][CH2:17][CH3:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH3:26])[N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([CH2:16][CH2:17][CH3:18])[NH:20][C:21]2=[N:22][N:23]([CH3:26])[CH:24]=[C:25]12
Reactant: Cn1ccc(N)n1
Reactant: CCCC(=O)C(=Cc1ccccc1Cl)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2Cl)c2cn(C)nc2N1

Procedure:
A solution of ethyl 3-ketohexanoate (7.5 g), 2-chlorobenzaldehyde (6.6 g), piperidine (1.2 g) and acetic acid (2.25 g) in benzene (50 ml) was heated under reflux for 5 hours, and the reaction mixture was dehydrated using a Dean-Stark condenser. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an eluent (hexane-ethyl acetate (3:1)) to give ethyl 2-(2-chlorophenyl)methylen-3-oxohexanoate ((E)/(Z)=1:1 mixture) as a yellow oil. A solution of ethyl 2-(2-chlorophenyl)methylene-3-oxohexanoate ((E)/(Z)=1:1 mixture, 2.8 g), 3-amino-1-methylpyrazole (0.25 g) and p-toluenesulfonic acid (25 mg) in toluene (5 mL) and dimethylsulfoxide (0.5 mL) was heated under reflux for one day. The solvent was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate (10 mL) and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil. The obtained oil was purified by silica gel column chromatography (eluent (ethyl acetate-methanol (10:1))) to give the title compound as colorless crystals.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([NH2:10])[CH:2]=1.[P:11](=[O:15])([OH:14])([OH:13])[OH:12]>[F-].Cl>[P:11]([O-:15])([O-:14])([O-:13])=[O:12].[CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([NH2:10])[CH:2]=1
Reactant: O=P(O)(O)O
Agent: Cl
Agent: Nc1ccc(C(=O)O)cc1
Agent: [F-]
Product: O=P([O-])([O-])[O-]

Procedure:
FIG. 2 presents the TEM image of a PABA dispersion prepared in 0.1 M phosphoric acid and fluoride. The PABA dispersion was purified and re-dispersed in the 0.1 M phosphoric acid without fluoride. The morphology of PABA prepared in 0.1 M phosphoric acid and fluoride is somewhat similar to that obtained in 0.1 M HCl and fluoride. In 0.1 M HCl solution and fluoride, spherical nanoparticles with diameter in the range of 2-15 nm are obtained.28 However, phosphate doped and complexed PABA produces irregular shape particles with size range 25-50 nm (FIG. 2). The difference observed in the size and shape of PABA prepared in phosphoric acid can be attributed to the boron-phosphate complexation.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCOCC1

Procedure:
Using 4-nitro-benzoic acid (334 mg) instead of 3-nitro-benzoic acid, and morpholine (209 μl) instead of 1-ethyl-piperazine, in the same manner as Step A in Example 1-D-101, the desired compound was obtained (363.5 mg, 77%).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.O.[CH2:11]([NH2:14])[CH:12]=[CH2:13].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:11]([NH:14][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)[CH:12]=[CH2:13]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCNc1nc(Cl)nc(Cl)n1

Procedure:
18.5 parts of cyanuric chloride were dissolved in 100 parts of acetone and added, while stirring, to a mixture of 300 parts of water and 400 parts of crushed ice. The suspension thus obtained was added to 5.7 parts of allylamine over a period of 30 minutes and subsequently to an aqueous solution of 5.3 parts of sodium carbonate. The white crystalline reaction product was suction-filtered, washed several times with iced water, and dried over phosphorus pentoxide.
Reaction SMILES: CC1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Cl:22])=[CH:16][CH:15]=3)[N:9]=2)C(C)=CC=1.C(O)C.Cl.NO>O>[ClH:22].[Cl:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:10]2[N:9]=[C:8]([NH2:3])[CH:13]=[CH:12][CH:11]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C)n1-c1cccc(-c2ccc(CCCl)cc2)n1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Nc1cccc(-c2ccc(CCCl)cc2)n1
Yield: 199.8 %

Procedure:
To a 500 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 9.0 g (29.0 mmol) 2-(2, 5-dimethylpyrrol-1-yl)-6-(4-(2-chloroethyl)phenyl)-pyridine, 250 mL ethanol, 50 mL water, and 10.1 g (145 mmol) hydroxylamine hydrochloride. The reaction was refluxed for 36 hours, cooled, and the solvent was evaporated. The residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using 2% methanol in methylene chloride as eluant to afford 7.8 g (88%) of the product as a light brown solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[C:10]([Mg]Cl)#[CH:11]>O1CCCC1>[CH3:6][C:5]([OH:7])([CH:4]=[CH:3][CH:2]([CH3:1])[CH2:8][CH3:9])[C:10]#[CH:11]
Reactant: CCC(C)C=CC(C)=O
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(C)(O)C=CC(C)CC
Yield: 83 %

Procedure:
126 g (1 mole) of 5-methyl-hept-3-en-2-one are added in the course of 1 hour, with stirring, to 1 liter of a 1.1 molar solution of ethynyl-magnesium chloride in tetrahydrofuran, at 10° C. After allowing about a further hour for reaction, the mixture is worked up similarly to Example 1. 126 g of 3,6-dimethyl-oct-4-en-1-yn-3-ol, of boiling point 41° C./0.05 mbar and nD25 =1.4514, are obtained. This corresponds to a yield of 83% of theory. Scent: woody, herbal, fatty.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([C:8]1[N:9]=[N+:10]([O-:23])[C:11]2[CH:20]=[C:19]3[C:15]([CH2:16][CH:17]([CH2:21]O)[CH2:18]3)=[CH:14][C:12]=2[N:13]=1)[CH3:7].CCN(C(C)C)C(C)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C(Cl)Cl.CN(C=O)C.CCOC(C)=O.O>[CH2:6]([C:8]1[N:9]=[N+:10]([O-:23])[C:11]2[CH:20]=[C:19]3[C:15]([CH2:16][CH:17]([CH2:21][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:18]3)=[CH:14][C:12]=2[N:13]=1)[CH3:7]
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CN1CCOCC1)C3
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Methanesulfonyl chloride (0.14 mL, 1.7 mmol) was added drop-wise to a stirred solution of alcohol 142 (347 mg, 1.42 mmol) and iPr2NEt (0.49 mL, 2.84 mmol) in DCM (25 mL) at 0° C., and the solution was stirred at 0° C. for 1 h. Water (25 mL) was added and the mixture extracted with EtOAc (3×30 mL). The organic fraction was washed with dilute Na2CO3 solution (25 mL) and water (25 mL). The organic solution was dried and the solvent evaporated to give a yellow solid, which was treated with morpholine (0.37 mL, 4.3 mmol) in DMF (10 mL) at 100-110° C. for 10 h. The solution was diluted with EtOAc (200 mL) and washed with Na2CO3 solution (50 mL) and water (30 mL). The organic solution was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (50-70%) of EtOAc/pet. ether, to give 1-oxide 143 (398 mg, 89%) as a pale yellow solid: mp (EtOAc) 111-112° C.; 1H NMR δ 8.24 (s, 1H, H-9), 7.73 (s, 1H, H-5), 3.73 (t, J=4.6 Hz, 4H, 2×CH2O), 3.19-3.29 (m, 2H, CH2), 3.02 (q, J=7.6 Hz, 2H, CH2), 2.88-2.99 (m, 2H, CH2), 2.77-2.88 (m, 1H, H-7), 2.47 (t, J=4.6 Hz, 4H, 2×CH2N), 2.38 (d, J=7.6 Hz, 2H, CH2), 1.43 (t, J=7.6 Hz, 3H, CH3); 13C NMR δ 167.1, 153.6, 147.7, 147.6, 132.3, 123.1, 114.7, 67.0 (2), 63.3, 53.9 (2), 37.6, 37.3, 36.7, 30.6, 12.3. Anal. calcd for C17H22N4O2: C, 65.0; H, 7.1; N, 17.8. Found: C, 64.9; H, 7.1; N, 17.9%.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:16][OH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([C:40](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:38][CH:37]=1>O1CCCC1.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:14][O:15][C:40]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:39]2[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:57][CH:56]=2)([CH2:16][OH:17])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
To a solution of nucleoside 1-(3-O-Benzyl-4-C-hydroxymethyl-β-D-xylofuranosyl)thymine 5 (5.38 g, 14.2 mmol) in anhydrous tetrahydrofuran (400 cm3) was added AgNO3 (2.66 g, 15.7 mmol) followed by anhydrous pyridine (5.7 cm3) and 4,4′-dimethoxytrityl chloride (5.30 g, 15.6 mmol). The mixture was stirred in the dark under nitrogen for 18 h at room temperature. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogen carbonate (10 cm3) and the resulting mixture was extracted with dichloromethane. The combined organic phase was evaporated to dryness under reduced pressure and the residue was co-evaporated with toluene and was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.5% methanol; 0.5% pyridine, v/v) as eluent to afford nucleoside 6 (3.13 g, 31%) as a white foam after evaporation of the solvents. δC ((CD3)2SO) 164.1 (C-4), 158.4, 145.1, 138.5, 137.0, 135.9, 135.7, 130.1, 130.1, 129.2, 128.5, 128.5, 128.2, 128.1, 127.7, 127.6, 127.0, 125.7, 113.5 (DMT, benzyl, C-6), 151.4 (C-2), 110.1 (C-5), 85.8, 85.2, 84.6, 83.5 (C-1′, C-3′, C-4′, DMT), 76.8 (C-2′), 72.3 (CH2Ph), 65.2 (C-5″), 62.1 (C-5′), 55.4 (2× CH3O), 12.6 (5-CH3).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2].[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1>[CH:1]([O:4][C:5](=[O:23])[NH:6][C:7]1[CH:8]=[C:9]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:24](=[O:26])[CH3:25])[CH:17]=3)[NH:13][C:10]2=[N:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)OC(=O)Nc1cnc2[nH]c(-c3cccc(N)c3)nc2c1
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-c2nc3cc(NC(=O)OC(C)C)cnc3[nH]2)c1

Procedure:
10 mg of the product from example 5-1 were dissolved in 1 ml dry pyridine and 7 μl acetyl chloride were added at room temperature. After stirring over night, the solvent was evaporated and the residue dissolved in 3 ml methanol. 1 ml conc. ammonia were added and the mixture stirred for 1 hr at room temperature.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17](OC)=[O:18].C1(C)C=CC=CC=1.C([Al]C(C)C)(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.CCOCC>[OH:18][CH2:17][C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2
Reactant: COC(=O)c1cc2c(OC)c(OC)c(OC)cc2n1C
Agent: CC(C)[Al]C(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc2c(cc(CO)n2C)c(OC)c1OC
Reaction time: 1 h

Procedure:
Methyl 1-methyl-4,5,6-trimethoxyindole-2-carboxylate (1.17 g) was dissolved in dry THF under an argon atmosphere at 0° C., a 1 M toluene solution (13.2 mL) of diisopropylaluminum bydride was added dropwise to the solution, and the mixture was stirred for 1 hour as it is. The reaction mixture was diluted with ether, the sodium sulfate decahydrate was added thereto, and the mixture was stirred further for 1 hour. After the reaction mixture was filtered, and the filtrate was concentrated, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2 to 1:1) to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:26](O)=[O:27].C(OC(=O)C)(=O)C>O1CCCC1>[CH2:24]([O:23][C@@H:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH:26]=[O:27])=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])[CH3:25]
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Reactant: O=CO
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.115 g, 0.314 mmole) in tetrahydrofuran (3 ml) was mixed with a mixture of formic acid (0.5 ml) and acetic anhydride (0.3 ml). The resulting mixture was stirred at room temperature overnight. Tetrahydrofuran was evaporated. Ethyl acetate and water were added into the residue. The phases were separated. The organic phase was washed with brine, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane, then methanol/dichloromethane (1%), followed by methanol/dichloromethane (2%) as eluants gave 0.07 g (yield 62%) of (S)-2-ethoxy-3-(4-{[4-(formylamino)phenethyl]oxy}phenyl)propanoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH:5][C:6]=1[Cl:7].CC(C)([O-])C.[K+].[CH2:24]([O:26][CH2:27]Cl)[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[C:3]([C:16]#[N:17])=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]([CH2:27][O:26][CH2:24][CH3:25])[C:6]=1[Cl:7]
Reactant: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Cl)c1Cl
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A sample of 4,5-dichloro-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (1.0 g, 0.003 mole) is dissolved in 10 mL of dry tetrahydrofuran. To this solution is added potassium t-butoxide (0.37 g, 0.0033 mole) followed by chloromethyl ethyl ether (0.312 g, 0.0033 mole) The mixture is stirred for about 1 hour at room temperature and then poured into a large volume of water precipitating the product. The white solid is collected and dried to give 1.0 g (91%) with m.p. 128°-130°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][C:2]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: [Mo]
Agent: O=C([O-])[O-]
Agent: [C-]#[O+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(Oc2ccc(C(F)(F)F)nc2)cc1

Procedure:
2.5 g of 5-bromo-2-(trifluoromethyl)pyridine, 5.8 g of 4-hydroxybenzonitrile, 10.8 g of caesium carbonate and 1.87 g of molybdenum hexacarbonyl in 100 ml 1,4-dioxan were heated under reflux until complete conversion. The reaction mixture was diluted with water, extracted several times with ethyl acetate, and the combined organic phases washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by column chromatography on silica gel using a hexane/ethyl acetate gradient. Yield: 1.35 g of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[OH:52][CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1.CCN(C(C)C)C(C)C>C1COCC1>[OH:52][CH:53]1[CH2:58][CH2:57][N:56]([C:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])[CH2:55][CH2:54]1
Reactant: OC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)s2)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)N3CCC(O)CC3)s2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
5-[2-(Acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-carboxylic acid, Compound (4) (50 mg; 0.18 mmol; 1 eq.), is dissolved in THF (8 ml). PyBOP (138.2 mg; 0.27 mmol; 1.50 eq.), 4-hydroxypiperidine (53.7 mg; 0.53 mmol; 3 eq.) and DIEA (0.06 ml; 0.35 mmol; 2 eq.) are added successively. The reaction mixture is stirred at room temperature for 2 hours. The solvents are evaporated and the crude product is suspended in MeCN, filtered and washed several times with MeCN, affording Compound (7) as brown solid (15.2 mg; 23%). 1H NMR (DMSO-d6) δ 1.30-1.45 (m, 2H), 1.72-1.85 (m, 2H), 2.14 (s, 3H), 2.42 (s, 3H), 3.25-3.38 (m, 2H), 3.75 (m, 1H), 3.85-4.02 (m, 2H), 4.80 (d, J=6 Hz, 1H), 7.13 (d, J=6 Hz, 1H), 7.36 (d, J=6 Hz, 1H), 12.18 (br s, 1H). M−(ESI): 364.12; M+(ESI): 366.10. HPLC, Rt: 2.35 min (purity: 97.9%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].[CH2:11]([O:13][C:14](=[O:20])[C:15](OCC)=[O:16])[CH3:12].CC[O-].[Na+]>CCO>[CH2:11]([O:13][C:14](=[O:20])[C:15]([CH:6]1[CH2:7][CH2:8][C:4]([CH3:10])([CH3:3])[C:5]1=[O:9])=[O:16])[CH3:12]
Reactant: CC1(C)CCCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCC(C)(C)C1=O
Temperature: 25 °C

Procedure:
Sodium hydride (0.428 g, 17.8 mmol) was added slowly to a NaCl ice bath containing EtOH (5.4 mL, 3.3 M) stirring under N2. 2,2-dimethylcyclopentanone (2.00 g, 17.83 mmol) and diethyloxalate (2.42 mL, 17.8 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred for 6 hours, at which point the reaction was judged complete by TLC. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield 3.4084 g (90.0%) of crude 2 that was sufficiently pure by NMR to go on to the next step without further purification. Note: NaOEt purchased from Aldrich may be substituted for the NaOEt synthesized in situ. 1H (CDCl3, 400 MHz): δ 4.29 (2H, q, J=7.3 Hz), 2.82 (2H, t, J=7.3 Hz), 1.76 (2H, t, J=7.3 Hz), 1.32 (3H, t, J=7.3 Hz), 1.07 (6H, s) ppm. 13C (CDCl3, 100 MHz): δ 218, 162.89, 153.15, 115.98, 62.12, 46.16, 36.39, 23.98, 23.87, 14.22 ppm.