Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[NH3:21]>CO>[NH2:21]/[C:17](/[CH3:18])=[CH:16]\[C:15]([NH:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[C:2]([Cl:1])[CH:3]=1)=[O:20]
Reactant: N
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Solvent: CO
Product: C/C(N)=C/C(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloro-4-morpholinophenyl)-3-oxobutanamide (2.0 g, 6.74 mmol), MeOH (15 mL) and ammonia (15 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [CH3:1][N-:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:7].[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20]>C(OCC)(=O)C>[C:18]([O-:23])(=[O:22])[C:19]([O-:21])=[O:20].[CH3:1][N-:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(O)C(=O)O
Agent: C[N-]c1cccc(C(=O)C2CCN(C)CC2)c1
Solvent: CCOC(C)=O
Product: O=C([O-])C(=O)[O-]

Procedure:
4-[3-(methylamidyl)benzoyl]-1-methylpiperidine (283 mg, 1.1 mmol) in ethyl acetate was added to oxalic acid (99 mg, 1.1 mmol) in ethyl acetate. The resulting precipitate was filtered, washed with ethyl acetate, and dried under vacuum to give 270 mg (71%) of tan powder.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClC(Cl)C.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CC(Cl)Cl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.35 g) in dichloroethane (10 ml) was added rhodium acetate (1 mg) under reflux in a nitrogen stream. The mixture was refluxed for 30 minutes and concentrated under reduced pressure to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in acetonitrile (10 ml). To the solution was added diphenyl phosphorochloridate (0.20 ml) at -10°~5° C. in nitrogen stream and dropwise added N,N-diisopropyl-N-ethylamine (0.20 ml) at the same condition. The mixture was stirred at the same condition for 1 hour. To the solution were added N,N-diisopropyl-N-ethylamine (0.2 ml) and then a solution of (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.46 g) in acetonitrile (2 ml) at -20° C. The mixture was stirred at the same temperature for 30 minutes and then at 0°-10° C. for 3 hours. The mixture was poured into a mixture of water (60 ml) and ethyl acetate (90 ml). The organic layer was washed with water (90 ml×2) and brine (90 ml) successively, dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of acetone and dichloromethane (5:95, 10:90, and 15:85, in turn) to give 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-{2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl}pyrrolidin-4-yl]thio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.45 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9].[K].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14]>C(#N)C>[O:14]=[C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:12][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: N#CN=C1CCCCN1
Agent: [K]
Solvent: CC#N
Product: Cc1ccc(C(=O)CN2CCCCC2=NC#N)cc1
Yield: 59.5 %

Procedure:
A suspension of N-(piperidin-2-ylidene)cyanamide (1.23 g; 10 mmol) in acetonitrile (20 mL) was heated gently until dissolution and then potassium hydrogenocarbonate (1.66 g; 12 mmol) and 2-bromo-1-p-tolylethanone (2.98 g; 14 mmol) were added. The well stirred mixture was heated at reflux for 21 h and an extra amount of 2-bromo-1-p-tolylethanone (0.426 g; 2 mmol) was then added. The reaction mixture was heated for 6 additional hours. After cooling, the precipitate was filtered, washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (1-20%) in dichloromethane to furnish 1.52 g (59%) of N-(1-(2-oxo-2-p-tolylethyl)piperidin-2-ylidene)cyanamide as an orange solid. ESI/APCI(+): 256 (M+H). 1H NMR (CDI3) δ 7.83 (d, J=8.22 Hz, 2H, Harom.); 7.29 (d, J=8.04 Hz, 2H, Harom.); 4.89 (s, 2H, COCH2); 3.43 (m, 2H, CH2); 2.89 (m, 2H, CH2); 2.43 (s, 3H, CH3); 1.92 (m, 4H, 2×CH2).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.O=S(Cl)Cl.Cl.[NH2:22][C:23]([NH2:25])=[NH:24]>[OH-].[Na+].C1COCC1>[ClH:13].[Cl:13][C:9]1[CH:8]=[C:7]([N:6]2[C:2]([CH3:1])=[C:3]([C:14]([NH:24][C:23]([NH2:25])=[NH:22])=[O:16])[CH:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: N=C(N)N
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1c(C(=O)NC(=N)N)cnn1-c1cccc(Cl)c1
Yield: 12.7 %

Procedure:
A mixture of 5-methyl-1-(3-chlorophenyl)pyrazole-4-carboxylic acid (234 mg, 1.0 mmol) and 5 ml SOCl2 was heated to reflux for 45 min. Excess SOCl2 was removed in vacuo via codistillation with toluene. The residue was dissolved in 2mL of anhydrous THF and added dropwise over 30 minutes to a vigorously stirred 40° C. solution of guanidine hydrochloride (344 mg, 3.6 mol) in 3.25 mL 2 N NaOH and 1.9 mL THF. The resulting mixture was heated to reflux for 4 hours and then cooled. The organic solvent was removed in vacuo. The residue was diluted with 10 mL 1 N NaOH and extracted with 5×5 mL EtOAc. The combined organic layers were dried (Na2SO4) filtered and concentrated in vacuo to a white solid. This material was dissolved in 1 mL MeOH and 18.4 μL 12 N HCl was added with stirring. The solvents were removed in vacuo with toluene azeotropes and the resulting solid was stirred in 1 mL ether/acetone (1:1) and filtered to remove residual H2O. Drying under high vacuum at 40° C. afforded the desired product (20 mg, 6%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.CC1N=C(N[CH2:45][CH2:46][OH:47])SC=1C1C=CN=C(NC2C=CC=C([N+]([O-])=O)C=2)N=1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:10]2[N:9]=[C:8]([C:4]3[S:3][C:2]([NH:1][CH2:45][CH2:46][OH:47])=[N:6][C:5]=3[CH3:7])[CH:13]=[CH:12][N:11]=2)=[CH:16][CH:17]=1
Reactant: Cc1nc(NCCO)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Product: Cc1nc(NCCO)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
This compound was prepared from [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine in a manner analogous to that described for compound [58]. 1H-NMR (DMSO-d6) δ: 2.44 (s, 3H, CH3), 3.54 (m, 2H, CH2), 4.78 (m, 2H, CH2), 6.87 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 7.09 (m, 2H, Ph-H), 7.75 (m, 2H, Ph-H), 8.30 (d, 1H, J=5.2 Hz, pyrimidinyl-H), 8.11 (m, 1H, NH), 9.43 (s, 1H, NH). DE MALDI-TOF MS: [M+H]+=345.79 (C16H16FN5OS requires 345.40).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:10]([C:14]([OH:16])=O)[C:11](O)=[O:12].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]([C:14]([Cl:19])=[O:16])=[C:11]=[O:12]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)c(C(C(=O)O)C(=O)O)cc1C
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(C(=C=O)C(=O)Cl)cc1C
Temperature: 95 °C

Procedure:
30 g of 2-(2,4,5-trimethylphenyl)-malonic acid were suspended in 60 ml of toluene at 50 to 60° C. and 62.5 ml of thionyl chloride were added dropwise. The mixture was then heated at 90 to 100° C. for 15 hours. It was then cooled, the volatile constituents were driven off with an inert gas and the excess thionyl chloride was distilled off. 30.6 g of 2,4,5-trimethylphenylchlorocarbonyl ketene were isolated as the residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[O:16][Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:7]=[CH:6][C:5]=1[OH:16]
Reactant: COC(=O)c1cc(N2CCOCC2)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyloxy)-5-morpholin-4-yl-benzoic acid methyl ester (1.0 g, 2.8 mmol) in tetrahydrofuran (35 mL) was treated with tetrabutylammonium fluoride (3.55 g, 11.25 mmol) and stirred for 2 h at room temperature. The reaction mixture was concentrated and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 80/20 hexanes/EtOAc) to yield the final product as a yellow solid (206 mg, 31%).
Reaction SMILES: CS(C1C=CC(N2CCCC2)=C(C=1)C(O)=O)(=O)=O.Cl[C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([OH:24])=[O:23].[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][NH:36][CH2:35]1>>[OH:33][CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:20]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])[CH2:35]1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: OC1CCCNC1
Agent: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(N2CCCC(O)C2)c(C(=O)O)c1
Yield: 9 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example Y) from 2-Chloro-5-methanesulfonyl-benzoic acid and rac-3-hydroxy-piperidine and obtained in 9% yield. MS (m/e): 298.1 (M−H 100%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:23][C:24]1[O:25][CH:26]=[C:27]([C:29](OC)=[O:30])[N:28]=1>C1COCC1>[OH:30][CH2:29][C:27]1[N:28]=[C:24]([CH2:23][N:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:20])([F:22])[F:21])=[CH:16][CH:17]=4)[CH:10]=3)[NH:5][CH2:4]2)[O:25][CH:26]=1
Reactant: COC(=O)c1coc(Cn2cnc3ccc(-c4ccc(OC(F)(F)F)cc4)cc3c2=O)n1
Solvent: C1CCOC1
Product: O=C1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2NCN1Cc1nc(CO)co1
Reaction time: 1 h

Procedure:
To a solution of methyl 2-((4-oxo-6-(4-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)methyl)oxazole-4-carboxylate Compound 177-A (200 mg) in THF (5 mL) lithium borohydride was added (10 mg) and stirred for 1 hour. Quenched with saturated ammonium chloride and extracted with dichloromethane. Purified by gradient chromatography 0 to 5% MeOH in dichloromethane and resulting 3-((4-(hydroxymethyl)oxazol-2-yl)methyl)-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydroquinazolin-4(1H)-one Compound 177-B (130 mg) submitted into next step. 1H NMR (δ, dmso-d6, 400 MHz): 7.92 (d, 1H); 7.86 (s, 1H); 7.71 (d, 2H); 7.65 (dd, 1H); 7.38 (d, 2H); 7.03 (br s, 1H); 6.85 (d, 1H); 5.14 (t, 1H); 4.74 (s, 4H); 4.32 (d, 2H). 19F NMR (δ, dmso-d6, 376 MHz): −57.29 (s). MS m/z (ESI)=420.1 (base peak, M+H+); 861.2 (2M+Na+).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][C:15]2[C:23]3[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=3[NH:17][C:16]=2[CH:24]=[O:25])[CH2:8][CH2:7]1)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH:24]([C:16]1[NH:17][C:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:23]=2[C:15]=1[CH2:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:26])=[O:3])[CH2:7][CH2:8]1)=[O:25]
Reactant: CCOC(=O)CN1CCN(CCCc2c(C=O)[nH]c3c2CCCC3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=Cc1[nH]c2c(c1CCCN1CCN(CC(=O)O)CC1)CCCC2

Procedure:
{(4-[3-(2-Formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid ethyl ester (80 mg), prepared as described in example 17, was treated with potassium carbonate (38 mg, 1 mmol) in methanol/water (6/1) at room temperature for over night. The reaction solution was rotary evaporated and the residue was washed with dichloromethane/methanol (10/1) 3 times. The combined organic solution was concentrated till dryness to give {(4-[3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-piperazin-1-yl}-acetic acid.
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1)([S:4]([O:7][CH2:8][CH3:9])(=[O:6])=[O:5])[CH3:3].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(=O)C1C=CC=CC=1>[CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][Br:17])=[CH:12][CH:11]=1)([S:4]([O:7][CH2:8][CH3:9])(=[O:5])=[O:6])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOS(=O)(=O)C(C)(C)c1ccc(C)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Product: CCOS(=O)(=O)C(C)(C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 105.4 %

Procedure:
To a solution of ethyl 1-methyl-1-(4-methylphenyl)ethanesulfonate (0.458 g, 1.89 mmol) in carbon tetrachloride (8 mL) was added N-bromosuccinimide (0.370 g, 2.08 mmol) and benzoyl chloride (0.009 g). The mixture was heated under reflux for 1.5 hours, cooled to rt, and filtered. The filtrate was washed with aqueous sodium bicarbonate and brine, dried, filtered and evaporated to give crude ethyl 1-methyl-1-(4-bromomethylphenyl)ethanesulfonate (0.64 g, 100%) which was used directly in the next reaction.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][N:5](S(C1C=CC=CC=1)(=O)=O)[CH2:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[ClH:26]>C1(C)C=CC=CC=1.C1COCC1>[ClH:26].[CH3:1][N:2]1[CH:7]2[CH2:8][O:9][CH2:10][CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CN1C2COCC1CN(S(=O)(=O)c1ccccc1)C2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1C2CNCC1COC2
Temperature: 110 °C
Yield: 43 %

Procedure:
To a solution of 112g (1.5 g, 5.3 mmol) in a mixture of toluene (15 ml) and THF (15 ml) was added LiAlH4 (0.42 g, 10.8 mmol). The reaction mixture was heated at 110° C. overnight. Then it was poured into HCl (2 mol/l). The organic layer was partitioned and the water layer was evaporated to dryness and dissolved in methanol. The resulting suspension was filtered and the filtrate was evaporated to give 112h (800 mg, 43%) as a colorless oil. MS: [M+H]+: 143
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[CH3:18][O:19][CH2:20]Cl.O>C1COCC1>[CH3:18][O:19][CH2:20][O:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc2ccccc2cc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1cc2ccccc2cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-hydroxy-2-naphthoate (7.01 g) in THF (200 ml) was cooled to 0° C., to which was added 60% sodium hydride (1.58 g) during 10 minutes. Then, the mixture was stirred for one hour at room temperature, to which was added dropwise chloromethyl methyl ether (2.8 ml). The mixture was then stirred for two hours, to which was added water to quench the reaction, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), and distilled off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give methyl 3-methoxymethoxy-2-naphthoate (7.11 g) (Compound B-19). The physical properties are shown in Table 7.
Reaction SMILES: [CH:1]([C:4]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][O:17]C)=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].O.I>CC#N.CCOC(C)=O>[CH:1]([C:4]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=[O:17])=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C=COC)ccc1C(C)C
Agent: I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cc(CC=O)ccc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Compound 1 (25.62 g, 103.2 mmol) was dissolved in CH3CN (370 mL) at room temperature under nitrogen. H2O (15.5 mL) and a 57% aqueous solution of HI (14.7 mL) were added. The reaction solution was stirred at room temperature for 1 hour, and then was diluted with EtOAc (1000 mL), washed with H2O (400 mL), 0.25N Na2S2O3 (400 mL), H2O (400 mL), and saturated aqueous NaCl (400 mL), dried over Na2SO4, filtered, evaporated, and dried under vacuum to afford 24.31 g (100%) of Compound 2 as a yellow oil, which was used without further purification. The following values were obtained by nuclear magnetic resonance spectroscopy:
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.O.[Br:16]Br.S([O-])(O)=O.[Na+]>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[Br:16][C:2]1[C:1](=[O:14])[C:13]2[C:5](=[CH:4][CH:3]=1)[C:6]1[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=2
Reactant: BrBr
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C(Br)=CC=C2C1=Cc1ccccc12
Reaction time: 12 h
Yield: 92.9 %

Procedure:
In a three-liter flask having four openings equipped with a stirrer, a thermometer, a dropping funnel, and a reflux condenser, respectively, 256 g (1.4 mol) of fluorenone, 1 L of water, three drops of a surfactant, and five drops of sulfuric acid were placed and stirred to mix. By adding 250 g (1.6 mol) of bromine into the mixture, a reaction was started. After the reaction had been conducted at 50° C. for 12 hours, unreacted bromine was decomposed with an aqueous solution of sodium hydrogen sulfite. The reaction product, which was a dark yellow solid, was filtered and thus 365 g of a crude product was obtained. The crude product was dissolved in toluene and was subsequently washed with water and a sodium hydrogencarbonate aqueous solution. The resulting organic liquid was dried using anhydrous magnesium sulfate. After filtration, the liquid was concentrated and then allowed to stand at 0° C., so that a yellow solid was precipitated. The precipitate was filtered and subsequently washed with toluene, followed by drying. Thus, 339 g (1.3 mol, yield of 92%) of a yellow solid product was obtained. This product was subjected to gas chromatography and the purity of the product was 99.4%.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([NH:17]C(=O)OC(C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:5]=[N:4][CH:3]=1.CC1N(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)C=CN=1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[C:9]([NH2:17])[CH:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Product: Cc1cncn1-c1cc(N)cc(C(F)(F)F)c1

Procedure:
Utilising the procedure described in Example 91d, but employing [3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 93c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 131–133° C.
Reaction SMILES: II.[CH2:3](Br)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH:22]([O:24][CH2:25][CH3:26])=[O:23].OS(O)(=O)=O>CCOCC>[CH:22]([O:24][CH:25]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:26][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:23]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCBr
Reactant: CCOC=O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.9 %

Procedure:
To a suspension of Mg turnings (1.64 g, 67.4 mmol) with one crystal of iodine in 500 mL of anhydrous ether under nitrogen was added a solution of linoleyl bromide (II, 18.5 g, 56.1 mmol) in 250 mL of anhydrous ether at room temperature. The resulting mixture was refluxed under nitrogen overnight. The mixture was cooled to room temperature. To the cloudy mixture under nitrogen was added dropwise ethyl formate (4.24 g, 57.2 mmol). Upon addition, the mixture was stirred at room temperature overnight. The mixture was treated with 10% H2SO4 aqueous solution (250 mL). The ether phase was separated and aqueous phase extracted with ether (150 mL). The combined organic phase was washed with water (400 mL), brine (300 mL), and then dried over anhydrous Na2SO4. Evaporation of the solvent gave 17.8 g of yellowish oil as a crude product (III). The crude product was used directly in the following step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[CH:15]([CH3:20])[CH2:16][C:17](O)=[O:18])=[CH:10][CH:9]=2)[CH:2]=1.O.[NH2:23][NH2:24].[ClH:25]>COCCO>[ClH:25].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]([CH3:20])[CH2:16][C:17](=[O:18])[NH:23][N:24]=3)=[CH:10][CH:9]=2)[CH:2]=1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1ccc(Cc2cccnc2)cc1
Agent: Cl
Solvent: COCCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc(Cc2cccnc2)cc1

Procedure:
7.1 g (0.025 mole) of 4-(4-(3-pyridylmethyl)-phenyl)-4-oxo-3-methyl-butyric acid and 1.5 ml (0.03 mole) of hydrazine hydrate are stirred in 30 ml of ethylene glycol monomethyl ether at 100° C. for 1 hour. After addition of ethanolic hydrochloric acid, the product is filtered off with suction and recrystallised from 96% strength ethanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][O:17]2)[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CCCO[C@H]1COCc1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: c1ccc(COC[C@@H]2OCCC[C@H]2OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.22 g of dl-trans-2-benzyloxymethyltetrahydropyran-3-ol (prepared as described in Preparation 2), 2.65 ml of dihydropyran and 0.05 g of pyridinium p-toluenesulfonate were dissolved in 40 ml of methylene chloride, and the mixture was stirred at room temperature for 4 hours. The solvent was then distilled off to give a residue, which was subjected to column chromatography through 80 g of silica gel. Those fractions eluted with mixtures of hexane and diethyl ether ranging from 6:1 to 5:1 by volume were worked up, to afford 2.93 g of the title compound as a colorless oil.