Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH2:22]=O>C(O)=O>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([CH3:22])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)CNCC2
Reactant: C=O
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(c1ccccc1)CN(C)CC2

Procedure:
A solution of 3.58 g. (0.0126 mol) of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine in 15 ml. of formic acid and 10 ml. of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml. of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml. of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give the liquid 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1cc(Cl)cc(Cl)c1
Yield: 83 %

Procedure:
The procedure used in Example 75 was used to prepare this compound from a mixture of 16.3 g (0.10 mole) of 3,5-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene. The compound was obtained in 83% yield as a white, fluffy solid, mp 146°-147° C. (benzene).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1)[CH3:5].[CH3:13][O:14][CH2:15]Cl.O>CN(C)C=O>[CH3:13][O:14][CH2:15][O:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=1)[CH3:5]
Reactant: COCCl
Reactant: Cc1ccc(C(C)O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOC(C)c1ccc(C)nc1
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
Sodium hydride in oil (60%, 7.0 g) was added with ice-cooling to a solution of 5-(1-hydroxyethyl)-2-methylpyridine (20.0 g) in N,N-dimethylformamide (120 ml). The mixture was stirred for 15 minutes. Then, chloromethyl methyl ether (14.1 g) was added dropwise at the same temperature. The reaction mixture was further stirred for 30 minutes with ice-cooling. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and subjected to distillation under reduced pressure to obtain 5-(1-methoxymethoxyethyl)-2-methylpyridine (21.5 g, yield: 81%), b.p. 78°-80° C./0.8 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.B.O1CCCC1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1CO
Yield: 95 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (10.75 g) in tetrahydrofuran (50 ml) was added borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 150 ml) by syringe under nitrogen atmosphere at 5° C. and the mixture was heated under reflux for 18 hours. After cooling, water (50 ml) and potassium carbonate (20 g) were added to the solution at 5° C. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 4-bromo-2-methylbenzyl alcohol (9.55 g). This compound was used to the next reaction without further purification.
Reaction SMILES: [CH2:1]([N:8]1[C:18]2=[C:19]3[C:14](=[N:15][C:16](S(C)(=O)=O)=[N:17]2)[N:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:12][CH2:11][C:10]3=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CS(C)=O.CCN(C(C)C)C(C)C>[CH2:1]([N:8]1[C:18]2=[C:19]3[C:14](=[N:15][C:16]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:17]2)[N:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:12][CH2:11][C:10]3=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(CN2CCc3nn(Cc4ccccc4)c4nc(S(C)(=O)=O)nc2c34)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CCc3nn(Cc4ccccc4)c4nc(N5CCOCC5)nc2c34)cc1
Temperature: 100 °C

Procedure:
The mixture of 1-benzyl-5-(4-methoxybenzyl)-7-(methylsulfonyl)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene (0.1 mmol) and morpholine (0.2 mmol) in anhydrous DMSO (1 mL) and DIPEA (0.06 mL) was heated at 100° C. for 64 h in 2-dram vials. The solvent was then removed on Genevac. The residue was re-brought up to DMSO (1.2 mL) and was purified by HPLC using reverse phase column chromatography with a Maccel AQ C18 column and a gradient of 1-95% ACN/water containing 0.05% trifluoroacetic acid , to yield the 4-(1-benzyl-5-(4-methoxybenzyl)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylen-7-yl)morpholine compound 131 White solid, 50% yiled, M.p. 118-120° C.; 1H NMR (CDCl3, 400 MHz) δ 7.33-7.23 (m, 7H), 6.86 (d, J=8.4 Hz, 2H), 5.33 (brs, 2H), 4.71 (s, 2H), 3.92 (m, 4H), 3.79 (m, 7H), 3.48 (m, 2H), 2.98 (t, J=6.4 Hz, 2H). LC-Mass (m/e): 457.56 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)=[N:17][CH:18]=1.[ClH:29]>C1COCC1.O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1
Reactant: COc1ccc2nccc(-c3ccc(CCNC(=O)OC(C)(C)C)nc3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc2nccc(-c3ccc(CCN)nc3)c2n1
Reaction time: 4 h
Yield: 100 %

Procedure:
To a stirred solution of 1,1-dimethylethyl (2-(5-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-pyridinyl}ethyl)carbamate (4.0 mmole) in dry THF (20 mL) at RT was added 4 M HCl in dioxane (10 mL). After 4 h, the reaction suspension was concentrated in vacuo and dried under high vacuum to give the title compound (100%.) as an off-white solid: LC-MS (ES) m/e 281 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9](=O)[CH:10]([CH3:12])[CH3:11]>>[CH:9](=[N:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: NCc1ccccc1
Reactant: CC(C)C=O
Product: CC(C)C=NCc1ccccc1

Procedure:
the procedure described in Example 1A was repeated using benzylamine (32 parts) in place of benzhydrylamine and isobutyraldehyde (22 parts) to give isobutylidenebenzylamine (49 parts).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1)=[O:8]
Reactant: ClCc1ccoc1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
To a solution of Example 340A (0.15 g, 0.53 mmol) in 5 mL DMF was added sodium hydride (0.016 g, 0.67 mmol, 95%). After the solution was allowed to stir at ambient temperature for 30 min, 3-(chloromethyl)furan (0.08 g, 0.67 mmol) was added. The reaction was held at ambient temperature overnight and then quenched with water. The crude was extracted with ethyl acetate and the organics washed with water, then dried over MgSO4, filtered, and concentrated. Flash chromatography over silica gel (50% ethyl acetate/hexane) gave 0.035 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (d, J=1.36 Hz, 3H) 3.80 (s, 3H) 5.38 (s, 2H) 6.39-6.55 (m, 2H) 7.12 (d, J=8.82 Hz, 1H) 7.26 (d, J=1.36 Hz, 1H) 7.46 (dd, J=8.82, 2.71 Hz, 1H) 7.64 (s, 1H) 7.75 (d, J=2.71 Hz, 1H). m/z 363.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21](=O)[CH:20](Br)[CH2:19][CH2:18][CH2:17][C:7]=2[N:8](C(OC(C)(C)C)=O)[CH:9]=1)=[O:4].[C:24]([NH2:27])(=[S:26])[CH3:25]>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:21]3[N:27]=[C:24]([CH3:25])[S:26][C:20]=3[CH2:19][CH2:18][CH2:17][C:7]=2[NH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Reactant: CC(N)=S
Solvent: CO
Product: COC(=O)c1c[nH]c2c1-c1nc(C)sc1CCC2
Yield: 64.1 %

Procedure:
A mixture of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4-H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester(880 mg, 2.27 mmol) and Thioacetamide(426 mg, 4.54 mmol) in MeOH(20 mL) is refluxed for 20 h and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (50% EtOAc/Hex to 10% MeOH/CH2Cl2) to yield 382 mg of 2-Methyl-4,5,6,7-tetrahydro-3-thia-1,7-diaza-cyclopenta[e]azulene-9-carboxylic acid methyl ester as a yellow foam(64%). 1H NMR (CD3OD) 2.18 (quint, 2H), 2.61 (s, 3H), 2.70 (t, 2H) 2.78 (t, 2H), 3.73 (s, 3H), 7.29 (s, 1H)
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3c(F)cccc3F)cc2=O)n1
Yield: 62 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 47) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide as a white solid (0.75 g, 62%); ES+-HRMS m/e calcd for C25H29N5O4F2 [M+H+] 502.2261 found 502.2258. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.24-1.75 (m, 8H), 1.93 (m, 1H), 2.28 (m, 1H), 3.89 (s, 2H), 4.68 (s, 1H), 5.47 (dd, J=4.2, J=10.9 Hz, 1H), 6.03 (d, J=3.0 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.34-7.51 (m, 3H), 7.53 (d, J=2.1 Hz, 1H), 8.28 (d, J=3.0 Hz, 1H), 10.86 (s, 1H).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([CH3:12])[N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:21].C([Li])CCC.CN([CH:30]=[O:31])C>O1CCCC1>[Cl:11][C:10]1[C:5]2[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:3]([CH3:21])=[C:2]([CH:30]=[O:31])[C:6]=2[N:7]=[C:8]([CH3:12])[N:9]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(Cl)c2c(n1)c(Br)c(C)n2COCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(Cl)c2c(n1)c(C=O)c(C)n2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Bromo-4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine from example A9 (12.41 g; 31.76 mmol) is dissolved in dry tetrahydrofurane (100 mL). At −78° C. n-butyllithium (12.7 mL; 31.76 mmol; 2.5M solution in n-hexane) is syringed into the stirred reaction mixture. After 30 min DMF (12.4 mL; 158.80 mmol) is added via syringe and the mixture is stirred for additional 2 hours at −78° C. and for 30 minutes at 0° C. The reaction is quenched by addition of 1M citric acid (32 mL) and brine (32 mL). After diluting with tert-butylmethylether the aqueous layer is separated and extracted with tert-butylmethylether (3×50 mL). The combined organic layers are dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by column chromatography on silica gel (cyclohexane:ethylacetate/7:3) affording the title compound as a white solid.
Reaction SMILES: [CH3:1][SiH:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([O:7][SiH](C)C)=[CH:5][CH:4]=1.C[O-].[Na+]>C(OCC)C.CO>[CH3:1][SiH:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: C[SiH](C)Oc1ccc([SiH](C)C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: C[SiH](C)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
To a cold solution (~9° C.) of 26.0 g of 4-dimethylsilylphenoxydimethylsilane in 250 ml of diethylether was added 10 ml of a solution of sodium methoxide (0.4N) in methanol and the mixture stirred overnight. Solvents were removed by evaporation on a rotary evaporator at room temperature to yield 15.6 g (83.0%) of crude product, m.p. 59°-60° C. After recrystallization from hexane, the phenol was obtained as needles, m.p. 61° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccc(Cl)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)c(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture solution of 3-amino-4-chloro-benzoic acid methyl ester (21 g, 113.2 mmol), 3-bromo-benzaldehyde (21 g, 113.2 mmol) and p-toluenesulfonic acid (431 mg, 2.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-4-chloro-benzoic acid methyl ester (39.8 g, quant.) as a pale-white solid: MS calcd. for C15H11BrClNO2 353.62, obsd. (ESI+) [(M+H)+] 351.9 & 353.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].[C:33](O)(=O)[CH3:34].C(=O)C>CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[CH2:33][CH3:34])=[CH:13][CH:14]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(=O)O
Reactant: CCCN(CCC)CCCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (289 mg) obtained in Example 23-4 was dissolved in anhydrous methanol (6.0 ml) and added with sodium cyanoborohydride (92.8 mg), acetic acid (1.00 ml), and acetaldehyde (61.3 μl). The whole was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, followed by stirring for a while. The resultant was subjected to extraction with chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (311 mg) as a pale-yellow oily substance.
Reaction SMILES: F[B-](F)(F)F.[F:6][C:7]([F:18])([F:17])[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]#[N:16])=[CH:11][CH:10]=1.[Cl:19][CH:20](C(C)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>N1C=CC=CC=1.O>[Cl:19][C:20](=[N:16][NH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]([F:17])([F:18])[F:6])=[CH:14][CH:13]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N#[N+]c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(Cl)=NNc1ccc(OC(F)(F)F)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
4-Trifluoromethoxybenzenediazonium tetrafluoroborate (63) (4.33 g, 15.7 mmol) was added to a solution of ethyl 2-chloroacetoacetate (64) (2.35 g, 14.3 mmol) in pyridine (6 mL) and water (6 mL) at −5° C. The mixture was stirred at −5° C. for 0.5 h and the precipitate was filtered and washed with ice cold water. Recrystallisation from EtOH/water gave ethyl 2-chloro{[4-(trifluoromethoxy)phenyl]hydrazono}ethanoate (65) (3.977 g, 82%) as pale orange needles: mp 128-130° C.; 1H NMR [(CD3)2SO] δ 10.68 (s, 1H), 7.43 (d, J=9.2 Hz, 2H), 7.34 (d, J=9.2 Hz, 2H), 4.30 (t, J=7.1 Hz, 2H), 1.30 (q, J=7.1 Hz, 3H). APCI MS m/z 309, 311 [M−H]−.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)=[O:5].CS(O)(=O)=[O:18]>>[NH:6]1[C:7]2[C:15](=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][CH2:10][CH2:11]3)[C:3](=[O:18])[C:4]1=[O:5]
Reactant: CS(=O)(=O)O
Reactant: O=C(C=NO)Nc1cccc2c1CCC2
Product: O=C1Nc2c(ccc3c2CCC3)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 72 %

Procedure:
Add 2-Hydroxyimino-N-indan-4-yl-acetamide (5.54 g, 27.1 mmol) in small portions at 80° C. to methanesulfonic acid (21 mL). Stir the mixture at this temperature for 25 min. Cool to room temperature, pour into ice water and filter the precipitate. Dissolve the solid in warmed 1N NaOH, and neutralize with acetic acid. Filter the resulting solid and acidify the filtrate with concentrated HCl. Filter the precipitate and wash with water. Dry the solid to yield the title compound (3.80 g, 72%). MS (ES−): 186 (M−H).
Reaction SMILES: [C@H:1]1([C:17]([O:19]CC2C=CC=CC=2)=[O:18])[CH2:6][CH2:5][C@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3][CH2:2]1.[OH-].[K+]>C(O)(C)(C)C>[CH2:10]([O:9][C:7]([C@H:4]1[CH2:5][CH2:6][C@H:1]([C:17]([OH:19])=[O:18])[CH2:2][CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: O=C(O)[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.0 g (2.8 mmole) dibenzyl trans-1,4-cyclohexanedicarboxylate in 20 ml tert.-butanol (warm) is added a solution of 1.9 g potassium hydroxide in 10 ml tert.-butanol. After stirring at room temperature overnight the cloudy mixture is evaporated to remove solvent, taken up in water and acidified to pH 5.3; then, after 30 minutes, acidified to pH 5.25 with dilute hydrochloric acid. The precipitated solid is collected on a filter, redissolved in dilute sodium bicarbonate solution and this readjusted to pH 5.25 to precipitate the purified monoester 1H-NMR (DMSO-D6) ppm (delta): 1.1-2.3 (m, 10H), 5.1 (s, 1H), 7.35 (s, 5H).
Reaction SMILES: [CH:1]([N:4](C(C)C)[CH2:5]C)(C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:20])=[C:15]([CH:19]=1)[C:16](O)=[O:17].CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:20])=[C:15]([CH:19]=1)[C:16]([N:4]([CH3:5])[CH3:1])=[O:17]
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(N)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl ethylamine (21 ml, 121 mmol) was dissolved in a solution of 5-amino-2-bromo benzoic acid (5 g, 23 mmol), dimethylamine (5 g, 115 mmol) and BOP (51 g, 121 mmol) in 100 ml DMF. And the reaction mixture was stirred at room temperature 30 minutes. Three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product. (3.1 g, 54%)
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:42][CH:41]=3)=[CH:38][CH:39]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)#[N:2]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(C#N)cc2)cc1
Yield: 90 %

Procedure:
A solution of 1150 mg (2.79 mmol) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate from Example 75A in 50 ml of dry acetonitrile is mixed with 908 mg (3.35 mmol) of 4-chloromethyl-4′-trifluoromethylbiphenyl from Example 23A and 579 mg (4.19 mmol) of anhydrous potassium-carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 1620 mg (2.51 mmol, 90% yield) of a solid are obtained.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCO
Reactant: O=C1C=CC(O)N1
Product: CCCCCOC1C=CC(=O)N1
Temperature: 50 °C

Procedure:
A mixture of 3 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one in 60 cm3 of n-pentyl alcohol and 1.5 g of Amberlite IR 120 H is heated to 50° C. for 3 hours. The temperature is allowed to return to the ambient, and after filtering, the solvent is distilled off under reduced pressure. The residue is distilled at 20° C. under 0.08 mbar. 3.8 g of the expected product is obtained, utilized as it is for the following stage.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:3]([OH:21])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (1.55 g, 5.41 mmol) in methanol (30 mL) and water (30 mL) was treated with lithium hydroxide (2.60 g, 61.9 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in water (100 mL) which was then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×120 mL). The combined organic extracts were then washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid (1.27 g, 86%) as an off-white solid.