Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([OH:13])=O)[O:8][N:7]=1)=[O:5])[CH3:2].[CH:14]1([NH2:17])[CH2:16][CH2:15]1>C(Cl)Cl>[CH:14]1([NH:17][C:11]([C:9]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: CCOC(=O)c1cc(C(=O)O)on1
Reactant: NC1CC1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)NC2CC2)on1
Yield: 43.5 %

Procedure:
The title compound was prepared starting from 3-(ethoxycarbonyl)isoxazole-5-carboxylic acid (3.78 mmol, 0.7 g) and cyclopropyl-amine (2.91 mmol, 0.166 g) using DCM (10 ml) as the solvent. The mixture was diluted with DCM and washed with 1 M Na2CO3 and water. The organic phase was dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.284 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6) δ 0.58-0.64 (m, 2H), 0.70-0.77 (m, 2H), 1.33 (t, 3H), 2.80-2.90 (m, 1H), 4.38 (q, 2H), 7.39 (s, 1H), 9.04 (bs, 1H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1>O>[CH2:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:40][N:32]1[C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=1[NH:21][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isonicotinoyl chloride hydrochloride (250 mg, 1.40 mmol, commercially available product) and triethylamine (287 μl, 2.07 mmol) were sequentially added at 0° C. to a dichloromethane (6 ml) solution of 2-[2-amino-4-(trifluoromethyl)phenyl]isoindoline (193 mg, 0.694 mmol), obtained as described in Referential Example 20-2. The resulting mixture was warmed to room temperature and stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5 g, hexane/ethyl acetate=1/1). Thus, N-[2-(2-isoindolinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0620) (266 mg, quant.) was yielded as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Cl.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:1][CH2:2][CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: O=C1CCC(CO)N1
Reactant: C1=COCCC1
Agent: Cl
Product: O=C1CCC(COC2CCCCO2)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A 5 g quantity of 5-hydroxymethyl-2-pyrrolidinone [Journal of Organic Chemistry, 45, 816 (1980)] was dissolved in 10 ml of dihydropyran, 0.1 ml of concentrated hydrochloric acid was added to the solution, and the mixture was stirred at room temperature for 4 hours. Excessive dihydropyran was distilled off in a vacuum, and the residue was subjected to silica gel column chromatography to obtain an eluate of benzene/ethyl acetate=9/1, which gave 7.9 g of 5-(2-tetrahydropyranoxy)methyl-2-pyrrolidinone (yield 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11]C)[C:8]2[N:7]([CH2:13][CH2:14][N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[N:6]=[C:5]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[S:22][C:3]=1[C:4]=23.Br>>[NH2:1][C:2]1[C:3]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:5]3=[N:6][N:7]([CH2:13][CH2:14][N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])[C:8](=[C:9]([OH:11])[CH:10]=1)[C:4]=23
Reactant: CCN(CC)CCn1nc2c3c(c(N)cc(OC)c31)Sc1ccccc1-2
Agent: Br
Product: CCN(CC)CCn1nc2c3c(c(N)cc(O)c31)Sc1ccccc1-2

Procedure:
Reaction of 5-amino-N,N-diethyl-3-methoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine with 48% HBr as described in Example 64 gave the product.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]C(C)(C)C.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.CCCCC>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1cc(I)cc(OC)c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1cc(OC)cc(OC)c1
Temperature: -20 °C
Yield: 70.9 %

Procedure:
To a solution of 5.28 g (20 mmol) of 1-iodo-3,5-dimethoxybenzene (W. Riedhl, F. Imhof, Justus Liebigs Ann. Chem., 1955;597:153–157) in 100 mL of THF at −78° C. is added 12.3 mL (21 mmol) of 1.7 M tert-BuLi in pentane, and after a further 5 minutes 4.4 g (30 mmol) of diethyl oxalate is added. After being allowed to warm to −20° C., the mixture is quenched with aqueous NH4Cl, and the THF is removed under vacuum. Work-up in EtOAc, followed by chromatography on silica, eluting with hexane/EtOAc (9:1) gives 3.38 g (71%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:4]1[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=[C:3]1[CH2:1][CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc(CC)[nH]c1C(=O)OCC
Product: CCOC(=O)c1nc(CC)n(Cc2ccccc2)c1C(=O)OCC

Procedure:
Following a procedure similar to that described in Preparation42(i), 4.00 g of diethyl 2-ethylimidazole-4,5-dicarboxylate were benzylated, using 2.20 ml of benzyl bromide. The product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 5.19 g of the title compound as a syrup.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:44]1([CH3:53])[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=1>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:16]1[N:17]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:18](=[O:26])[C:19]2[C:24]([CH3:25])=[N:23][S:22][C:20]=2[N:21]=1)[CH:13]([CH3:15])[CH3:14])[C:50](=[O:51])[C:47]1[CH:48]=[CH:49][C:44]([CH3:53])=[CH:45][CH:46]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1nsc2nc(C(NCCCNC(=O)OC(C)(C)C)C(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3snc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 60 °C

Procedure:
To a solution of {3-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propylamino]-propyl}-carbamic acid tert-butyl ester obtained from method 31 alternative procedure above in chloroform (300 ml), diisopropylethylamine (6 g, 46.5 mmol) was added and the reaction mixture was heated to 60° C. To the hot solution a solution of the p-toluoyl chloride (3.78 g, 24.4 mmol) in chloroform (150 ml) was added dropwise and the resulting solution was refluxed overnight. The TLC showed the disappearance of most of the SM. The reaction mixture was washed with water (2×100 ml), satd, NaHCO3 (200 ml) brine (100 ml) and dried (Na2SO4). Concentration of the organic layer provided the crude product which was purified by column (silica gel) chromatography using 10-30% EtOAc in hexanes as eluent. Yield=6.14 g (62%) of {3-[[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester. White foam, mp. 70-71° C. m/z 604 (MH+), 1H NMR (DMSO-d6, 300 MHz, 95° C.) δ: 0.48 (d, 3H), 0.90 (d, 3H), 1.26 m, 1H), 1.28 (s, 9H), 2.33 (s, 3H), 2.47 (d, 2H), 2.72-2.64 (m, 1H), 2.72 (s, 3H), 3.24 (t, 2H), 5.08 (d, 1H), 5.60 (d, 1H), 5.90 (d, 1H), 7.20-7.40 (m, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]([S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C:13](=[O:15])[CH3:14].O>C(Cl)Cl.B(Br)(Br)Br>[C:13]([N:12]([S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([CH:9]([CH3:11])[CH3:10])=[CH:8][C:3]=1[OH:2])(=[O:15])[CH3:14]
Reactant: COc1cc(C(C)C)ccc1N(C(C)=O)S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)N(c1ccc(C(C)C)cc1O)S(=O)(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 5 h
Yield: 70.8 %

Procedure:
To a solution of 2-(N-acetyl-phenylsulfonylamino)-5-isopropylphenyl methyl ether (2.28 g; prepared in Reference Example 40.) in methylene chloride (15 ml), boron tribromide (1.36 ml) was added at 0° C. The mixture was stirred for 5 hours at 10° C. The reaction mixture was poured into iced water, extracted with ethyl acetate. The organic layer was washed, dried over and concentrated. The residue was purified on silica gel column chromatography (benzene:AcOEt=23:2) and recrystallized from AcOEt-hexane mixture solution to give the title compound (1.55 g) having the following physical data.
Reaction SMILES: [CH2:1]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([F:25])[CH:19]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:26](O)(=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([C:12]1[N:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:20]([F:25])[CH:19]=2)=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCC(=O)O
Reactant: CCCCCCCCCCCc1ncc(-c2ccc(O)c(F)c2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCCc1ncc(-c2ccc(OC(=O)CCCC)c(F)c2)cn1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
In a 200 ml-round bottom flask, 2.00 g (5.81 mM) of 2-undecyl-5-(3-fluoro-4-hydroxyphenyl)pyrimidine, 0.60 g (5.87 mM) of valeric acid and 50 ml of dichloromethane were placed and dissolved. To the solution, 1.21 g (5.86 mM) of N,N'-dicyclohexylcarbodiimide and 0.10 g of 4-pyrrolidinopyridine were successively added under stirring at room temperature, followed by further stirring for 4 hours and 45 minutes at room temperature. After stirring, the mixture was left standing at room temperature to precipitate N,N'-dicyclohexylurea. The resultant, N,N'-dichclohexylurea was filtered off and the solvent of the filtrate was distilled-off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=100/1) and recrystallized two times from a minute solvent of acetone-methanol to obtain 1.91 g of 2-undecyl-5-(3-fluoro-4-pentanoyloxyphenyl)pyrimidine (Yield: 76.8). ##STR28##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].S(=O)(=O)(O)O.[Br:19]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2].CO>[Br:19][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrBr
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A mixture of methyl 3-nitrobenzoate (122 g, 674 mmol), silver sulphate (100 g, 320.7 mmol) and concentrated sulfuric acid (750 mL) was stirred mechanically and heated at 90° C. To this mixture was added bromine (37 mL), dropwise, over 2 h. The reaction was stirred another hour, cooled and filtered. The filtrate was mixed with 2 L water and 1 Kg crushed ice. The solid was filtered and dried to afford a mixture of the desired methyl ester and free acid hydrolysis product. The mixture was taken up into methanol (1 L), treated with 10 drops concentrated sulfuric acid and refluxed for 12 h. The reaction mixture was allowed to cool and the crystals that were deposited were collected and dried in a desiccator to afford 126 g (72% yield) of methyl 3-bromo-5-nitrobenzoate (EX-119A): 1H NMR (300 MHz, CDCl3) δ 8.65 (s, 1 H), 8.44 (s, 1 H), 8.37 (s, 1 H), 3.94 (s, 3H).
Reaction SMILES: B(Br)(Br)Br.[I:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[C:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]=1.O.C(Cl)Cl.CO>C(Cl)Cl>[I:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH:7]=1
Reactant: COc1ccc(I)cc1CC(C)C
Agent: BrB(Br)Br
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)Cc1cc(I)ccc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
2.43 ml (2.43 mmol, 2.98 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 176.0 mg (0.61 mmol) 4-Iodo-2-isobutylanisole in 25 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 12 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (3+1)) yielded 84.5 mg (0.31 mmol, 50.17%) 4-Iodo-2-isobutylphenol as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a mixture of 26 g of 4-bromo-2-ethyl-6-methylphenol, 24.8 g of benzyl bromide and 200 ml of N,N-dimethylformamide was added 21.7 g of potassium carbonate, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was poured into ice water, and extracted twice with 500 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 35.6 g of 4-bromo-2-ethyl-6-methyl-1-benzyloxybenzene (97% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[NH:24]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:22])[CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:25]
Reactant: O=C(CCCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc2c(nn1)CCN(C(=O)CCCc1ccccc1)C2

Procedure:
11.8 g of 3-chloro-5,6,7,8-tetrahydro-6-(4-phenylbutyryl)pyrido[4,3-c]pyridazine and 60 cc of hydrazine hydrate are stirred at a bath temperature of 50° for 53 hours with the addition of 50 cc of dioxane. The mixture is worked up as described in Example 10. The qentisinate of the title compound has a M.P. of 203°-205° (decomp., from methanol/water 2:1).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:17]1[CH:18]=[CH:19][C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1ccncc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccncc2)sc2ccccc12
Yield: 30.7 %

Procedure:
Methyl thiosalicylate (2.0 g, 11.9 mM) and 4-cyanopyridine (1.2 g, 11.5 mM) were dissolved in toluene (5 ml), and triethylamine (2 ml) was added to the solution. After heating for 22 hours under reflux, the same procedures as in REFERENCE EXAMPLE 1 were carried out to give the title compound as crystals (850 mg, 30.7%).
Reaction SMILES: Cl.[CH3:2]/[C:3](/[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]2([CH3:25])[CH3:24])=[CH:16][C:15]=1[CH3:28])=[CH:4]\[C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH2:29](O)[CH3:30]>>[CH3:2]/[C:3](/[C:14]1[CH:23]=[C:22]2[C:17]([C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]2([CH3:25])[CH3:24])=[CH:16][C:15]=1[CH3:28])=[CH:4]\[C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:29][CH3:30])=[O:10])=[CH:12][CH:13]=1
Reactant: CCO
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: Cl
Product: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1
Reaction time: 4 h

Procedure:
Gaseous hydrogen chloride was passed into a solution of 4.0 g of E-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoic acid in 300 ml of ethanol at the boiling point of the reaction mixture, until the solution was saturated. Thereafter, the mixture was kept at the boil for a further 4 hours, cooled, flushed with nitrogen and then evaporated down. The residue was digested with 30 ml of methanol, and the product was filtered off and dried. 3.6 g of ethyl E-4-[2-methyl-2-(1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphth-7-yl)-vinyl]-benzoate of melting point 109°-110° C. were obtained (cf. Example 1).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3].Cl.[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([N:21]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)N=CC)=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1>O>[OH2:3].[CH3:1][C:2]1[N:21]([C:15]2[C:14]3[C:19](=[CH:20][C:11]([Cl:10])=[CH:12][CH:13]=3)[N:18]=[CH:17][N:16]=2)[C:25]2[C:26]([C:4]=1[CH2:5][C:6]([OH:8])=[O:7])=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2
Reactant: CC(=O)CCC(=O)O
Reactant: CC=NN(c1ccc(OC)cc1)c1ncnc2cc(Cl)ccc12
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A mixture of laevulinic acid (15g.) and acetaldehyde N1 -(7-chloroquinazolin-4-yl)-p-methoxyphenylhydrazone hydrochloride (3.3g.) was heated at 95°-100° C. for 18 hours. The mixture was poured into water (ca 300ml.), and the precipitated pale yellow solid was collected by filtration and dissolved in a mixture of water (80ml.) and ammonia solution (specific gravity 0.88, ca 5ml.). The solution was washed with ethyl acetate (2 × 25ml.). Addition of sodium chloride (ca 10g.) to the aqueous phase caused a yellow solid to precipitate. This was collected by filtration, and then dissolved in water. The solution was acidified with glacial acetic acid until precipitation was complete. The mixture was filtered to give, as solid residue, 2-methyl-5-methoxy-1-(7-chloroquinazolin-4-yl)indol-3-ylacetic acid monohydrate, m.p. 98°-100° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+].Cl>CO.C1COCC1.CCOCC>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:18])=[O:2])=[CH:8][CH:9]=1
Reactant: COC(=O)C(C)(C)c1ccc(-c2ccco2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C(=O)O)c1ccc(-c2ccco2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
To a solution of 2-(4-(furan-2-yl)-phenyl)-2-methyl-propionic acid methyl ester (2.0 g, 8.2 mmol) (reference example 30a) in MeOH/THF (20 mL, 1/1) is added NaOH (2 mL, 6M). The resulting solution is stirred for 1 hour then heated to 65° C. and stirred at this temperature for 2 hours. The reaction mixture is then cooled and acidified (to pH 1) with hydrochloric acid (2 M). The resulting mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated to give 1.78 g of the title compound as a solid. 1H NMR (CDCl3) d 1.61 (s, 6H), 6.45 (dd, J 3, 2 Hz, 1H), 6.62 (d, J=3 Hz, 1H), 7.42 (m, 2H), 7.45 (d, J=2 Hz, 1H), 7.64 (m, 2H). MS (EI) m/z 230 (M+)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N([CH2:27][CH3:28])CC)C.C(Cl)Cl.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[C:32]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:39])[CH2:33][CH2:34][CH2:35][CH2:21][CH2:2][CH2:3][CH2:4][CH2:27][CH3:28]
Reactant: CCN(CC)CC
Reactant: OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: CCCCCCCCCC(=O)OCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
To a solution of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (2.0 g, 6.84 mmol), triethylamine (1,0 g, 10 mmol) in DCM (70 ml) decanoyl chloride (1.7 g, 8.9 mmol) was added dropwise at room temperature. The mixture was stirred for 1 hour, then was concentrated to a crude solid. The solid was extracted into ethyl acetate, and the insoluble salts were filtered. The solvents were removed. The crude product was purified by flash chromatography (Sorbsil C-30, 30 g, eluted with a mixture of MeOH in DCM). The oil thus obtained (2.5 g, 81%) was converted to a fumarate salt with fumaric acid (650 mg, 1.0 eq) in ethanol. Crystals were collected: 1.48 g, m.p.=109°-110° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]#[N:21])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni].CO>[C:1]([O:5][C:6]([N:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][NH2:21])[C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccccc1C#N
Agent: [Ni]
Solvent: CO
Product: C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)c1ccccc1CN
Reaction time: 60 h
Yield: 40 %

Procedure:
A mixture of (S)-N-t-butyloxycarbonyl(2-cyanophenyl)alanine (1.0 g), Raney® Nickel (1.0 g), and methanol (20 mL) was hydrogenated in a Parr apparatus at 50 psi for 60 h at room temperature. The catalyst was filtered and rinsed with methanol (20 mL three times). The combined filtrate and rinses were evaporated under vacuum, and the resulting residue was triturated with diethyl ether (30 mL five times) to obtain (S)-N-t-butyloxycarbonyl(2-aminomethylphenyl)alanine (406 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[C:11]=2C(OC)=O)[C:5]([CH3:8])=[CH:6][N:7]=1.CO>S(=O)(=O)(O)O.O>[CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nn2c(C)cnc(C)c2c1C(=O)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2c(C)ncc(C)n2n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
A solution of dimethyl 4,7-dimethylpyrazolo[1,5-a]pyrazine-2,3-dicarboxy late (900 mg, 3.42 mmol) in sulfuric acid (4 mL) and water (1 mL) was stirred and heated to 180° C. After stirring for 2 h at that temperature, the reaction mixture was cooled, and 40 mL of methanol (MeOH) was added. The mixture was refluxed at 70° C. for 2 h. Then the mixture was concentrated to dryness. The residue was treated with water and adjusted with saturated sodium bicarbonate solution to pH 8, then extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to give 560 mg (80% yield) of the title compound as a yellow solid. ESI MS: m/z 206.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=0.8 Hz, 1H), 7.36 (s, 1H), 4.03 (s, 3H), 2.77 (s, 3H), 2.75 (s, 3H).