Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]2([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])OCC[O:41]2)[C@@:22]([OH:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:32]=[CH:33]/[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:41])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C@@:22]([OH:31])([CH3:30])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@](C)(O)C(=O)OC(C)(C)C)C(=O)OC)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@](C)(O)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
(2S,3S,E)-tert-Butyl 3-((S)-3-(4-(but-2-ynyloxy)phenyl)-1-methoxy-1-oxopropan-2-ylcarbamoyl)-11-(2-heptyl-1,3-dioxolan-2-yl)-2-hydroxy-2-methylundec-4-enoate (540 mg, 0.756 mmol) was dissolved in dichloromethane (3.5 mL), and water (0.35 mL) was added. Trifluoroacetic acid (10 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated. The residue was then purified by diol column chromatography (n-hexane/acetone) to obtain the target compound as pale yellow oil at a yield of 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH3:9].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.C(O)(=O)C.C1C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:13]([C:11]#[N:12])=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[CH3:9])[CH3:18]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)c1ccccc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2′-chloroacetophenone (50 mmole), ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL) ammonium acetate (400 mg), and benzene (50 mL) is heated to reflux in a Dean-Stark apparatus. After approximately 10 hours, additional ethyl cyanoacetate (50 mmole), acetic acid (1.14 mL), and ammonium acetate (400 mg) are added. After an additional 10 hours, the reaction is cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water (240 mL), brine (40 mL), and dried (Na2SO4). After filtering, the extract is concentrated in vacuo and the desired product, as a mixture of E- and Z-isomers, is isolated by column chromatography on silica gel, eluting with 5% ethyl acetate/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.C(=O)=O.C(#N)C.[B]1OC2C(=CC=CC=2)O1.C1COCC1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=3)[C:10]([CH3:11])=[C:6]2[N:5]=[C:4]([CH3:19])[C:3]=1[C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(=O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](O)c1c(C)nc2c(C)c(-c3cccc(Cl)c3)nn2c1Cl
Temperature: -40 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
To a stirred suspension of ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (3.45 g, 8.80 mmol) in anhydrous toluene (200 ml) was added 1.1 M (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole in toluene (3.20 ml, 3.52 mmol). The mixture was cooled (−40° C., dry ice/acetonitrile) and a solution of 1.0 M catecholborane in THF (17.59 ml, 17.59 mmol) was added over 1 min. The mixture was maintained at −40° C. for 2 hrs, and then warmed to room temperature with stirring for 16 hrs. The reaction was diluted with EtOAc (600 mL) and sat. Na2CO3 (200 mL). The mixture was stirred vigorously for 30 min, the layers were separated, and the organic layer washed with sat Na2CO3 (5×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography, eluting with 10%-30% EtOAc in hexanes, affording the product, (S)-ethyl 2-(7-chloro-2-(3-chlorophenyl)-3,5-dimethylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (3.08 g, 7.81 mmol, 84% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ: 7.85-7.79 (m, 1H), 7.69 (dt, J=7.1, 1.6 Hz, 1H), 7.40-7.32 (m, 2H), 5.71 (s, 1H), 4.26 (q, J=7.1 Hz, 2H), 4.02 (br. s., 1H), 2.60 (s, 3H), 2.47 (s, 3H), 1.21 (t, J=7.2 Hz, 3H). LCMS (M+H)=394.2. Chiral column analysis indicated 98.1% chiral purity (ee: 96.2%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH3:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.C([BH3-])#N.[Na+].[CH:35](=O)[CH3:36].C(O)(=O)C>CO.O1CCCC1>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH2:35][CH3:36])[CH3:18])[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CC=O
Reactant: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2NC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(C)CC)cc1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To 1.5 g (3.6 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-methylamino-4,5,-dihydro-1H-pyrazole-1-carboxamide (Example 434) dissolved in 10 ml of methanol and 5 ml of tetrahydrofuran was added 0.15 g (2.4 mmole) of sodium cyanoborohydride and 0.2 g (4.3 mmole) of acetaldehyde. To this stirred solution was dropwise added 0.6 g (9.5 mmole) of acetic acid dissolved in 3 ml of methanol. After 30 minutes, the reaction was concentrated in vacuo, dissolved in 50 ml of diethyl ether, washed with water, washed with 1M aqueous sodium hydroxide, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Trituration with diethyl ether and hexanes yielded 1.4 g of the desired compound, mp 130°-132° C.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[Na][Na].[Na].[Cl-].[Na+].[OH-:20].[Na+]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([Br:1])=[CH:3][CH:4]=2)=[O:20])=[O:13])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(O)c1ccc(Br)c2ccccc12
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: O=C(OC(=O)c1ccc(Br)c2ccccc12)c1ccc(Br)c2ccccc12

Procedure:
When the chlorination reaction is complete, the mixture is worked up according to known methods. After clarification by filtration, where required, the solution may be acidified with a mineral acid at room temperature or at a temperature of up to about 90°C, the bromination product which has precipitated may be separated, washed with water and dried at 100°-120°C. An especially pure product is obtained by salting out the resulting 4-bromo-naphthalic acid in the form of the disodium salt by an addition of sodium ions to the reaction solution, for example in the form of sodium chloride and/or sodium hydroxide, separating the salt and converting it into the anhydride by introducing it into a dilute mineral acid. The 4-bromo-naphthalic acid anhydride so obtained is a valuable intermediate product for the preparation of dyestuffs and optical brighteners of the series of the naphthalic acid derivatives substituted in 4-position by phenols, thiophenols and aromatic amines.
Reaction SMILES: C(OC([N:8]([C:16]1[S:17][CH2:18][C@@H:19]2[C@@H:24]([CH3:25])[O:23][CH2:22][C@:20]2([C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[CH:28][C:27]=2[F:41])[N:21]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.I[C:43]1[N:44](COCC[Si](C)(C)C)[CH:45]=[CH:46][N:47]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>COCCOC.C([O-])(O)=O.[Na+].C(Cl)Cl.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C.O>[F:41][C:27]1[CH:28]=[CH:29][C:30]([C:43]2[NH:44][CH:45]=[CH:46][N:47]=2)=[CH:31][C:26]=1[C@:20]12[CH2:22][O:23][C@H:24]([CH3:25])[C@H:19]1[CH2:18][S:17][C:16]([NH2:8])=[N:21]2
Reactant: C[Si](C)(C)CCOCn1ccnc1I
Reactant: C[C@H]1OC[C@]2(c3cc(B4OC(C)(C)C(C)(C)O4)ccc3F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)SC[C@H]12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1OC[C@]2(c3cc(-c4ncc[nH]4)ccc3F)N=C(N)SC[C@H]12
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
di-tert-Butyl{(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate (0.1 g, 0.17 mmol) was dissolved in 1,2-dimethoxyethane (1.5 mL), water (0.7 mL) and ethanol (0.5 mL). The resulting solution was heated to 100° C. and to it was added 2-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole (0.1 g, 0.31 mmol), cesium carbonate (0.33 g, 1.0 mmol) and dichloropalladium-triphenylphosphane (0.02 g, 0.03 mmol) and the reaction was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with saturated aqueous NaHCO3 and extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified using column chromatography (gradient 0-100% EtOAc in hexane) to give a mixture of mono and bis BOC products. 1H NMRs consistent with desired structures. The residues were combined and dissolved in DCM (2 mL). Trifluoroacetic acid (1 mL) was added and the solution stirred at room temperature for 1 hour. The solvents were removed in vacuo and saturated aqueous NaHCO3 added. The solution was extracted with DCM (×3). The combined organics were dried (MgSO4), filtered and concentrated to give the title compound (48 mg). 1H NMR (400 MHz, CDCl3) δ ppm: 7.76-7.89 (m, 2 H), 7.06-7.13 (m, 3 H), 4.57 (d, J=9.1 Hz, 1 H), 4.32-4.40 (m, 1 H), 3.81 (dd, J=8.8, 1.8 Hz, 1 H), 3.07 (dd, J=13.4, 3.5 Hz, 1 H), 2.71 (dd, J=13.3, 3.9 Hz, 1 H), 2.57-2.64 (m, 1 H), 1.37 (d. J=6.1 Hz, 3 H)
Reaction SMILES: C(OC(=O)NC[C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:30][CH2:29]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C1(N2C(=O)C3C(=CC=CC=3)NC2=O)CC1.[CH3:55][O:56][C:57](C1C=CC2N(CCC(C)C)C(CCl)=NC=2C=1)=[O:58].Cl>O>[CH3:55][O:56][C:57]([C:9]1[CH:38]=[CH:37][C:12]2[N:13]([CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=[O:27])[N:19]([CH:28]4[CH2:29][CH2:30]4)[C:18]3=[O:31])=[N:15][C:11]=2[CH:10]=1)=[O:58]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C3CC3)c(=O)c3ccccc32)nc2cc(CNC(=O)OC(C)(C)C)ccc21
Reactant: COC(=O)c1ccc2c(c1)nc(CCl)n2CCC(C)C
Agent: Cl
Agent: O=c1[nH]c2ccccc2c(=O)n1C1CC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCC(C)C
Yield: 90 %

Procedure:
The procedure for the preparation of [2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester was followed starting from 3-cyclopropyl-1H-quinazoline-2,4-dione (309 mg, 1.53 mmol) and 2-chloromethyl-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester; HCl salt (506 mg, 1.53 mmol). At the end of the reaction a precipitate had formed. The mixture was diluted with water, and the solid collected by filtration. After washing with water and diethyl ether and drying in vacuo, 2-(3-Cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (634 mg, 90%) was obtained as a white solid:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:46][C:47]1[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[O:49][N:48]=1>CN(C=O)C.C1COCC1>[O:49]1[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[C:47]([CH2:46][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[N:48]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: BrCc1noc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3noc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a stirring solution of 390 mg (0.86 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL of DMF at 0° C. is added 1.03 mL (1.03 mmol, 1.2 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and a solution of 200 mg (0.94 mmol, 1.1 equiv.) of 3-bromomethyl benzo[d]isoxazole (Uno, H.; Kurokawa, M.; Natsuka, K.; Yamato, Y.; Nishimura, H. Chem. Pharm. Bull. 1976, 24, 632)in 1 mL of DMF is added. The resulting solution is stirred for 14 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 303 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.81 (d, 1H, J=7.8), 7.55-7.10 (m, 14H), 6.97 (m, 2H), 5.01 (m, 1H), 4.28 (m, 3H), 3.85 (m, 4H), 3.58 (dd, 1H, J=5.1, 16.6), 1.07 (d, 6H, J=6.6); low resolution MS (FAB)m/e 589 (MH+), 588 (M+), 424, 396; Anal. (C35H32N4O5) Calcd. C, 71.41; H, 5.48; N, 9.52 Found C, 71.48; H, 5.49; N, 9.47.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:12])([CH3:11])O>C1(C)C=CC=CC=1.II>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:12])=[CH2:11]
Reactant: Cc1cccc(C(C)(C)O)c1N
Agent: II
Solvent: Cc1ccccc1
Product: C=C(C)c1cccc(C)c1N

Procedure:
49B was dissolved in 60 ml of toluene containing 5 mg of iodine, and the mixture was refluxed overnight. The solvent was evaporated and the residue was distilled in a short-path bantumware apparatus to give 2-(2-amino-3-methylphenyl)propene (49C), as a colorless oil, b.p.: 82°-85° C. (2 Torr.).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:34][C:35]1[CH:50]=[CH:49][C:38]([C:39]([NH:41][CH:42]2[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]2)=[O:40])=[CH:37][C:36]=1[O:51][CH3:52].CC(C)CC(O)C>CO>[CH2:16]([C:8]1([CH2:18][CH3:19])[C:7](=[O:20])[N:6]([CH3:21])[C:5]2[C:11](=[N:12][C:2]([NH:34][C:35]3[CH:50]=[CH:49][C:38]([C:39]([NH:41][CH:42]4[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]4)=[O:40])=[CH:37][C:36]=3[O:51][CH3:52])=[N:3][CH:4]=2)[N:10]([CH:13]([CH3:15])[CH3:14])[CH2:9]1)[CH3:17]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2N(C)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)CC(C)O
Solvent: CO
Solvent: O
Product: CCC1(CC)CN(C(C)C)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O
Temperature: 120 °C

Procedure:
10-chloro-4,4-diethyl-6-methyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 198; 100 mg, 0.322 mmol), p-toluene sulphonic acid monohydrate (153 mg, 0.81 mmol) and 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 84 mg, 0.322 mmol) were added to 4-methyl-2-pentanol (7 mL). The reaction was heated at 120° C. over the weekend. The reaction mixture was loaded on to an SCX column (10 g), pre-wet with methanol, washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound, after drying under vacuum at 70° C., as a white solid (97 mg, 56%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([C:7](N(OC)C)=[O:8])=[CH:5][C:4]=1[CH3:15].COC1C=CC(C(O)=O)=CC=1C.Cl.CNOC.[Br:33][C:34]1[CH:39]=[C:38]([CH2:40][CH2:41][O:42][CH3:43])[CH:37]=[C:36](Br)[CH:35]=1.C([Li])CCC>>[Br:33][C:34]1[CH:35]=[C:36]([C:7]([C:6]2[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[C:4]([CH3:15])[CH:5]=2)=[O:8])[CH:37]=[C:38]([CH2:40][CH2:41][O:42][CH3:43])[CH:39]=1
Reactant: COCCc1cc(Br)cc(Br)c1
Reactant: COc1ccc(C(=O)N(C)OC)cc1C
Agent: CNOC
Agent: COc1ccc(C(=O)O)cc1C
Agent: Cl
Product: COCCc1cc(Br)cc(C(=O)c2ccc(OC)c(C)c2)c1
Yield: 53 %

Procedure:
In analogy to the procedure described for the preparation of the Building Block AU, the reaction of 4,N-dimethoxy-3,N-dimethyl-benzamide, beforehand prepared by a standard condensation of 4-methoxy-3-methyl-benzoic acid and N,O-dimethylhydroxylamine hydrochloride, and 1,3-dibromo-5-(2-methoxy-ethyl)-benzene, beforehand reacted with n-butyl lithium, yielded the title compound as a colourless oil (yield: 53% of theory). Mass (calculated) C18H19BrO3 [362]; (found) [M+H]+=363, 365.
Reaction SMILES: CC(=CCCC(C=C)=C)CCC=O.[CH3:14]/[C:15](/[CH2:23][CH2:24]/[CH:25]=[C:26](/[CH:28]=[O:29])\[CH3:27])=[CH:16]\[CH2:17]/[CH:18]=[C:19](/[CH:21]=[CH2:22])\[CH3:20]>>[CH3:14]/[C:15](/[CH2:23][CH2:24]/[CH:25]=[C:26](/[CH:28]=[O:29])\[CH3:27])=[CH:16]\[CH2:17][CH2:18][C:19]([CH:21]=[CH2:22])=[CH2:20]
Reactant: C=C/C(C)=C/C/C=C(\C)CC/C=C(\C)C=O
Agent: C=CC(=C)CCC=C(C)CCC=O
Product: C=CC(=C)CC/C=C(\C)CC/C=C(\C)C=O

Procedure:
4-Methyl-8-vinyl-4,8-nonadienal was used in place of 4-methyl-8-vinyl-4,7-nonadienal in the reaction described in Example 1 d). for preparing α-sinensal. The resulting aldehyde, β-sinensal, was obtained in comparable yields and had the same constants as the product obtained according to Example 4 d).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([O-])([O-])=O.[Ca+2].[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]([CH:60]([CH3:62])[CH3:61])[CH:54]=1)[C:46]([OH:48])=[O:47]>CO.C(Cl)Cl>[Cl:42][C:43]1[C:44]([CH3:64])=[C:45]([CH:49]=[C:50]([Cl:63])[C:51]=1[O:52][C:53]1[CH:54]=[C:55]([CH:60]([CH3:61])[CH3:62])[C:56]([OH:59])=[C:57]([Br:1])[CH:58]=1)[C:46]([OH:48])=[O:47]
Reactant: [Br-]
Reactant: Cc1c(C(=O)O)cc(Cl)c(Oc2ccc(O)c(C(C)C)c2)c1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(C(=O)O)cc(Cl)c(Oc2cc(Br)c(O)c(C(C)C)c2)c1Cl
Yield: 32.7 %

Procedure:
A suspension of benzyltrimethylamonium tribromide (2.2 g, 5.63 mmol) and CaCO3 (0.28 g, 2.82 mmol) was stirred for 2 hr at 20° C. in a 1:1 MeOH/CH2Cl2 solution (10 mL) containing 3,5-dichloro-2-methyl-4-(4-hydroxy-3-isopropylphenoxy)-benzoic acid (1.0 g, 2.82 mmol). Once HPLC analysis indicated that conversion to the desired monobrominated phenol was optimal, the reaction was quenched by addition of 15 mL of 1N HCl. After removal of the organic solvents under vacuum using a rotary evaporator, the aqueous suspension was extracted twice with EtOAc. After drying the combined EtOAc layers over MgSO4, the salts were filtered prior to removal of the EtOAc under vacuum. The resulting residue after purification by gradient elution from a reverse phase C18 column employing MeOH/H2O containing 0.1% TFA yielded 3,5-dichloro-2-methyl-4-(3-bromo-4-hydroxy-5-isopropylphenoxy)benzoic acid (400 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.COC(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:16])[C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-bromo-5-formylbenzoate (5.7 g, 20.0 mmol) in tetrahydrofuran (133 mL) at 0° C. were added trimethyl(trifluoromethyl)silane (4.44 mL, 30.0 mmol) and activated 4 Å molecular sieves. Tetrabutylammonium fluoride (1.0 M in THF; 6.0 mL, 6.0 mmol) was added dropwise. The reaction mixture was warmed to ambient temperature. After 3 h, aqueous 1N HCl (25 mL) and tert-butyl methyl ether (100 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [O-]CC.[Na+].[Na].Br[CH:7]([CH2:20][Br:21])[CH2:8][C:9]1[CH:10]=[C:11]([F:19])[CH:12]=[CH:13][C:14]=1[O:15]C(=O)C>C(O)C>[Br:21][CH2:20][CH:7]1[CH2:8][C:9]2[CH:10]=[C:11]([F:19])[CH:12]=[CH:13][C:14]=2[O:15]1
Reactant: CC(=O)Oc1ccc(F)cc1CC(Br)CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Fc1ccc2c(c1)CC(CBr)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sodium ethoxide solution, prepared in the conventional manner starting from 15.2 parts of sodium in 100 parts of ethanol, is added dropwise to a mixture of 231 parts of 3-(2,3-dibromopropyl)-4-acetoxy-fluorobenzene in 800 parts of ethanol (exothermic reaction: temperature rises to 50° C.). Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled to room temperature, filtered from some insoluble matter and the filtrate is evaporated. The residue is divided between water and ether. The aqueous layer is separated and extracted once more with ether. The combined ethereal phases are dried over calcium chloride, filtered and evaporated. The oily residue is distilled in vacuo, yielding 102 parts of 2-bromomethyl-2,3-dihydro-5-fluorobenzofuran; bp. 100°-105° C. at 1.5 mm. pressure.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21](C=O)=[CH:20][CH:19]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2CC(O)=CC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 5 mL of methyl acetoacetate, 2.0 g of NaH 60% dispersion in oil, 25 mL of 2.0M n-butyl lithium in hexane, 7.0 mL of 4-methoxybenzaldehyde and 150 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 159°-162° C. (dec.)). 1H NMR (CDCl3) δ2.91 (dd, 2H), 3.57 (dd, 2H), 3.83 (s, 3H), 5.66 (dd, 1H), 6.93-6.97 (m, 2H), 7.30-7.34 (m, 2H).