Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:10]1[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22]O)=[CH:12][CH:11]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:16]([O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1
Reactant: OCCOCCOCc1ccccc1
Reactant: N#Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1OCCOCCOCc1ccccc1
Reaction time: 2 h
Yield: 70.6 %

Procedure:
2-Hydroxybenzonitrile (300 mg, 2.52 mmol), di(ethylene glycol) benzyl ether (593 mg, 3.02 mmol), and 1,1′-azobis(N,N-dimethylformamide) (867 mg, 5.04 mmol) were dissolved in toluene (15 ml). Thereafter, tri-n-butylphosphine (1.26 ml, 5.04 mmol) was added at 20° C. to the obtained solution, and the obtained mixture was stirred at the same above temperature for 2 hours. The generated precipitate was filtrated, and the filtrate was then diluted with ethyl acetate (20 ml). The ethyl acetate solution was washed with water twice, and then with a saturated saline solution once. The resultant was dried over anhydrous sodium sulfate, and was then concentrated under reduced pressure. The obtained pale brown oil product was purified by silica gel column chromatography (dichloromethane), so as to obtain 2-[2-(2-benzyloxyethoxy)ethoxy]benzonitrile (529 mg, 71%) in the form of a colorless oil product.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=6[OH:36])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:55][CH2:56][CH2:57][CH:58]=[CH2:59]>CC(C)=O>[CH2:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:15]3[N:20]4[N:21]=[C:22]([C:24]5[CH:25]=[C:26]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=6[O:36][CH2:59][CH2:58][CH2:57][CH:56]=[CH2:55])[CH:27]=[CH:28][CH:29]=5)[CH:23]=[C:19]4[N:18]=[C:17]([CH3:37])[C:16]=3[C@H:38]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:39]([O:41][CH3:42])=[O:40])=[C:13]([Cl:14])[C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCCCBr
Reactant: C=CCN1CCOc2ccc(-c3c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc4cc(-c5cccc(-c6ccccc6O)c5)nn34)c(Cl)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCCOc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(-c4ccc5c(c4Cl)N(CC=C)CCO5)n3n2)c1
Temperature: 70 °C
Yield: 44.9 %

Procedure:
A solution of (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.058 g, 0.089 mmol) and K2CO3 (0.042 g, 0.304 mmol) in dry acetone (5 mL) was treated with 5-bromopent-1-ene (0.026 g, 0.174 mmol), and the reaction was stirred with heating (70° C. oil bath) for 16 h. The reaction was cooled, then concentrated under reduced pressure. The residue was taken up in CH2Cl2 (5 mL) and washed with 1N HCl (5 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by biotage column chromatography (5%-50% EtOAc in hexanes). Product fractions were pooled and concentrated under reduced pressure. The product, (2S)-methyl 2-(7-(4-allyl-5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methyl-2-(2′-(pent-4-en-1-yloxy)-[1,1′-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.031 g, 0.040 mmol, 45.4% yield) was isolated as a clear film. 1H NMR (400 MHz, CDCl3) δ 8.04-7.99 (m, 1H), 7.85-7.79 (m, 1H), 7.54-7.49 (m, 1H), 7.44-7.38 (m, 1H), 7.36 (dd, J=7.5, 1.8 Hz, 1H), 7.31 (td, J=7.8, 1.6 Hz, 1H), 7.03 (td, J=7.5, 0.9 Hz, 1H), 7.01-6.94 (m, 3H), 6.90 (s, 1H), 6.03 (ddt, J=16.9, 10.5, 6.0 Hz, 1H), 5.74 (ddt, J=17.0, 10.3, 6.7 Hz, 1H), 5.33 (dd, J=17.1, 1.5 Hz, 1H), 5.24 (d, J=10.0 Hz, 1H), 5.05 (s, 1H), 4.96-4.86 (m, 2H), 4.26 (t, J=4.4 Hz, 2H), 3.96 (t, J=6.4 Hz, 2H), 3.78-3.69 (m, 1H), 3.65 (s, 3H), 3.64-3.55 (m, 1H), 3.20 (q, J=4.2 Hz, 2H), 2.84 (s, 3H), 2.11 (q, J=6.9 Hz, 2H), 1.83-1.71 (m, 2H), 1.63 (s, 1H), 1.17 (s, 9H). LCMS (M+H)=721.5.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([OH:38])=O)=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:36]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=2)=[O:38])=[CH:31][C:30]=1[N+:45]([O-:47])=[O:46]
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.8 %

Procedure:
A solution of triphenylphosphine (105 mg, 0.403 mmol) in methylene chloride (1 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (72 mg, 0.403 mmol). The reaction mixture was stirred at 0° C. for 20 min and then treated with 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.336 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C., where it was stirred for 20 min. The reaction mixture was then treated with 2-aminopyridine (70 mg, 0.739 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was treated with a solution of hexanes/ethyl acetate (2 mL, 3:1) and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate). The pure 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (60 mg, 48%) was obtained as a pale yellow foam: mp 48-52° C. (foam to gel); EI-HRMS m/e calcd for C19H20ClN3O3 (M+) 373.1193, found 373.1185.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]=[O:10])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH:9]=[O:10])=[CH:6][CH:7]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: O=CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=CC(=O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reaction time: 4 h
Yield: 84.1 %

Procedure:
To a solution of (4-hydroxy-phenyl)-oxo-acetaldehyde (756 mg) in dry DMF (10 mL) were added 3,4-dichlorobenzylbromide (1.2 g) and potassium carbonate (1.03 g). After 4 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were then combined and washed with brine (2×50 mL) and a saturated sodium bicarbonate solution (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give [4-(3,4-dichloro-benzyloxy)-phenyl]-oxo-acetaldehyde (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([SH:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.Cl[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[O:16])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(S)c1C#N
Reactant: O=C(CCl)Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1nc(N)nc(SCC(=O)Nc2cccc(C(F)(F)F)c2)c1C#N
Yield: 78 %

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4-mercapto-6-methylsulfanyl-pyrimidine-5-carbonitrile (3, 153 mg, 0.77 mmol, 1.0 eq.), 2-Chloro-N-(3-trifluoromethyl-phenyl)-acetamide (4, 184 mg, 0.77 mmol), potassium carbonate (106 mg, 0.77 mmol) and acetone (10 mL). The reaction mixture was heated to reflux for 10 min. After removal of potassium carbonate by filtration, the reaction mixture was concentrated to solid. Recrystallization with ether-ethyl acetate gave white solid (240 mg, 80%). LC-MS: (ES+) m/z 400.0 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 10.50 (s, 1H), 8.04(s, 1H), 7.73 (d, 1H), 7.54 (t, 1H), 7.39 (d, 1H), 4.07 (s, 2H), 2.44 (s, 3H) ppm.
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[CH:22]=[CH:21][C:11]2[O:12][C:13]([C:16]([O:18][CH2:19]C)=[O:17])=[CH:14][O:15][C:10]=2[CH:9]=1)(=O)C>CO>[OH:7][C:8]1[CH:22]=[CH:21][C:11]2[O:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][O:15][C:10]=2[CH:9]=1
Reactant: CCOC(=O)C1=COc2cc(OC(C)=O)ccc2O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1=COc2cc(O)ccc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
Add 3.8 mmol of a 2M solution of sodium methanolate to a solution of 0.38 mmol of ethyl 6-acetoxy-1,4-benzodioxin-2-carboxylate in 5 cm3 of anhydrous methanol. After stirring for 4 hours at room temperature and neutralising with acid Dowex resin, the reaction mixture is concentrated under reduced pressure and the crude product obtained is purified by chromatography on a silica column (eluant: petroleum ether/diethyl ether, 80:20). Methyl 6-hydroxy-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 87%.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([CH:17]=O)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCOC(C)=O>[C:27]1([CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)/[N:19]=[CH:17]/[C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[CH:16][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[N:8]3)=[CH:13][CH:12]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=Cc1ccc2ccc(-c3ccccc3)nc2c1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: C(=N/C(c1ccccc1)c1ccccc1)\c1ccc2ccc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 0.03 h

Procedure:
2-Phenylquinoline-7-carbaldehyde (85.00 g, 0.364 mol) and EtOAc (255 mL) were added to a rbf and heated in a 70° C. oil bath. Half of aminodiphenylmethane (70.11 g, 0.38261 mol) was added quickly. After 2 min, a light brown solid precipitated. The reaction was exothermic and the reaction temperature increased to 73° C. The remaining aminodiphenylmethane was then added within 3 min. The reaction temperature decreased to 67° C. slowly. After 30 min, heating was discontinued and the reaction was cooled in an ice bath to about 15° C. The yellow solid was collected by vacuum filtration and dried in vacuo at 45° C. overnight. The title compound was isolated as a yellow solid (115.77 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ ppm 5.69 (s, 1H), 7.21-7.28 (m, 2H), 7.31-7.38 (m, 4H), 7.43-7.50 (m, 5H), 7.50-7.57 (m, 2H), 7.84 (d, J=8.59 Hz, 1H), 7.90 (d, J=8.59 Hz, 1H), 8.13-8.19 (m, 2H), 8.22 (d, J=8.08 Hz, 1H), 8.26 (dd, J=8.46, 1.64 Hz, 1H), 8.37 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+].C1([CH:31]([B-](F)(F)F)[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)C=CC=CC=1.[K+]>O1CCOCC1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([CH2:31][N:32]4[CH2:33][CH2:34][CH:35]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:36][CH2:37]4)=[C:3]([C:17]#[N:18])[C:4]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: F[B-](F)(F)C(c1ccccc1)N1CCCCC1
Reactant: N#Cc1c(Cl)ccn2c(-c3ccccc3)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#Cc1c(CN2CCC(c3ccccc3)CC2)ccn2c(-c3ccccc3)cnc12
Temperature: 150 °C
Yield: 61.9 %

Procedure:
To a mixture of compound D6 (0.15 g, 0.593 mmol) and K2CO3 (0.35 g, 2.55 mmol) in 1,4-dioxane (4 ml) and DMF (1.5 ml) was added compound D7 (0.237 g, 0.85 mmol). The resulting mixture was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.098 g, 0.085 mmol). The reaction mixture was then subjected to microwave heating in a sealed tube at 150° C. for 10 min. The reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The residue thus obtained was purified by preparative reverse phase HPLC to yield compound E1 (0.072 g, 31%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:20]=[CH:19][C:9]2[O:10][C:11]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].C(=O)([O-])[O-:22].[Cs+].[Cs+]>O.C(#N)C>[CH:7]1[C:8]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[O:10][C:9]=2[CH:19]=[CH:20][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][OH:22]
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C(CO)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 7.2 %

Procedure:
A mixture of 2-chloro-N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-ylacetamide (0.115 g, 0.51 mmol) and cesium carbonate (0.34 g) in water (2 mL) and acetonitrile (4 mL) was heated in the microwave for 15 min. The reaction mixture was concentrated and the crude material was purified by HPLC to provide N-6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl-2-hydroxyacetamide (0.010 g). MS (ESI) m/z 274 ([M+H]+);MS (ESI) m/z 272 ([M−H]−).
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([F:15])[CH:17]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1cccc(F)c1
Product: COC(=O)c1cc(Cl)ccc1COc1cccc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3-fluorophenol:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH3:13].[C-:14]#[N:15].[Na+]>CCO>[CH3:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][C:14]#[N:15]
Reactant: [C-]#N
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: [Na+]
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])cc1CC#N

Procedure:
2-Bromomethyl-1-methoxy-4-nitro-benzene (25 g) was dissolved in warm EtOH (45 mL) and stirred while slowly adding a solution of NaCN (6.0 g in 12 mL H2O) at 70° C. After the addition was complete, the reaction was stirred at 70° C. for 90 min. The inorganic solid, which separated on cooling, was collected and washed well with CH3CN. The CH3CN filtrate was filtered again giving further inorganic solid, and again washed with CH3CN. The final CH3CN filtrate was evaporated giving a red-brown solid. This solid was triturated with CH2Cl2 until the washings were colorless. Evaporation of the CH2Cl2 filtrate gave (2-methoxy-5-nitrophenyl)-acetonitrile as a red-brown solid, which was used without further purification.
Reaction SMILES: [OH-].[NH4+:2].[Br:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6](Cl)=[O:7]>C(Cl)Cl>[Br:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([NH2:2])=[O:7]
Reactant: [NH4+]
Reactant: COc1ccc(Br)c(C(=O)Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(Br)c(C(N)=O)c1

Procedure:
A 30% ammonium hydroxide solution (56 mL) is added dropwise to a solution of 2-bromo-5-methoxybenzoyl chloride in methylene chloride at 0° C. After the addition is complete, the reaction mixture is filtered to obtain a solid which is air-dried and recrystallized from a methanol/water solution to give the title product as a white solid, mp 158°-159° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:2][C:1](=[O:3])[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 88 %

Procedure:
To a suspension of 4-(carboxymethyl)benzoic acid (2.43 g, 13.5 mmol) in methanol (30 mL) was added thionyl chloride (50 μL, 0.67 mmol). The reaction mixture was stirred at room temperature for 5.5 h, and a clear solution was obtained. The solvent was removed under reduced pressure. The residue was taken up in ether (100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and water (30 mL). The combined NaHCO3 and water extract was acidified with concentrated HCl in an ice bath. The white precipitation was collected and washed with water, dried to yield 2.30 g (88%) compound 150 as white solid. The material was used without further purification. mp 134-136° C. 1H NMR (400 MHz, CDCl3): δ 3.71 (s, 5H), 7.40 (d, J=8.2 Hz, 2H), 8.07 (d, J=8.2 Hz, 2H). LCMS (ESI), m/z, 193 (M−H)−.
Reaction SMILES: CN[C@@H:3]([C:11]1C=CC=C[CH:12]=1)[CH2:4]N1CCCCC1.C([Li])CCC.[C:22]1([CH:28]=[CH:29][C:30](=[O:32])[CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CCOCC.[Cu]I>[C:22]1([CH:28]([CH2:4][CH2:3][CH2:11][CH3:12])[CH2:29][C:30](=[O:32])[CH3:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN[C@H](CN1CCCCC1)c1ccccc1
Reactant: CC(=O)C=Cc1ccccc1
Agent: [Cu]I
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCC(CC(C)=O)c1ccccc1
Temperature: -65 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
(S)-N-methyl-1-phenyl-2-(1-piperidinyl)ethanamine (361.1 mg, 1.66 mmol) was dissolved in ether (12 mL) and n-butyllithium (2.5M in hexanes, 0.66 mL, 1.65 mmol) was added to the solution at -65° C. The solution was stirred for 5 min at -65° C., warmed to 0° C. and stirred for 10 min at 0° C. To a second flask was added CuI (263 mg, 1.38 mmol) and 10 mL of diethyl ether. This solution was cooled to -40° C. and treated with n-butyl lithium (0.55 mL, 1.38 mmol). The solution in the first flask was cooled to -35° C. and added via canula to the solution of n-BuCu in the second flask. The resulting solution was stirred for 15 min at -35° C., for 10 min at -30° C., and cooled to -78° C. After 30 min, the ether (1 mL) solution of 4-phenyl-3-buten-2-one (201.5 mg, 1.38 mmol) was added slowly at -78° C. The reaction mixture was stirred for 1 hr at -78° C. and warmed to -20° C. The reaction was quenched by adding 4N NH4Cl (15 mL) at -20° C. and extracted with ether (20 mL). The extract was washed with 1N HCl (15 mL), dried (Na2SO4) and concentrated. The oily residue was purified by column chromatography on silica gel (8:1=hexanes/ethyl acetate) to afford (+)-4-phenyl-2-octanone (95.6 mg, 34% chemical yield, 2% ee, [α]D =0.06 (c=5.00, chloroform)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:23][CH:12]2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:24][O:25][CH:26]([O:29][CH3:30])[CH2:27][NH2:28].ClCCl>CC(O)CC>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([C@H:12]([OH:23])[C@@H:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:28][CH2:27][CH:26]([O:29][CH3:30])[O:25][CH3:24])[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: COc1ccc(C2OC2c2ccc(OC)c(OC)c2)cc1OC
Reactant: COC(CN)OC
Solvent: ClCCl
Solvent: CCC(C)O
Product: COc1ccc([C@@H](NCC(OC)OC)[C@@H](O)c2ccc(OC)c(OC)c2)cc1OC

Procedure:
57 g (0.17 mol) of 3,3',4,4'-tetramethoxy-stilbene oxide, 120 ml (1.1 mol) of aminoacetaldehyde dimethyl acetal, 1.5 l of dichloromethane, 80 ml of 2-butanol.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[F-].[Cs+]>COCCOC>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1-c1ccccc1
Temperature: 120 °C
Yield: 90 %

Procedure:
0.1 g (0.24 mM) of 2-chloro-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylo-pyranoside, 30 ml of DME, 0.037 g (0.29 mM) of phenylboronic acid, 0.102 g (0.66 mM) of cesium fluoride and 0.021 g (0.024 mM) of [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) dichloromethane are mixed. The mixture is heated for 2 hours at 120° C. under an inert atmosphere in a microwave oven. The reaction medium is then filtered on a Whatman filter, the material on the filter is rinsed with ethyl acetate and the filtrate is extracted. The pH is neutralized with ammonium chloride solution. The organic phase is dried over sodium sulfate and the product is concentrated under reduced pressure. It is purified by chromatography on a silica column (eluent: dichloromethane/ethyl acetate 99/1; v/v) to give the expected product in the form of a white powder with a yield of 90%.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([O:11][CH2:12][CH:13]([C:20]2[N:21]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:22]=[C:23]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]=23)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:6]([CH3:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:21]2[C:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:7]3[C:8]([CH3:10])=[CH:9][C:4]([C:3]([OH:38])=[O:2])=[CH:5][C:6]=3[CH3:37])=[C:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:23]3=[N:22]2)=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCCCC3)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)O)cc(C)c1OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 2, 4-{2-[2-(4-chloro-phenyl)-2,4,5,6,7,8-hexahydro-cycloheptapyrazol-3-yl]-2-cyclohexyl-ethoxy}-3,5-dimethyl-benzoic acid methyl ester was hydrolysed using aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH:19]=2)[C:17]#[N:18])[N:10]=[N:9][N:8]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:3][CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][C:15]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH:19]=2)[C:17]#[N:18])[N:10]=[N:9][N:8]=1
Reactant: N#Cc1cc(-n2nnnc2CO)ccc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1cc(-n2nnnc2CCl)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 521 %

Procedure:
Thionyl chloride (4.25 g, 3.57 mmol) was added dropwise to a solution of 5-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 40, 8.0 g, 29.7 mmol) in toluene (200 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and then heated to reflux for 4 hr. The mixture was diluted with EtOAc and washed with ice-water, and saturated NaHCO3, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-40% ethyl acetate/pet ether to give the title compound (5.35 g) as a white powder.