Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1cccc(Br)c1
Solvent: C1CCOC1
Product: Cc1cc(Cc2cccc(Br)c2)oc1C
Yield: 91.6 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol), commercial 3-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5M n-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet. ether gave 12.63 g (85%) of the title compound. 1H NMR (DMSO-d6) δ1.85 (s, 3H), 2.10 (s, 3H), 3.86 (s, 2H), 5.90 (s, 1H), 7.21-7.30 (m, 2H), 7.34-7.47 (m, 2H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.FC(F)(F)C(O)=O.C(Cl)Cl>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:27][C:25]1[S:26][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C@H:2]([OH:1])[CH2:3][N:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[CH:28][C:23]=2[N:24]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate, a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroacetic acid/methylene chloride (20 ml) was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo) to yield an oil. The oil was diluted with acetone (20 ml) and solid potassium carbonate was added until the foaming stopped. The resulting mixture was allowed to stir overnight. The solution was filtered through Celite 512, and the filtrate was evaporated (in vacuo), to yield an oil. The oil was placed under high vacuum overnight, to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol as a clear viscous oil (3.4 g. 6.3 mmol).
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[Li+]>CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@H:28]([CH2:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COCCC[C@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCCC[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A reaction mixture of 43.2 (32.0 mg, 61 μmol) and lithium hydroxide (0.2 mL, 3.33M in water) in MeOH (1.0 mL) was stirred at ambient temperature for 16 hours. The reaction mixture was purified by HPLC (reverse phase) to give the title compound 43. 1H NMR (400 MHz, CD3CN) δ ppm 1.16 (s, 9H) 1.19-1.36 (m, 1H) 1.45-1.67 (m, 1H) 2.45 (d, J=8.61 Hz, 1H) 2.53 (d, J=6.65 Hz, 1H) 3.14 (s, 3H) 3.20 (t, J=6.46 Hz, 2H) 3.72 (s, 3H) 4.97 (s, 2H) 6.77 (dd, J=6.26, 3.13 Hz, 1H) 6.83-6.91 (m, 3H) 6.99-7.10 (m, 4H) 7.37 (dd, J=8.22, 1.96 Hz, 1H) 7.57 (d, J=8.22 Hz, 1H). MS ESI (neg.) m/e: 507.2 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:36][NH2:37]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH:37][CH3:36])[CH2:14][C:13]=3[CH:12]=[C:11]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(-c3ccccc3)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3ccc(OC)cc3)c2O1

Procedure:
The title compound was prepared (0.081 g, 99%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(4-methoxyphenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.30 g, 9.8 mmol). mp >250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH:18]=[O:19])=[CH:17][C:7]1=2.C1COCC1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]2[O:15][C:16]([CH2:18][OH:19])=[CH:17][C:7]1=2
Reactant: COC(=O)c1cc2oc(C=O)cc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2oc(CO)cc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 114.3 %

Procedure:
Methyl 4-(3,4-dichlorobenzyl)-2-formylfuro[3,2-b]pyrrole-5-carboxylate (0.2 g) was dissolved in methanol (10 mL) and THF (10 mL) and cooled to 0° C. Sodium borohydride (26 mg) was added and the reaction stirred for 2 hours. The mixture was acidified with 2M HCl, partially evaporated, and extracted with ethyl acetate. Combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a white solid (0.23 g), NMR d(CDCl3) 3.8 (3H, s), 4.65 (2H, d), 5.6 (2H, s), 6.2 (1H, s), 6.85 (1H, s), 7.0 (1H, dd), 7.2 (1H, d), 7.35 (1H, d); M/z (+) 340 (MH+), 332, 278.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(OC)c2)c1C

Procedure:
4-[2-(3-Methoxy-phenyl)-acetyl]-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (91) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-methoxyphenyl)-acetyl chloride following the procedure described in Example 32. crude yield: 95%. 1H-NMR (400 MHz, CDCl3): δ 1.36 (t, 3H), 2.61 (s, 3H), 3.77 (s, 3H), 3.99 (s, 2H), 4.32 (q, 2H), 6.81 (m, 3H), 7.24 (m, 1H), 7.45 (d, 1H), 9.41 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 11.75, 14.40, 47.59, 55.19, 60.66, 112.19, 115.04, 121.71, 127.22, 129.58, 136.75, 159.75, 193.65 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.75, 14.40, 55.19; CH2 carbons: 47.59, 60.66; CH carbons: 112.19, 115.04, 121.71, 127.22, 129.58 ppm. LC/MS: 60.20%, m/z=301
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][OH:12])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:15]>C([O-])(C([O-])=O)=O.C([O-])(C([O-])=O)=O.O=[Ti+2].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][OH:12])(=[O:9])[O:4][CH2:5][CH2:6][OH:15])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCO
Reactant: OCCO
Agent: O=[Ti+2]
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: CCP(=O)(CCO)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 388 g (2 mol) of butyl ethyl(2-hydroxyethyl)phosphinate (produced as in Example 5) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyloxalate, followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuation to leave 315 g (96% of theory) of 2-hydroxyethyl ethyl-(2-hydroxyethyl)phosphinate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].Cl[CH2:20][C:21]1[S:25][C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:20][C:21]2[S:25][C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)=[N:23][C:22]=2[CH3:36])=[CH:8][C:7]=1[CH3:14]
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 14 b], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester (example 103 e]) was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate and potassium iodide to yield (S)-3-{2,6-dimethyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-2-ethoxy-propionic acid methyl ester as yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH:10]([C:12]#[N:13])[CH2:11][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:15][OH:16]>N1C=CC=CC=1.ClCCl.O>[OH:16][N:15]=[CH:2][CH2:1][C:4]1[C:9]2[CH:10]([C:12]#[N:13])[CH2:11][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cccc2c1C(C#N)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: N#CC1Cc2cccc(CC=NO)c21

Procedure:
10.07 g of the product of Step 1 and 6.13 g of hydroxylamine hydrochloride in 200 ml of pyridine are stirred at ambient temperature for 19 hours. After removal of the pyridine by evaporation, the yellow oil obtained is taken up in dichloromethane and water. The organic phase is removed, dried and concentrated, allowing the expected product to be isolated.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9].IC.[Cl-].[NH4+]>O1CCCC1>[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[C@H:13]([CH3:1])[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9]
Reactant: CC(C)NC(C)C
Reactant: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@H]1[C@@H](O)[C@H](C)C(=O)N1c1ccc(C#N)c(OC)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of diisopropylamine (0.291 mL) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium-hexane solution (1.24 mL, 1.6 mol/L) at −78° C., the mixture was stirred for 1 hr, and a solution of 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (206.5 mg) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, iodomethane (0.247 mL) was added dropwise at −78C, and the mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/4) to give the title compound as a colorless solid (yield: 108.8 mg, 50%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][CH:9]([O:19][CH2:20][CH3:21])[C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=1)[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:18][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([O:8][CH2:6][CH3:7])[O:19][CH2:20][CH3:21])[CH:11]=1)(=[O:4])=[O:3]
Reactant: CCOC(OCC)c1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(OCC)c1cccc(CCOS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.18 g) in dichloromethane (0.2 mL) was added to a stirred solution of 2-(3-(diethoxymethyl)phenyl)ethanol (example 20, step c) (0.23 g) and triethylamine (0.429 mL) in dichloromethane (2.5 mL) cooled in an ice bath. After 1 h, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.28 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH3:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[C:16]([CH3:15])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Reactant: Nc1cccc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=Cc1ccccc1)C(=O)Nc1cccc(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of 3-chloroaniline (0.98 mL, 9.3 mmol) in CH2Cl2 (25 mL) at 0° C. is added pyridine (0.78 mL, 9.5 mmol). To the resulting solution is added dropwise a solution of α-methyl cinnamic acid chloride (1.6 g, 9.3 mmol) in CH2Cl2 (8 mL). After 3 hours, the solution is concentrated. The crude product is purified by column chromatography eluting with 5% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound is obtained as a solid (2.5 g, 9.2 mmol). 1H NMR (CDCl3, 300 MHz) δ7.95 (m, 1H), 7.73 (s, 1H), 7.46 (m, 1H), 7.33 (m, 6H), 7.22 (m, 1H), 7.03 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][N:6]1[S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10])=[O:4].[OH-].[Li+]>CO>[C:13]1([CH2:12][S:9]([N:6]2[CH2:7][CH2:8][CH:5]2[C:3]([OH:4])=[O:2])(=[O:11])=[O:10])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1CCN1S(=O)(=O)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN1S(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Yield: 82829.6 %

Procedure:
1-Phenylmethanesulfonyl-azetidine-2-carboxylic acid methyl ester (1.13 g, 4.19 mmoles) was dissolved in methanol (20 mL) and cooled to 0° C. Treatment of this solution with aqueous lithium hydroxide (7.75 mL, 1 M) was followed by warming to ambient temperature over a 3 hour period. Most of the methanol was removed in vacuo and the pH was adjusted to 1 by treatment with 1 M HCl. The product was extracted into ethyl acetate, dried over anhydrous sodium sulfate and concentrated to afford 886 g (83%) of the product as a white solid. 1H NMR (CDCl3) δ2.37–2.57 (m, 2H); 3.21–3.31 (m, 1H); 3.81 (s, 3H); 4.01 (q, 1H, J=8.6); 4.33 (d, 1H, J=13.7); 4.44 (d, 1 H, J=13.7); 4.98 (dd, 1H, 9.4, 8.6); 7.34–7.53 (series of m, 5H).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[CH:3]([CH3:5])[CH3:4].Br[C:8]1[CH:9]=[C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1[F:14]>CN1C(=O)CCC1.C1COCC1.CCOC(C)=O.C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[F:14][C:13]1[CH:12]=[CH:11][C:10]([C@:15]([C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([F:34])[CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][C:8]=1[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C[Zn+]
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(Br)c1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc([C@](N)(Cc2ccccc2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 75 °C
Yield: 18 %

Procedure:
To a solution of [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (8 mg, 0.01 mmol) in NMP (0.5 mL) was added isobutylzinc(II) bromide in THF (0.5 M, 0.7 mL, 0.35 mmol) followed by (S)-1-(3-bromo-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine, prepared as described Procedure 62, 5 and 6, (50 mg, 0.11 mmol) in anhydrous THF. The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with EtOAc and the organic layer was washed with sat. NH4Cl, dried over Na2SO4 and concentrated to yield (R)-1-(4-fluoro-3-isobutylphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine. LCMS: RT=3.62 min [M−NH2] 417 (Waters Sunfire-S5-C18 4.6×50 mm, eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [Br-].[C:2]1([CH:8](O[P+](N(CC)CC)(N(CC)CC)N(CC)CC)[C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C2C(=CC=CC=2)CCC1>>[F:10][C:9]([F:11])([F:12])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)[P+](OC(c1ccccc1)C(F)(F)F)(N(CC)CC)N(CC)CC
Agent: [Br-]
Solvent: c1ccc2c(c1)CCCC2
Product: FC(F)(F)Cc1ccccc1
Temperature: 200 °C
Yield: 63.7 %

Procedure:
In distillation apparatus, a mixture of 50 g (0.1 mol) of (1-phenyl-2,2,2-trifluoroethoxy)tris(diethylamino)phosphonium bromide according to Example 1 and 40 g (0.3 mol) of tetrahydronaphthalene were heated for 2 hours at about 200° C. After about an hour, the reaction product was slowly distilled off through a small column, in which the boiling temperature at the column head did not exceed 140° C. The remaining product was distilled off from the reaction mixture at 40 mbar, after the reaction was completed. Repeated distillation of the combined fractions gave 10.2 g (64% of yield) of (2,2,2-trifluoroethyl)benzene of b.p. 71° to 72° C./100 mbar.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:19])[C@@H:13]3[C@H:16]([OH:18])[CH3:17])[C:10]=2[C:20]([O-:22])=[O:21])=[CH:5][CH:4]=1)#[N:2].[Na+].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:15][C@H:14]3[N:11]([C:12](=[O:19])[C@@H:13]3[C@H:16]([OH:18])[CH3:17])[C:10]=2[C:20]([O:22][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:21])=[CH:5][CH:4]=1)#[N:2]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccc(C#N)cc3)C[C@H]12
Reactant: ClCCN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCCN3CCOCC3)=C(c3ccc(C#N)cc3)C[C@H]12
Yield: 33 %

Procedure:
Sodium (5R,6S)-3-(4-cyanophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.2 g) in dry DMF (4.0 ml) was ice-cooled. Thereto ware added tetrabutylammonium iodide (0.53 g), and 4-(2-chloroethyl)-morpholine (1M toluene, 8 mL), and the mixture was stirred. Thirty minutes later, after removal of the bath the mixture was stirred for 48 hours and thereto was added ethyl acetate. The mixture was washed succesively with aqueous phosphate buffer (pH 6.86), water and brine. The organic layer was dried over sodium sulfate, concentrated, and the residue was purified with silica gel column chromatography (chloroform:methanol=1:0→10:1) to give 2-morpholin-4-ylethyl(5R,6S)-3-(4-cyanophenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.10 g, yield 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:23](O)=[O:24])[CH2:21][CH3:22].S(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[O:19][CH:20]([C:23](=[O:24])[NH:8][CH2:5][CH2:4][CH3:3])[CH2:21][CH3:22]
Reactant: CCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCNC(=O)C(CC)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reaction time: 1 h

Procedure:
A mixture of 2.00 g. of N-[4-chloro-3-(1-carboxypropoxy)phenyl]-3,4,5,6-tetrahydrophthalimide and 5 ml. of thionyl chloride was refluxed with stirring for 1 hour and excess thionyl chloride was distilled off under a reduced pressure. The product was dissolved in 10 ml. of toluene and a mixture of 0.36 g. of n-propylamine, 0.6 g. of triethylamine and 5 ml. of toluene was added and the mixture was stirred at room temperature for 2 hours. Chloroform was added and the resulting organic phase was washed with water and dried and the product was purified by a chromatography on a column of silica gel (developing solvent:chloroform) and recrystallized from a mixture of ethyl acetate and n-hexane to obtain 1.62 g. of Compound No. 286 shown in Table 1.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[CH2:1]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:46]1[CH:47]2[CH2:50][CH2:51][N:44]([CH2:49][CH2:48]2)[CH2:45]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(NCc1ccccc1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A mixture of 2-(benzylamino)-2-phenylacetic acid (I23) (0.94 g, 3.90 mmol), DCC (0.97 g, 4.70 mmol), HOBt (0.63 g, 4.07 mmol) and 3(R)-quinuclidinol (1.51 g, 11.7 mmol) in dry THF (30 mL) is stirred at room temperature overnight under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated and the residue is taken up with EtOAc and washed twice with water. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by flash chromatography (DCM/MeOH=98/2, 0.2% NH3(aq.) to 95/5, 0.5% NH3(aq.)) to give a mixture of diastereoisomers 1 and 2 of C24 (231 mg, 52% yield, mixture of diasteroisomers).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH2:9]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][CH:19]=[N:18][C:17]=2[N:16]([CH2:24][CH2:25][CH2:26][CH3:27])[C:14]1=[O:15])[CH2:10][CH2:11][CH3:12].[Na]>C(O)C>[O:8]=[C:6]([CH3:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:20]1[C:21]2[C:22](=[O:23])[N:13]([CH2:9][CH2:10][CH2:11][CH3:12])[C:14](=[O:15])[N:16]([CH2:24][CH2:25][CH2:26][CH3:27])[C:17]=2[N:18]=[CH:19]1
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: CC(=O)CCCCBr
Agent: [Na]
Solvent: CCO
Product: CCCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(CCCC)c1=O

Procedure:
21.5 g (0.12 mol) of freshly distilled 1-bromo-5-hexanone are dissolved in 200 ml of absolute ethanol in a 500 ml capacity flask, followed by the gradual dropwise addition at boiling temperature of 34.7 g (0.12 mol) of sodium 1,3-dibutyl xanthine dissolved in 200 ml of absolute ethanol. The solution is heated under reflux. The reaction is over after about 24 hours. Removal of the alcohol by distillation in a rotary evaporator leaves a solid white residue. This residue is introduced into an extraction tube in which it is extracted with petrol 40/80 in a Soxhlet apparatus until no more starting material can be detected. The petrol is distilled off in a rotary evaporator, leaving 25 g (0.069 mol) of 7-(5'-oxohexyl)-1,3-dibutyl xanthine, corresponding to 75% of the theoretical, based on the sodium 1,3-dibutyl xanthine reacted.