Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[CH3:13][N:14]([CH3:41])[C:15]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][CH2:19][C:18]([CH2:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([F:34])[CH:32]=3)[NH:27][CH:26]=2)(O)[CH2:17][CH2:16]1>ClCCl>[F:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]1[C:18]3([CH2:19][CH2:20][C:15]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([N:14]([CH3:41])[CH3:13])[CH2:16][CH2:17]3)[CH2:22][CH2:23][CH2:24][C:25]2=1
Reactant: CN(C)C1(c2ccccc2)CCC(O)(CCCc2c[nH]c3ccc(F)cc23)CC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC2(CCCc3c2[nH]c2ccc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
Trifluoromethane sulphonic acid trimethylsilyl ester (822 mg, 671 μL, 3.70 mmol) was added to a suspension of 4-dimethylamino-1-[3-(5-fluoro-1H-indol-3-yl)propyl]-4-phenyl-cyclohexanol (365 mg, 0.92 mmol) in absolute dichloromethane (50 mL), and stirred for 10 d at room temperature. The reaction solution was then diluted with dichloromethane (10 mL), washed with 1 N sodium carbonate solution (2×10 mL), water and saturated sodium chloride solution (10 mL each), the organic phase dried with sodium sulphate and concentrated to low volume in a vacuum. The residue (249 mg) was mixed with methanol (50 mL) and stirred over the weekend at room temperature, wherein a light-coloured solid formed, which was filtered off and washed with a little methanol (2 mL).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CCO>[OH-].[Na+].O>[CH:6]1([CH2:5][C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:3]2[CH2:2][O:20]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
tert-Butyl (2S,3S)-4-chloro-1-cyclohexyl-3-hydroxybutan-2-ylcarbamate (1 g, 3.28 mmol) was dissolved in a solution of 0.71 N NaOH in EtOH (5.6 mL, 3.95 mmol, 1.2 eq). After stirring for 1 h, the mixture was concentrated to give a residue, which was dissolved in water and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (0.84 g, 95%). 1H NMR: 0.83 (m, 1H), 0.95 (m, 1H), 1.10-1.42 (m, 5H), 1.45 (s, 9H), 1.68 (m, 5H), 1.76 (m, 1H), 2.72 (m, 2H), 2.83 (m, 1H), 3.55 (m, 1H), 4.38 (m, 1H). MS (E/Z): 270 (M+H+).
Reaction SMILES: [Cl-].[Li+].[CH2:3](C([Sn])=C(CCCC)CCCC)[CH2:4]CC.[C:18]1([C:24]2[C:33]([CH3:34])=[CH:32][C:31]3[C:26](=[C:27](OS(C(F)(F)F)(=O)=O)[CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1.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:18]1([C:24]2[C:33]([CH3:34])=[CH:32][C:31]3[C:26](=[C:27]([CH:3]=[CH2:4])[CH:28]=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc2cccc(OS(=O)(=O)C(F)(F)F)c2nc1-c1ccccc1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cccc2cc(C)c(-c3ccccc3)nc12
Temperature: 110 °C
Yield: 96 %

Procedure:
6.3 g (150 mmol) of lithium chloride, 16.8 ml (57 mmol) of tributylvinyltin and 1.6 g (1.5 mmol) of Pd(PPh3)4 are added sequentially at ambient temperature to a solution of 17.7 g (48 mmol) of 2-phenyl-3-methyl-8-trifluoromethanesulfonyloxyquinoline in 250 ml of dioxane, degassed beforehand using a stream of nitrogen. The reaction medium is then heated at 110° C. for 16 hours. After evaporating the dioxane, the residue is taken up in 200 ml of water and 200 ml of ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography (eluent: ethyl acetate/cyclohexane 3/7) to provide 11.3 g of 2-phenyl-3-methyl-8-vinylquinoline in the form of a colorless oil. (Yield: 96%)
Reaction SMILES: C([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:6]2([CH:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[CH2:10][C:9](=O)[NH:8][CH:7]2[C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=O)C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:50]>C1COCC1.C1(C)C=CC=CC=1>[Cl:47][C:44]1[CH:45]=[C:46]2[NH:4][C:5](=[O:48])[C:6]3([CH:11]([C:12]4[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=4[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[O:22])[CH2:10][C:9](=[S:50])[NH:8][CH:7]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:41]2=[CH:42][CH:43]=1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(Cl)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-1-acetyl-6-chloro-2′-(5-chloro-2-methyl-phenyl)-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.04 mmol) and P2S5 (26 mg, 0.12 mmol) in THF (2 mL) was stirred at room temperature overnight, then diluted with toluene (10 mL). The resultant mixture was concentrated and washed with DCM for two times. The DCM solution was collected and purified by flash column chromtography. The product was then stirred with K2CO3 (20 mg) in MeOH for 15 min, and then partitioned between ethyl acetate and diluted HCl solution. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title product as white solid (25 mg).
Reaction SMILES: [CH3:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)([CH2:5][CH3:6])[CH:3]=[O:4].[BH4-].[Na+].Cl>C(O)C>[CH3:1][C:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)([CH2:5][CH3:6])[CH2:3][OH:4]
Reactant: CCC(C)(C=O)Cc1cccc(C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(C)(CO)Cc1cccc(C)c1

Procedure:
29 g of 2-methyl-2-(3-methylbenzyl)-butyraldehyde (according to Example 11) were stirred for 20 hours at room temperature with 3 g of sodium borohydride in 80 ml of ethanol. Excess sodium borohydride was then decomposed with 2N HCl. After removing the ethanol, the residue was taken up in ether and extracted with water. The organic phase was extracted by shaking with 2N NaOH and water and dried with solid potassium carbonate. After removing the solvent, fractional distillation was carried out. 20 g of end product were obtained in a temperature range of from 72° C. to 73° C. at 0.12 mbar.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC([O-])=O.[Na+].[Br:17]Br>CC(O)=O>[Br:17][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4](=[O:9])[NH:5][CH:6]=1
Reactant: O=c1[nH]cccc1C(F)(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cc(Br)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(trifluoromethyl)pyridin-2(1H)-one (25.0 g, 0.15 mol) in AcOH (300 mL) were added NaOAc (15.1 g, 0.18 mol) and dropwise Br2 (8.6 mL, 0.17 mol). Then the mixture was stirred at 80° C. overnight, concentrated, diluted with sat aq. NaHCO3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=7/2) to give compound P45a (29.7 g, 80%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][C:18]([CH3:24])([CH3:23])[CH2:19][C:20]([OH:22])=[O:21])=[CH:5][CH:4]=1>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][C:18]([CH3:23])([CH3:24])[CH2:19][C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2c(CC(C)(C)CC(=O)O)nc3ccccc32)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(CC(=O)O)Cc1nc2ccccc2n1Cc1ccc(O)cc1
Yield: 20.8 %

Procedure:
2 g of 4-[1-(4-methoxybenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoic acid, prepared in Example 68, are dissolved in 40 ml of acetic acid and 40 ml of 48% hydrobromic acid. The mixture is refluxed for 3 hours and the solvents are evaporated off under vacuum. The residue is taken up with a 1 N solution of sodium hydroxide so as to adjust the pH to 9-10, and the resulting aqueous phase is washed with ether and then acidified with sulfur dioxide to pH 5.5. The crystals obtained are filtered off, washed with water and then with ether and then chromatographed on silica gel in a 9:1 chloroform/methanol eluent to give 0.4 g of 4-[1-(4-hydroxybenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoic acid in the form of crystals melting at 215°-216° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH3:18])=[N:15][C:14]=2[CH:19]=1>C(Cl)(Cl)(Cl)Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[S:17][C:16]([CH2:18][Br:1])=[N:15][C:14]=2[CH:19]=1
Reactant: Cc1nc2cc(Br)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(Br)ccc2s1
Yield: 39 %

Procedure:
N-Bromosuccinimide (4.45 g, 25 mmol, 1.4 equiv.) and subsequently α,α′azoisobutyronitrile (110 mg, 0.7 mmol, 0.04 equiv.) were added to a solution of 5-bromo-2-methyl-benzothiazole (4.07 g, 17.85 mmol, 1 equiv.) in CCl4 (110 ml). The reaction mixture was stirred at reflux for 24 hrs. After cooling, succinimide was removed by filtration and was rinsed with CCl4 (100 ml). The filtrate was evaporated to dryness under reduced pressure and the orange solid residue was purified by column chromatography on silica, eluted with CH2Cl2/hexane (20%-70% gradient), to give the desired product as a white solid, 2.15 g (39% yield). Mp 116-117, HPLC-MS (method 1): m/z 308 [M+H]+, Rt=4.84 min. The reaction gave also 1.40 g (20% yield) of the by-product 5-bromo-2-dibromomethyl-benzothiazole, as well as 0.89 g (22%) of un-reacted starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5](Cl)[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C-:17]#[N:18].[Na+]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:17]#[N:18])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: Clc1ccc2nc3ccccc3c(Cl)c2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Product: N#Cc1c2ccccc2nc2ccc(Cl)cc12
Yield: 55.1 %

Procedure:
A mixture of 1 gm of 2,9-dichloroacridine [obtained by the process of Bogucka, Roczniki, Chem. Vol. 40 (1966) p 677]230 mg of sodium cyanide and 20 cc of methanol was heated for 4 hours at 140°C in a sealed tube and after cooling, the mixture was filtered. The precipitate was washed with acetone and dried. The product was purified by sublimation in vacuo at 0.1 mm Hg to obtain 530 mg of 2-chloro-9-cyano-acridine melting at 208°C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:17][C:18]1[C:23]([F:24])=[C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[N:21]=[C:20](F)[C:19]=1[F:37]>C(OCC)C>[F:24][C:23]1[C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[N:21][C:20]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[C:19]([F:37])[C:18]=1[CH3:17]
Reactant: Cc1c(F)c(F)nc(Oc2cccc(C(F)(F)F)c2)c1F
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(F)c(Oc2cccc(C(F)(F)F)c2)nc(-c2ccc(C(F)(F)F)cc2)c1F
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Butyl lithium (2.6 ml, 6.6 mmol, 2.5 M solution in hexane) is added to a solution of 1-bromo-4-trifluoromethyl benzene (0.84 ml, 6 mmol) in anhydrous diethyl ether (5 ml) at −30° C. The mixture is stirred for 60 min at −20 ° C. and for 60 min at 10° C. The solution is allowed to warm to ambient temperature. This solution is then added to a mixture of 4-methyl-2,3,5-trifluoro-6-(3-trifluoromethylphenoxy)pyridine 2A (1.5 g, 5 mmol) in anhydrous diethyl ether (100 ml) at −50° C. during 2.5 hours. The mixture is further stirred for 7 hours at −50° C. and washed with saturated aqueous ammonium chloride and water. After drying and evaporation of the organic layer, the residue is purified by vacuum destillation. One obtains colorless crystals (0.37 g, 0.85 mmol, bp. 130 ° C. at 0.01-0.02 mbar) of mp. 87° C.
Reaction SMILES: [CH2:1]([Sn:5]1([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH:9]=[CH:8][CH:7]=[C:6]1[Li])[CH2:2][CH2:3][CH3:4].C([Sn]1(CCCC)C=CCC=C1)CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:38]([Sn:42]1([CH2:51][CH2:52][CH2:53][CH3:54])[CH:47]=[CH:46][CH:45]([CH2:48][CH2:49]Br)[CH:44]=[CH:43]1)[CH2:39][CH2:40][CH3:41]>C1COCC1.O>[CH2:1]([Sn:5]1([CH2:12][CH2:13][CH2:14][CH3:15])[CH:10]=[CH:9][CH:8]([CH2:49][CH2:48][CH:45]2[CH:44]=[CH:43][Sn:42]([CH2:51][CH2:52][CH2:53][CH3:54])([CH2:38][CH2:39][CH2:40][CH3:41])[CH:47]=[CH:46]2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn]1(CCCC)C=CC(CCBr)C=C1
Reactant: [Li]C1=CC=CC[Sn]1(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: CCCC[Sn]1(CCCC)C=CCC=C1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn]1(CCCC)C=CC(CCC2C=C[Sn](CCCC)(CCCC)C=C2)C=C1
Reaction time: 16 h

Procedure:
A solution of 1 ,1-dibutyl-1-stannacyclohexadienyllithium prepared from 1,1-dibutyl-1-stannacyclohexa-2,5-diene (0.08 g, 2.67 mmol) and 2.67 mmol of lithium diisopropylamide (LDA) in 20 mL of THF was added to a solution of 1,1 -dibutyl-4-(2-bromoethyl)-1-stannacyclohexa-2,5-diene (1.0 g, 2.46 mmol) in 5 mL THF at -78° C. After stirring approximately 16 hours, 10 mL of water were added and the product was extracted with pentane, dried over MgSO4, and evaporated to dryness. The red residue left contained 1.25 g (81 percent) of crude product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH3:7].[CH3:8][N:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].Cl[Sn](Cl)(Cl)Cl.Cl>C(Cl)Cl>[CH3:8][N:9]1[C:13]([C:14]([C:6]2[N:2]([CH3:1])[C:3]([CH3:7])=[CH:4][CH:5]=2)=[O:15])=[C:12]([CH3:17])[CH:11]=[C:10]1[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)n(C)c1C(=O)Cl
Reactant: Cc1cccn1C
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CC(=O)OC(C)(C)C)n(C)c1C(=O)c1ccc(C)n1C
Temperature: 0 °C
Yield: 50 %

Procedure:
Ten mmole (0.95 g) of 1,2-dimethyl-pyrrole and an equivalent amount of t-butyl 1,4-dimethyl-5-chlorocarbonyl-2-pyrrole acetate were dissolved in 10 ml of methylene chloride and stirred at 0° C. under nitrogen atmosphere. Three grams (12 mmole) of SnCl4 in 10 ml methylene chloride was added dropwise and the resulting mixture was stirred at room temperature for three hours followed by pouring into 25 ml 6 N HCl at 0° C. with vigorous stirring. The resulting suspension was extracted three times with 20 ml portions of methylene chloride. The crude extract was column chromatographed and crystallized from ether/hexane to give 1.6 g (50%) of t-butyl 1,4-dimethyl-5-(1,5-dimethylpyrrol-2-oyl)pyrrole-2-acetate.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18].Br[CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(#N)C>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:13]1=[O:18]
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: CN1CCNCC1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCN(C)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
DIPEA (0.52 ml, 2.96 mmol) and 1-methylpiperazin-2-one hydrochloride (0.22 g, 1.48 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) in acetonitrile (4 ml). The reaction was stirred at room temperature for 1.5 hours. DIPEA (0.13 ml, 0.74 mmol) was added again and the reaction was stirred at room temperature overnight. The solvent was evaporated and the crude was purified by flash chromatography (DCM/Acetone=9/1) to obtain ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (256 mg, 75% yield) as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[NH2:14][CH2:15][C:16]([N:18]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>ClCCl>[C:19]1([N:18]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:16](=[O:17])[CH2:15][NH:14][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[O:13])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1
Reactant: O=C(O)c1ccc2ccccc2n1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CN(C(=O)CNC(=O)c1ccc2ccccc2n1)c1ccccc1
Reaction time: 3 h
Yield: 38 %

Procedure:
A solution of 0.85 g of N,N'-carbonyldiimidazole in 10 cm3 of anhydrous dichloromethane is added dropwise, at a temperature close to 20° C., to a solution of 0.87 g of 2-quinolinecarboxylic acid in 15 cm3 of anhydrous dichloromethane. The suspension obtained is stirred for 3 hours at a temperature close to 20° C. and a solution of 2.6 g of tert-butyl 2-(2-amino-N-phenylacetamido)acetate in 25 cm3 of anhydrous dichloromethane is then added. The reaction mixture is stirred for 16 hours at a temperature close to 20° C. and 50 cm3 of water are then added. The aqueous phase is separated off by decanting and then reextracted with twice 15 cm3 of 1,2-dichloroethane. The organic phases are combined, washed with twice 25 cm3 of a saturated aqueous sodium bicarbonate solution and then with twice 25 cm3 of distilled water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization of the residual solid from a mixture of cyclohexane and ethyl acetate (90/10 by volume), 0.8 g of tert-butyl 2-(N-phenyl-2-quinolinecarboxamidoacetamido)acetate melting at 114° C. is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.[CH2:18]([O:22][C:23]1[CH:24]=[C:25](/[CH:30]=[C:31](\[O:36][CH3:37])/[C:32]([O:34][CH3:35])=[O:33])[CH:26]=[CH:27][C:28]=1I)[CH2:19][CH2:20][CH3:21].O>COCCOC.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(OCC)(=O)C>[NH2:8][C:9]1[CH:10]=[C:11]([C:28]2[CH:27]=[CH:26][C:25](/[CH:30]=[C:31](\[O:36][CH3:37])/[C:32]([O:34][CH3:35])=[O:33])=[CH:24][C:23]=2[O:22][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:13][CH:14]=1
Reactant: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1I
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCCCOc1cc(/C=C(\OC)C(=O)OC)ccc1-c1cccc(N)c1
Temperature: 100 °C
Yield: 93.8 %

Procedure:
11.2 mL (22.4 mmol) of aqueous 2 N potassium carbonate solution and 0.52 g (0.45 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 1.87 g (10.8 mmol) of 3-aminophenylboronic acid hydrochloride and 3.5 g (9 mmol) of methyl (Z)-3-(3-butoxy-4-iodophenyl)-2-methoxyacrylate (prepared according to Example 24c) in 70 mL of ethylene glycol dimethyl ether. The reaction mixture is heated at 100° C. for 4 hours. After addition of 30 mL of water and extraction with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 3 g (93%) of methyl (Z)-3-(3′-amino-2-butoxybiphenyl-4-yl)-2-methoxyacrylate are obtained in the form of a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][S:16]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=2[S:29](=[O:32])(=[O:31])[NH2:30])(=[O:18])=[O:17])=[CH:10][CH:9]=1>O1CCCC1>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][S:16]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([CH2:24][OH:25])=[CH:22][C:21]=2[S:29]([NH2:30])(=[O:32])=[O:31])(=[O:17])=[O:18])=[CH:10][CH:9]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1NS(=O)(=O)CCc1ccc(Br)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(CO)ccc1NS(=O)(=O)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
Lithium aluminum hydride (1 M in tetrahydrofuran, 1.9 mL, 1.9 mmol) was added dropwise to a solution of 4-[2-(4-bromo-phenyl)-ethanesulfonylamino]-3-sulfamoyl-benzoic acid (0.22 g, 0.47 mmol) in anhydrous tetrahydrofuran (20 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 hours, cooled to 0° C. and quenched by addition of saturated sodium sulfate solution (20 mL). The precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 0.15 g (71% yield) of the title compound.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:10]1[O:12][CH2:11]1)=[O:7])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[OH:12][CH2:11][C@@H:10]1[O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCO
Product: O=C1N[C@@H](Cc2ccccc2)[C@H](CO)O1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
Ethanol (27.5 ml) was added to (2S, 3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2.75 g), followed by addition of aqueous 6.8% citric acid solution (29.5 g) and agitation at 70° C. for 2 hours. After cooling to ambient temperature, ethanol was removed under reduced pressure. The product was extracted by using ethyl acetate, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. Furthermore, a mixture solvent of hexane (2.5 ml) and ethyl acetate (2.5 ml) was added, to generate crystal. The crystal was filtered, and then, the crystal was rinsed twice by using a mixture solvent of hexane/ethyl acetate (1/1). The resulting crystal was dried, to afford the objective (4S, 5R)-5-hydroxymethyl-4-phenylmethyloxazolidin-2-one (1.79 g) in 80% yield.