Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH2:27][C:28]([O-:30])=[O:29].[Na+].Cl>CN(C)C=O.O>[CH:21]1[CH:22]=[CH:23][C:18]([C@@H:8]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][O:17][CH2:27][C:28]([OH:30])=[O:29])[CH2:13][CH2:14]2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:19][CH:20]=1
Reactant: OCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)COCCN1CCN([C@H](c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 12.5 °C
Yield: 85.1 %

Procedure:
Levorotatory (−)-[2-[4-[(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethanol (100 gm) is dissolved in dimethylformamide (200 ml) and cooled to 10-15° C. Potassium hydroxide (44 gm) is added to the reaction mixture and maintained for 30 minutes. Sodium monochloroacetate (85 gm) is added to the reaction mixture and further maintained for 1 hour at 10-15° C. The temperature of the reaction mixture is then raised to 25° C. and maintained for 1 hour. The temperature of the reaction mixture is further raised to 35-38° C. and maintained for 3 hours. Water (1800 ml) is added to the reaction mixture and the pH of the reaction mixture is adjusted to 9.6-9.8 with hydrochloric acid. The reaction mixture is then washed five times with ethyl acetate (each time 400 ml) and the layers are separated. The pH of the aqueous layer is adjusted to 5-5.5 with hydrochloric acid and extracted with dichloromethane (400 ml) followed by two times with dichloromethane (each time 100 ml). The extracted dichloromethane layer is washed with water and solvent distilled off to afford 100 gm of levocetirizine as a residue, which is dissolved in acetone (1000 ml). Activated carbon (10 gm) is added, stirred and filtered. To the filtrate hydrochloric acid gas is passed till the pH of the reaction mass is 2. The reaction mass is refluxed for 30 minutes, cooled to 25-35° C. and filtered. The product is washed with acetone (100 ml) and dried to constant weight to obtain 105 gm of Levocetirizine dihydrochloride [M.R: 215-220° C.; [α]36525: +12.8 (c=1, water); Chiral Purity by HPLC: 99.8%].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]=[O:23]>C1COCC1>[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH:22]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)[OH:23]
Reactant: Cn1ccnc1C=O
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Product: Cn1ccnc1C(O)c1ccc(OC2CCCCO2)cc1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5 M in THF, 160 mL, 80 mmol) was added slowly to a solution of 1-methyl-2-imidazolecarboxaldehyde (8 g, 72.7 mmol) in THF (100 mL) via syringe at −78° C. The reaction mixture was stirred at this temperature for 3 hours and quenched with saturated NH4Cl (aq). The mixture was extracted with EtOAc (2×100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford M12.1 as a colorless oil (21 g), which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21]CSC)[CH:6]=[CH:7][C:8]1[S:9][C:10]2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[N:17]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.O>[OH:21][C:20]1[CH:19]=[CH:18][C:5]([CH:6]=[CH:7][C:8]2[S:9][C:10]3[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[N:17]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1OCSC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COc1cc(C=Cc2nc3c(s2)NCCCC3)ccc1O
Yield: 20.3 %

Procedure:
2-(3-Methoxy-4-methylthiomethoxystyryl)-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]azepine (1.88 g) obtained in Example 87, was dissolved in a mixture of dimethylformamide, acetonitrile and water, following by addition of mercuric chloride (2.11 g). The mixture was refluxed for 15 hrs. After completing the reaction, an aqueous sodium hydrogen carbonate was added to the mixture. The mixture was extracted with a mixture of chloroform and methanol, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was subjected to a column chromatography on silica gel eluting a mixture of chloroform and methanol (98:2, v/v) to give the title compound (yield 318 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH:4]=[C:5]([C:10](=O)[CH3:11])[C:6]([O:8][CH3:9])=[O:7].Cl.[C:19]([NH2:27])(=[NH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC([O-])=O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([CH3:11])[NH:27][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:26]1
Reactant: N=C(N)c1ccccc1
Reactant: COC(=O)C(=Cc1ccc(Cl)cc1Cl)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(c2ccccc2)=NC1c1ccc(Cl)cc1Cl
Temperature: 60 °C
Yield: 88.8 %

Procedure:
To a stirred solution of methyl 2-(2,4-dichlorobenzylidene)-3-oxobutanoate (480 mg, 1.8 mmol) and benzamidine HCl salt (275 mg, 1.8 mmol) in DMF (6 mL) was added NaOAc (144 mg, 1.8 mmol). The reaction was heated to 60° C. for 3 days and was quenched by 1N HCl (10 mL). The reaction was diluted with EtOAc (10 mL) and the organic layer was washed with 1N HCl, saturated NH4Cl solution (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give the crude product as a yellow oil (600 mg). The crude reaction product was moved onto next step without further purification.
Reaction SMILES: BrC1S[C:4](Cl)=[C:5]([Cl:23])[C:6]=1[CH2:7][CH:8]([NH:10][C:11]([C:13]1[C:14]([C:19]([F:22])([F:21])F)=[N:15][N:16]([CH3:18])[CH:17]=1)=[O:12])[CH3:9].[Br:25][C:26]1[S:30]C(Cl)=C(CC(NC(C2C(C(F)(F)F)=NN(C)C=2)=O)C)C=1Cl.ClC1SC(Cl)=C(Cl)C=1CC(NC(C1C(C(F)(F)F)=NN(C)C=1)=O)C>>[Br:25][C:26]1[S:30][C:6]([CH2:7][CH:8]([NH:10][C:11]([C:13]2[C:14]([CH:19]([F:21])[F:22])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:12])[CH3:9])=[C:5]([Cl:23])[CH:4]=1
Reactant: CC(Cc1c(Cl)sc(Br)c1Cl)NC(=O)c1cn(C)nc1C(F)(F)F
Reactant: CC(Cc1c(Br)sc(Cl)c1Cl)NC(=O)c1cn(C)nc1C(F)(F)F
Agent: CC(Cc1c(Cl)sc(Cl)c1Cl)NC(=O)c1cn(C)nc1C(F)(F)F
Product: CC(Cc1sc(Br)cc1Cl)NC(=O)c1cn(C)nc1C(F)F

Procedure:
In a sulfonation flask 2.07 g (7.2 mmol) of the amine isomer mixture prepared in example P5b) and 1.45 g (14.4 mmol) triethylamine are dissolved in 50 ml of methylenechloride. Then a mixture of 1.65 g (7.2 mmol) 3-trifluoromethyl-1-methyl-1-H-pyrazole 4-carboxylic acid chloride and 50 ml methylenechloride is added at room temperature under stirring. After stirring for 16 hours the solvent is evaporated in a water jet vacuum and the residue purified by column chromatography over silicagel (eluent: ethylacetate/heptane 1:2-2:1). 1.52 g of an isomeric mixture of amides is obtained in the form of slightly brown crystals (m.p.: 134-138° C.). The mixture consists of 27% of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(2-bromo-4,5-dichlorothiophen-3-yl)-1-methylethyl]amide, 30% of 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(5-bromo-2,4-dichlorothiophen-3-yl)-1-methylethyl]amide and 43% of the undesired 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(2,4,5-trichlorothiophen-3-yl)-1-methylethyl]amide.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[O:31][N:30]=[C:29]([CH2:32][CH3:33])[N:28]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.COCCOC>[CH2:32]([C:29]1[N:28]=[C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[F:34])[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])[O:31][N:30]=1)[CH3:33]
Reactant: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4F)cc32)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Tert-butyl 4-{6-bromo-1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (1.00 g, B99), (2-fluorophenyl)boronic acid (337 mg), dichlorobis(tricyclohexylphosphine)palladium (137 mg) and aqueous cesium carbonate solution (1.4 ml, 2.0 M) are placed in a microwave tube and DME (15 ml) is added. The reaction vessel is sealed and the mixture is subjected to microwave irradiation at 150° C. with stirring for 40 min. The mixture is allowed to cool to RT, additional (2-fluorophenyl)boronic acid (52 mg) is added and the vessel is subjected to microwave irradiation at 150° C. for additional 40 min. The mixture is allowed to cool to RT and then filtered over a plug of silica (eluent: DCM). After removal of all volatile materials the residue is purified by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/0 to 2/3 (v/v)] to afford tert-butyl 4-{1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(2-fluorophenyl)-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate which is crystallized from toluene and directly used for step 2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][N:10]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[O:12][C:11]2=[O:25])=[C:4]([O:26][CH3:27])[CH:3]=1.N1C=CC=CC=1.[Br:34][CH2:35][C:36](Br)=[O:37].[K+].[Br-]>C1COCC1>[Br:34][CH2:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([O:26][CH3:27])[C:5]([CH2:9][N:10]2[N:14]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=3)[O:12][C:11]2=[O:25])=[CH:6][C:7]=1[Cl:8])=[O:37]
Reactant: O=C(Br)CBr
Reactant: COc1cc(N)c(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)CBr)c(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3-[(4-Amino-5-chloro-2-methoxyphenyl)methyl]-5-[4-(trifluoromethyl) phenyl]-1,3,4-oxadiazol-2(3H)-one (3 g, 7.5 mmol) and pyridine (0.68 ml, 8.41 mmol) were dissolved in THF (35 ml) under N2 and cooled to 0° C. Bromoacetyl bromide (0.72 ml, 8.26 mmol) was added dropwise and the reaction mixture stirred for 18 h at 24° C. before being partitioned between ethyl acetate (400 ml) and 0.1N HCl solution (50 ml). The organic phase was washed with saturated NaHCO3 solution and brine, and dried over MgSO4. Active carbon (500 mg) was added and the solution filtered through a plug of Celite. Concentration gave 3.8 g (98%); mp 140-182° C. (dec); IR(KBr, υ=cm-1) 3348, 2972, 1784, 1672, 1594, 1234, 1168, 1066; 1H NMR (300 MHz, DMSO-d6) δ 3.77 (3H, s), 4.15 (2H, s), 4.90 (2H, s), 7.47-7.48 (2H, m), 7.86 (2H, d, J=8.4 Hz), 7.96 (1H, d, J=8.3 Hz), 9.30 (1H, s); MS(ESl)m/z: 520(MH+)
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:20]2[CH:25]=[C:24]([O:26]CC3C=CC=CC=3)[CH:23]=[CH:22][C:21]=2[CH3:34])[N:4]=[C:5]2[C:14]3[CH:13]=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[CH:10][C:9]=3[NH:8][C:7](=[O:19])[C:6]=12.CO.[H][H]>[Pd].C(OCC)(=O)C>[NH2:1][C:2]1[N:3]([C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=2[CH3:34])[N:4]=[C:5]2[C:14]3[CH:13]=[C:12]([O:15][CH3:16])[C:11]([O:17][CH3:18])=[CH:10][C:9]=3[NH:8][C:7](=[O:19])[C:6]=12
Reactant: [H][H]
Reactant: COc1cc2[nH]c(=O)c3c(N)n(-c4cc(OCc5ccccc5)ccc4C)nc3c2cc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2[nH]c(=O)c3c(N)n(-c4cc(O)ccc4C)nc3c2cc1OC
Yield: 62.3 %

Procedure:
A mixture of 3-amino-7,8-dimethoxy-2-(5-benzyloxy-2-methylphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (50 mg), 10% palladium/active carbon (50% water, 25 mg), methanol (20 ml) and ethyl acetate (20 ml) was stirred under the hydrogen atmosphere for 1 day. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was solidified by adding ethyl acetate-hexane. The solid was collected by filtration, washed with ethyl acetate-hexane, and then dried to obtain the target compound (25 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[O:14]=[S:15]1(=[O:32])[CH2:20][CH2:19][N:18]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[C:17]2=[N:16]1.O>CS(C)=O>[CH:9]1([CH2:8][O:31][C:28]2[CH:27]=[CH:26][C:25]([C:24]3[C:17]4=[N:16][S:15](=[O:32])(=[O:14])[CH2:20][CH2:19][N:18]4[CH:21]=[CH:22][CH:23]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: ICC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OCC4CCCC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
A mixture of potassium carbonate (450 mg), (iodomethyl)cyclopentane (684 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (5 mL) was stirred at 130° C. for 2 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with Et2O to give the title compound (311 mg) as a pale yellow solid. The solid was crystallized from CH3CN-IPE to give a pale yellow solid.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:20]1[C:19]1[CH:21]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccc(OC(F)(F)F)cc2)C1=O
Yield: 82.3 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 4-(trifluoromethoxy)aniline (0.595 mL; 4.41 mmol) in ethanol (3 mL). 2-oxo-1-(4-(trifluoromethoxy)phenyl)pyrrolidine-3-carboxylic acid 0.350 g (82%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)cc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=566.93 (M+H+); retention time=0.91 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OC(C)(C)C(C)(C)O2)=[C:18]([F:31])[C:17]=1[F:32].[F-].[Cs+]>COCCOC.O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([F:32])[C:18]=2[F:31])[N:6]=1)=[O:4]
Reactant: CC1(C)OB(c2ccc(Cl)c(F)c2F)OC1(C)C
Reactant: C=Cc1c(N)nc(Cl)nc1C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(F)c2F)nc1C(=O)OC
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
6-Amino-2-chloro-5-vinylpyrimidine-4-carboxylic acid methyl ester (0.6 g, 2.81 mmol), 2-(4-chloro-2,3-difluorophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.0 g, 3.65 mmol), bis(triphenylphosphine)-palladium(II) dichloride (197 mg, 0.28 mmol), and cesium fluoride (0.85 g, 5.6 mmol) were combined in 10 mL of 1,2-dimethoxyethane (DME) and 10 mL of water. The reaction mixture was heated in a CEM microwave reactor at 100° C. for 15 min (other temperature/time pairs used in the subsequent examples were 110° C. for 15 min; 150° C. for 5 min). The cooled reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.336 g, 36.7% yield) as a yellow solid (mp 130-132° C.); 1H NMR (CDCl3) δ 7.74 (m, 1H), 7.22 (m, 1H), 6.8 (dd, 1H), 5.62-5.7 (m, 2H), 5.67 (m, 1H), 5.42 (br s, 2H), 3.94 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[O:17]C(C)(C)C)#[N:2].CCOCC.O>C(#N)C.Cl.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][C:4]=1[OH:17])#[N:2]
Reactant: CCOC(=O)CCCc1ccc(C#N)c(OC(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)CCCc1ccc(C#N)c(O)c1
Reaction time: 1.33 h
Yield: 82.1 %

Procedure:
Ethyl 4-(4-cyano-3-t-butoxyphenyl)butanoate (6.8 g, 23.5 mmol) was dissolved in a mixture of acetonitrile (42 mL) and conc. HCl (3.85 mL) and allowed to stand for 80 min. The reaction was poured into ether/water and the ether layer separated. The ether layer was washed with water and brine, and the combined aqueous washes were reextracted once with ether. The combined ether layers were dried over sodium sulfate and concentrated to give 5.1 g of an off white waxy solid. This material was loaded onto a silica gel column (5×15 cm) in CHCl3 and eluted with 20% EtOAc in CHCl3 to yield 4.5 g of ethyl 4-(4-cyano-3-hydroxyphenyl)butanoate: 1H-NMR (CDCl3) 8.2 (1H, s), 7.42 (1H, d), 6.95 (1H, s), 6.77 (1H, d), 4.2 (2H, q), 2.63 (2H, dd), 2.39 (2H, dd), 1.96 (2H, m), 1.28 (3H, t); 13C (CDCl3) 174.4, 159.5, 149.2, 132.8, 120.8, 117.0, 116.1, 97.1, 60.9, 35.2, 33.6, 25.7. 14.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH:11](OC)(OC)[O:12][CH3:13]>>[CH3:11][O:12][CH:13]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: COC(OC)OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: COC=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (D-2) (10.0 g, 70 mmol, 1.0 eq) in trimethyl orthoformate (100 mL, 365 mmol, 5.0 eq) is stirred at reflux for 3 h. The resulting mixture is cooled to RT and concentrated in vacuo. The residue is triturated with diethyl ether and then filtered. The filter cake is washed with cooled diethyl ether and dried in vacuo to afford the product, 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (D-3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:36](O)=[O:37])[CH2:34][OH:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.Cl.C([O:46][C:47](=[O:57])[C@@H:48]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[NH2:49])(C)(C)C.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:40]=[CH:39][C:27]([O:28][CH2:29][C:30]([NH:32][C@@H:33]([C:36]([NH:49][C@@H:48]([C:47]([OH:57])=[O:46])[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:37])[CH2:34][OH:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@H](CO)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)N[C@H](CO)C(=O)N[C@H](Cc1ccccc1)C(=O)O
Reaction time: 25 h
Yield: 49.6 %

Procedure:
A solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-([2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-D-serine (diastereomeric mixture) (0.008 g, 0.014 mmol), D-phenylalanine tert-butyl ester hydrochloride (0.005 g, 0.018 mmol) and N-Methylmorpholine (0.006 ml, 0.055 mmol) in DCM (3 ml) was stirred at RT for 5 min. TBTU (0.008 g, 0.025 mmol) was added. After 3 days the conversion to the ester (M/z: 776.1) was complete and the mixture was concentrated under reduced pressure. The residue was dissolved in formic acid (3 ml) and the solution was stirred for 25 h. The mixture was concentrated under reduced pressure and the residue was dissolved in MeOH (4 ml) and TEA (1 ml). The solution was stirred at 40° C. for 6 h. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-50% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.005 g (53% yield) of the title product was obtained as a white solid. M/z: 720.1. 1H NMR (DMSO, 400 MHz): δ 2.78-2.96 (m, 3H), 3.03-3.11 (m, 1H), 3.44-3.60 (m, 2H), 4.20-4.36 (m, 3H), 4.51 (s, 2H), 4.67-4.76 (m, 1H), 5.01-5.06 (m, 1H), 5.70 (bs, 1H), 6.90-6.98 (m, 2H), 7.05-7.25 (m, 1H), 7.29-7.37 (m, 4H), 7.84-8.00 (m, 2H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20](N)=[O:21])=[CH:18][C:12]=3[C:11](=[O:24])[CH2:10][C:9]=2[CH:25]=1)([O-:4])=[O:3].C(O)(=[O:28])C>>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]2[S:14][C:13]3[CH:15]=[CH:16][C:17]([CH:19]([CH3:23])[C:20]([OH:28])=[O:21])=[CH:18][C:12]=3[C:11](=[O:24])[CH2:10][C:9]=2[CH:25]=1)([O-:4])=[O:3]
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Reactant: CC(=O)O
Agent: Cl
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc([N+](=O)[O-])ccc1S2
Reaction time: 3.5 h
Yield: 43 %

Procedure:
A mixture of 3 ml of conc. hydrochloric acid, 3 ml of acetic acid and 0.33 g of 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide was refluxed with stirring for 3.5 hours. The reaction mixture was concentrated, and to this was added water. Threafter, the resulting mixture was extracted with ethyl acetate, and the extract was reextracted with a saturated sodium hydrogen carbonate solution. The extract was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a brown solid substance, which was chromatographed over 6 g of silica gel and eluted with chloroform, and there were obtained light yellow crystals. The thus obtained crystals were recrystallized from chloroform to give 0.14 g (yield: 43%) of 2-(10,11-dihydro-8-nitro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow powder having a melting point of 209.5°-211° C.