Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1.BrCl>>[Br:1][C:2]1[CH:11]=[C:10]([C:27]#[C:26][C:23]2[C:22]([F:28])=[CH:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)=[CH:25][N:24]=2)[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Reactant: OCCOc1ccc(I)cc1Br
Agent: ClBr
Product: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1Br

Procedure:
The product was prepared analogously to Example 7.1e starting from 2-(2-bromo-4-iodophenoxy)ethanol and 5-(4-chlorophenyl)-2-ethynyl-3-fluoropyridine. Yield: 1.60 g (82% of theoretical); C21H14BrClFNO2 (M=446.697); calc.: molpeak (M+H)+: 446/448/450 (BrCl); found: molpeak (M+H)+: 446/448/450 (BrCl); HPLC-MS: 6.38 minutes (method B).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCCCCC.C([Li])CCC.[B:27](OC)([O:30]C)[O:28]C.Cl>C1(C)C=CC=CC=1.O1CCCC1>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[B:27]([OH:30])[OH:28])=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1c2ccccc2cc2ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OB(O)c1c2ccccc2cc2ccccc12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
9-Bromoanthracene 38.6 g was dissolved in dehydrated toluene 80 ml and dehydrated THF (tetrahydrofuran) 160 ml, and the solution was cooled to −40° C. A 1.58M n-butyllithium hexane solution 106 ml was dropwise added thereto and stirred at −40° C. for 30 minutes, the temperature was elevated up to −10° C. The solution was cooled again down to −70° C., and a dehydrated THF solution of trimethyl borate 50.0 ml was gradually dropwise added thereto. The solution was stirred at −70° C. for 2 hours and then slowly heated up to room temperature. After left standing for a night, a 10% hydrochloric acid aqueous solution 100 ml was added thereto and stirred, and then it was extracted twice with toluene. The organic layer was washed with saturated brine and dried on anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized from toluene/hexane, filtered and dried, whereby targeted 9-anthraceneboronic acid 24.4 g was obtained in the form of pale brown crystal (yield: 73%).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=1[CH3:42]>CN(C)C=O>[CH3:42][C:33]1[C:34]([C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:13]1[C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=2[N:11]=[C:12]1[C:14]([F:17])([F:15])[F:16]
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.12 %

Procedure:
A suspension of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 15 min. 1-(Bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (1.729 g, 6.83 mmol) was added in and the resulting reaction mixture was stirred for 3 h at 80° C. The mixture was then cooled to room temperature and poured into ice/water. The precipitate was collected by filtration, washed with water, then hexanes (turned into a gum on the filter paper—some material was lost). The crude material was purified on a silica gel column (ISCO, eluting with 0-5% MeOH in DCM) to give the desired product (580 mg, 1.099 mmol, 24.12% yield) (several mixed fractions obtained were discarded). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (d, J=2.53 Hz, 1H), 7.61 (d, J=7.83 Hz, 1H), 7.37 (d, J=2.27 Hz, 1H), 7.23 (t, J=7.96 Hz, 1H), 6.29 (d, J=7.58 Hz, 1H), 5.76 (s, 2H), 3.93 (s, 3H), 3.70-3.78 (m, 4H), 3.12-3.22 (m, 4H), 2.53 (s, 3H). MS (ES+) m/e 502 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[CH:37](O)=O>CC1C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:1]=[CH:37]3)[CH2:10][CH2:11]2)=[CH:23][CH:24]=1
Reactant: O=CO
Reactant: Nc1ccccc1C(=O)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: Cc1ccccc1
Product: O=c1c2ccccc2ncn1CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 73 %

Procedure:
A mixture of 4.86 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide, 1.4 parts of formic acid and 45 parts of methylbenzene was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane, water and ammonium hydroxide. The organic phase was separated, dried, filtered and evaporated. The residue was crystallized from acetonitrile, yielding 3.6 parts (73%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4(3H)-quinazolinone; mp. 190.6° C. (compound 137).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[OH:11].[CH2:12]([N:19]1[CH2:26][CH2:25][C:22]2([O:24][CH2:23]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[ClH:3].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[O:11][CH2:23][C:22]1([OH:24])[CH2:25][CH2:26][N:19]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: OC1(COc2c(Cl)cccc2Cl)CCN(Cc2ccccc2)CC1
Temperature: 76 °C

Procedure:
The potassium salt of 2,6-dichlorophenol was formed by heating at 76° C. a mixture of 6.6 g (0.1 mole) of potassium hydroxide pellets (85%) and 16.3 (0.1 mole) of 2,6-dichlorophenol in 150 ml of dry dimethylformamide until a clear brown solution was obtained. The stirred solution was treated dropwise with 20.3 g (0.1 mole) of 6-benzyl-1-oxa-6-azaspiro[2.5]octane in 50 ml of dry dimethylformamide and heated at 80° C. for 120 hours. TLC (5% methyl benzene/silica gel G) indicated that the reaction was only 40% complete. The reaction mixture was treated with 4 volumes of water and the suspension extracted with three 100 ml portions of benzene. The extracts were combined, washed with 50 ml of 3N sodium hydroxide followed by three 50 ml portions of water, dried over magnesium sulfate and evaporated under reduced pressure to give 26.2 g of dark brown oil. The oil was chromatographed on a 500 g column of silica gel 60 and eluted with benzene followed by 1 to 10% acetone-benzene gradient. A small amount of 2,6-dichlorophenol was collected and discarded. The column was then eluted with a mixture of 1% methanol and 10% acetone in benzene. Fractions containing the product were combined and evaporated under reduced pressure to give 10.5 g of a yellow oil. The residual oil was converted to the hydrochloride salt in the usual way and recrystallized from acetone to give 5.2 g of product, m.p. 203°-205° C. with a phase change at 140°-153° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[CH:5][S:4][CH:3]=1.[C:8](Cl)(=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[C:6]([NH:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5][S:4][CH:3]=1)(=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: Nc1cscc1N
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1cscc1NC(=O)CCCCCCCCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3,4-Diaminothiophene (2.0 g, 17 mmol) was dissolved in pyridine and the solution was added dropwise to a stirred solution of 6.5 g (34 mmol) of decanoyl chloride (boiling point 125° C. at 45 mbar) via a syringe. It was stirred overnight. The reaction mixture was poured into ice water mixed with concentrated hydrochloric acid and extracted with chloroform. The organic layers were washed with water, 2% strength NaOH and again with water and then dried over MgSO4 which was mixed with active carbon to remove the colored impurities. After evaporating the solvent, a solid was obtained which was recrystallized from a toluene-hexane mixture. The solid had a melting point of 99-100° C. The yield was 6.7 g (90% of theory).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[CH2:17]1[C:25]2[C:20](=[CH:21][C:22]([N:26]=[C:27]=[O:28])=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>C1COCC1.CO.C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:27]([NH:26][C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH2:19]4)=[O:28])=[CH:12][CH:11]=2)[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1c(-c2ccc(N)cc2)csc1N
Reactant: O=C=Nc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1c(-c2ccc(NC(=O)Nc3ccc4c(c3)CCC4)cc2)csc1N
Reaction time: 0.5 h

Procedure:
Crude 2-amino-4-(4-amino-phenyl)-thiophene-3-carboxylic acid amide (0.15 mmoles, 1 eq) is dissolved in 5 mL THF and treated with 400 μL of 0.35 M THF solution of 5-indanyl isocyanate (0.15 mmoles, 1 eq). When the reaction is complete, as judged by TLC analysis, the reaction mixture is diluted with 1 mL methanol and 1 mL triethylamine, stirred for 30 minutes, and concentrated to dryness. The residue is purified by prep HPLC yielding pure 2-amino-4-[4-(3-indan-5-yl-ureido)-phenyl]-thiophene-3-carboxylic acid amide.
Reaction SMILES: C1C2C(=CC3C(C=2COC(=O)[NH:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])=CC=CC=3)C=CC=1.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl.C1(OC)C=CC=CC=1>[F:33][C:34]([F:39])([F:38])[C:35]([O-:37])=[O:36].[Cl:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][NH3+:18]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(NCCOCCOCCCCCCCl)OCc1c2ccccc2cc2ccccc12
Solvent: ClCCl
Solvent: COc1ccccc1
Product: O=C([O-])C(F)(F)F
Product: [NH3+]CCOCCOCCCCCCCl
Reaction time: 0.5 h

Procedure:
To {2-[2-(6-Chloro-hexyloxy)-ethoxy]-ethyl}-carbamic acid anthracen-9-ylmethyl ester (0.56 g, 1.2 mmol) dissolved in 4 ml dichloromethane was added 2 drops of anisole. The reaction mixture is cooled by means of an ice/NaCl bath. After 10 minutes trifluoroacetic acid (2 ml) is added. The reaction mixture turns dark brown upon addition and is allowed to stir for 30 minutes. All volatiles are removed under reduced atmosphere. The residue is re-dissolved in CH2Cl2 and washed twice with water. The aqueous fractions are frozen and lyophilized overnight. An oily residue remains and is dissolved in anhydrous DMF to be used as a stock solution in further reactions. Mass spectrum, m/e Calcd for C10H23ClNO2+: 224.14 (100%), 226.14 (32%). Found: 224.2, 226.2.
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C[C:12]([CH3:15])([O-])[CH3:13].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>CN(C=O)C>[CH2:13]([O:10][C@@H:2]1[CH2:1][O:5][C@@H:4]2[C@@H:6]([O:9][CH2:19][CH:18]=[CH2:17])[CH2:7][O:8][C@H:3]12)[CH:12]=[CH2:15]
Reactant: C=CCBr
Reactant: CC(C)(C)[O-]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCO[C@H]1CO[C@H]2[C@@H]1OC[C@H]2OCC=C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven dried, two neck round bottomed flask equipped with a Teflon magnetic stir bar was charged with 3.00 g of isosorbide (20.5 mmol), 5.30 g potassium t-butoxide (47.2 mmol), and 50 mL of anhydrous DMF. This heterogeneous mixture was stirred for 30 minutes at room temperature, then brought to about 0 degrees Celsius in an ice/saturated brine bath. While stirring and under argon, 3.90 mL of allyl bromide (45.2 mmol) was added dropwise via syringe. After addition was complete, the ice bath was removed and the solution warmed to room temperature. The reaction was continued for 4 hours at room temperature under argon. After this time, the heterogeneous solution was filtered to remove potassium bromide and other solids. The filtrate was then transferred to a 250 mL boiling flask containing a Teflon stir bar, was diluted with 50 mL of methylene chloride and 50 mL of water, and vigorously stirred. The biphasic solution was poured into a 250 mL separatory funnel and the bottom organic layer removed into a 125 mL Erlenmeyer flask. This solution was then diluted with another 50 mL volume of water, the resultant biphasic solution mixed as before, and the organic phase was extracted, dried with anhydrous magnesium sulfate and concentrated in vacuo, producing a light yellow oil, 4.12 g (89%). This material was spectroscopically confirmed by GC/MS (EI), providing one signal (m/z 226.1) corresponding to (3R,3aR,6S,6aR)-3,6-bis(allyloxy)hexahydrofuro[3,2-b]furan (diallyl isosorbide, B).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].I[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:15])[CH3:16])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18])[CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2C(C)C
Reactant: CCCCI
Product: CCCCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)ethanone (Compound 62, 205 mg, 0.65 mmol) and 1-iodobutane (0.35 mL, 3.24 mmol) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@@H:5]([N:17]1[CH2:25][C:24]2[C:19](=[C:20]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:21]=[CH:22][C:23]=2[Cl:26])[C:18]1=[O:33])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1.[OH-].[Na+].O>C1COCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([NH:27][C:28]([CH:30]2[CH2:31][CH2:32]2)=[O:29])=[C:19]2[C:24]=1[CH2:25][N:17]([C@@H:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:4][C:3]([OH:34])=[O:2])[C:18]2=[O:33]
Reactant: CCOc1cc([C@@H](CC(=O)OC)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CC(=O)O)N2Cc3c(Cl)ccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a solution of (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid methyl ester (3.0 g, 6.2 mmol) in THF (60 ml) was added NaOH (10N, 1.2 ml, 12 mmol). The mixture was stirred at room temperature overnight. To it was added water (50 ml). The mixture was extracted with EtOAc (50 ml×2). The aqueous layer was acidified by conc. HCl until pH=6. The resulted cloudy mixture was extracted with EtOAc (50 ml×2). The organice layer was washed with water (30 ml×2), brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo to give (3R)-3-[4-chloro-7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-ethoxy-4-methoxy-phenyl)-propionic acid as a white solid (2.8 g, 99%): mp, 118–120° C.; 1H NMR (CDCl3) δ 0.86–0.91 (m, 2H, c-CH2), 1.05–1.11 (m, 2H, c-CH2), 1.45 (t, J=7.0 Hz, 3H, OCH2CH3), 1.65–1.70 (m, 1H, c-CH), 3.13 (dd, J=6, 15 Hz, 1H, CHH), 3.23 (dd, J=10, 15 Hz, 1H, CHH), 3.86 (s, 3H, OCH3), 4.00–4.11(m, 3H, NCHH+OCH2CH3), 4.32 (d, J=18 Hz, 1H, NCHH), 5.80–5.86 (m, 1H, CHN), 6.83–6.92 (m, 3H, Ar), 7.35 (d, J=9 Hz, 1H, Ar), 8.41 (d, J=9 Hz, 1H, Ar), 10.39 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.4, 8.5, 14.7, 16.1, 36.7, 45.9, 51.8, 55.9, 64.6, 111.5, 112.4, 118.9, 119.0, 1198, 121.9, 130.1, 132.9, 136.7, 139.0, 148.7, 149.5, 168.7, 172.8, 173.8; Anal Calcd for C24H25ClN2O6+0.37 H2O: C, 60.11; H, 5.41; N, 5.84. Found: C, 60.11; H, 5.25; N, 5.64, H2O, 1.40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:45][CH2:46][CH2:47][OH:48]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:17][CH2:18][C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:22]([NH2:24])=[O:23])[CH2:20][CH2:21]2)=[O:15])=[CH:11][C:10]=1[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:45][CH2:46][CH2:47][OH:48])=[CH:35][CH:36]=1
Reactant: OCCCCl
Reactant: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(O)cc3)c(-c3ccc(Cl)cc3Cl)s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(OCCCO)cc3)c(-c3ccc(Cl)cc3Cl)s2)CC1
Temperature: 90 °C
Yield: 65.8 %

Procedure:
1.65 g of the compound obtained in stage 1G), 0.57 g of K2CO3 and 0.83 g of 3-chloropropan-1-ol are added to 10 ml of DMF. The reaction medium is heated at 90° C. for 3 hours. The reaction medium is then poured onto distilled water and the expected compound is extracted with ethyl acetate. The organic phase is dried and evaporated. After crystallizing in ethyl acetate, 1.2 g of the expected compound are obtained.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]([C:13]2[CH:35]=[CH:34][C:16]([O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]([C:28]([O:30]C)=[O:29])[CH2:23][CH2:24][O:25]4)=[CH:20][C:19]=3[C:32]#[N:33])=[CH:15][CH:14]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C1COCC1.FC(F)(F)C(O)=O>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([O:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][O:25]4)=[CH:20][C:19]=3[C:32]#[N:33])=[CH:34][CH:35]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC4c4ccccc4)cc3)c(C#N)cc21
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cc2c(cc1Oc1ccc(C(=O)NC3CC3c3ccccc3)cc1)OCCC2C(=O)O
Temperature: 25 °C
Reaction time: 17 h
Yield: 30.6 %

Procedure:
Methyl 7-(4-((2-phenylcyclopropyl)carbamoyl)phenoxy)-6-cyano-3,4-dihydro-2H-chromene-4-carboxylate (25.9 mg, 0.0553 mmol) was dissolved in THF (1.5 ml) and 1M LiOH-monohydrate solution in water (0.111 ml, 0.111 mmol) was added. The mixture was stirred for 17 hours at ambient temperature. A few drops of trifluoroacetic acid were added to the mixture and the mixture was purified on silica gel (MeOH in dichloromethane gradient with 1% acetic acid) to provide 7.7 mg of the title compound as a thin film (30%). MS (apci) m/z=453.0 (M−H).
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6](NC)(=[O:8])=[O:7].[CH2:13](Br)[CH2:14]Br.C(=O)([O-])[O-].[K+].[K+].[CH3:23][N:24](C)C=O>>[NH2:1]/[C:2](/[CH3:12])=[CH:3]\[C:4]([CH:5]1[S:6](=[O:7])(=[O:8])[CH:13]([CH3:14])[NH:24][CH2:23]1)=[O:11]
Reactant: CN(C)C=O
Reactant: CNS(=O)(=O)CC(=O)C=C(C)N
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C/C(N)=C/C(=O)C1CNC(C)S1(=O)=O
Reaction time: 6 h

Procedure:
In accordance with the procedure described in Example 7, a solution of 3.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide and 4 ml of ethylene bromide in 50 ml of dimethylformamide were treated with 12 g of potassium carbonate and the mixture was stirred intensively at 80° in an oil bath for 6 hours. The product was firstly chromatographed on 300 g of silica gel with methylene chloride/ethyl acetate (1:1) as the elution agent and then recrystallized from ethanol. There were obtained 1.9 g of 5-(3-aminocrotonyl)-2-methylthiazolidine 1,1-dioxide in the form of colorless crystals, m.p. 113°-115°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH2:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18].CN(C)C=O>C(#N)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]2[NH:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]([NH2:19])=[O:18]
Reactant: NC(=O)C(N)c1ccccc1
Reactant: COc1cccc2c(Cl)cc(C)nc12
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cccc2c(NC(C(N)=O)c3ccccc3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 19, method 19.2. Starting materials were 4-chloro-8-methoxy-2-methylquinoline and 2-amino-2-phenyl-acetamide. Acetonitrile was used as solvent instead of dimethylformamide.
Reaction SMILES: [CH3:1][N:2]1[C:5](=[O:6])[CH2:4][C@H:3]1[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[H][H]>CO.[Pd]>[CH3:1][N:2]1[C:5](=[O:6])[CH2:4][C@H:3]1[C:7]([OH:9])=[O:8]
Reactant: CN1C(=O)C[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)C[C@H]1C(=O)O
Yield: 97.4 %

Procedure:
In 10 ml of methanol was dissolved 450 mg of compound (11) and 45 mg of 10% Pd-C was added to the solution followed by catalytic hydrogenation at ambient temperature under an atmospheric pressure of hydrogen. The catalyst was filtered off and the solvent was removed by distillation under reduced pressure to obtain 258 mg of (S)-1-methyl-4-oxo-2-azetidinecarboxylic acid (12).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:77]=[N:78][CH:79]=[C:80](/[CH:82]=[CH:83]/[C:84]2[CH:89]=[CH:88][CH:87]=[C:86]([O:90][CH3:91])[CH:85]=2)[CH:81]=1>C(O)CC.O>[Br:75][C:76]1[CH:81]=[C:80]([C@@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@H:83]([OH:12])[C:84]2[CH:89]=[CH:88][CH:87]=[C:86]([O:90][CH3:91])[CH:85]=2)[CH:79]=[N:78][CH:77]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: COc1cccc(/C=C/c2cncc(Br)c2)c1
Reactant: CC(C)(C)OCl
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: COc1cccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)c2cncc(Br)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl carbamate (4.63 g, 39.5 mmol) in propanol (45 mL) was added sodium hydroxide (1.556 g, 38.9 mmol) in water (81 mL) followed by tert-butyl hypochlorite (4.39 mL, 38.9 mmol). After 5 min, the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (0.497 g, 0.638 mmol) in propanol (45 mL). To this was added a solution of (E)-3-bromo-5-(3-methoxystyryl)pyridine (3.7 g, 12.75 mmol) in propanol (76 mL). To this was added potassium osmate dihydrate (0.188 g, 0.510 mmol) as a solid in one portion. The reaction was allowed to gradually warm in the glass dewar over 36 h. The reaction was quenched by addition of sodiumthiosulfate (4.2 g) in water (45 mL). After stirring for 30 min, the reaction was poured into water (ca. 600 mL) and extracted with diethyl ether (2×). The combined organics were washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. The resulting residue was concentrated from toluene (3×) to help remove an unknown impurity. The resulting residue was purified by column chromatography (25%-->40% EtOAc/Hex) to give 3.76 g (70%) as a mixture of regioisomers which was used without further purification. Mass spec.: 423.15 (MH)+.