Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-:21].[Ca+2].O1CCOCC1.O>C1COCC1>[OH:21][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1NC(=O)c1ccc(CO)cc1
Reaction time: 25 h
Yield: 88.3 %

Procedure:
4-Chloromethyl-N-(2-methoxyphenyl)benzamide (500 mg, 1.81 mmol) and precipitated calcium carbonate (970 mg, 9.7 mmol) were suspended in a dioxane-water (1:1) mixture solution (9 ml) and subjected to 25 hours of heating under reflux. After adding THF (25 ml) and filtering off the formed insoluble materials, the organic solvent was removed by evaporation. The thus obtained residue was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate. After removing the solvent by evaporation, the resulting colorless solid material was purified by subjecting it to a silica gel column chromatography (ether:hexane=3:1), thereby obtaining 411 mg (88.3%) of the title compound in the form of colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][N:9]1[C:13](=[O:14])[CH2:12][S:11][CH:10]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.Br[CH2:22][CH2:23][CH2:24][CH3:25].[I-].[Na+].P([O-])([O-])([O-])=O>CCCCCC.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH2:22]([CH:12]1[S:11][CH:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:9]([CH3:8])[C:13]1=[O:14])[CH2:23][CH2:24][CH3:25]
Reactant: CN1C(=O)CSC1c1cccnc1
Reactant: CCCCBr
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC1SC(c2cccnc2)N(C)C1=O
Reaction time: 1 h
Yield: 19.2 %

Procedure:
Dry diisopropylamine (1 ml, 5.7 mmol) was added to dry tetrahydrofuran (3 ml), and a butyllithiium solution (3.9 ml, 6.2 mmol) in hexane was added dropwise at -40° C., the mixture was kept at -10° C. for 1 hour. A solution of 3-methyl-2-(3-pyridyl)thiazolidin-4-one (1 g, 5.2 mmol) in dry tetrahydrofuran (7 ml) was added dropwise to the mixture at -20° to -10° C. After this reaction mixture had been kept between those temperatures for 1 hour, there were added at -10° C. 1-bromobutane (0.78 g, 5.7 mmol) dissolved in tetrahydrofuran (2 ml), sodium iodide (0.77 g, 5.2 mmol), and hexamethylphosphorotriamide (1 ml). This reaction mixture was kept at room temperature for 2 hours. The resulting mixture, after addition of a phosphate buffer (pH 7.0), was extracted with ethyl acetate. The extract was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated by evaporation under reduced pressure. The residue was chromatographed on silica gel (hexeneethyl acetate), giving 5-butyl-3-methyl-2-(3-pyridyl)-thiazolidin-4-one (250 mg, 20% yield). NMR (CDCl3) δ [ppm]; 0.93 (3 H, t, J=7.0 Hz), 1.2-2.3 (6 H, m), 2.74 (3 H, m), 3.9-4.3 (1 H, m), 5.4-5.5 (1 H, m). IR (CHCl3) [cm-1 ]; 2925, 2855, 1670, 1590, 1578, 1390, 1303, 1020.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=O.[C:19](#[N:21])[CH3:20]>>[O:13]=[C:11]([C:10]1[CH:16]=[CH:17][CH:18]=[C:8]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)[CH2:20][C:19]#[N:21]
Reactant: CCOC(=O)c1cccc(OCc2cccs2)c1
Reactant: CC#N
Product: N#CCC(=O)c1cccc(OCc2cccs2)c1

Procedure:
Condensation between ethyl 3-(thiophen-2-ylmethoxy)benzoate and acetonitrile gave after flash column chromatography 3-oxo-3-(3-(thiophen-2-ylmethoxy)phenyl)propanenitrile as a pale yellow solid. Yield (2.60 g, 83%); 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 1H), 7.48-7.41 (m, 2H), 3.73 (d, J=3.2 Hz, 2H), 7.27 (s, 1H), 7.15 (d, J=4.8 Hz, 1H), 5.13 (s, 2H), 4.05 (s, 2H); MS: m/z 258.0.
Reaction SMILES: [C:1]1(=O)[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1.[NH2:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:27])[CH:22]=2)[N:17]=1.CCN(CC)CC>>[NH2:15][C:16]1[N:25]=[C:24]([NH2:26])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH:27][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH:22]=2)[N:17]=1
Reactant: Nc1ccc2nc(N)nc(N)c2c1
Reactant: O=C1C=CC=C2C1=Cc1ccccc12
Solvent: CCN(CC)CC
Product: Nc1nc(N)c2cc(NC3c4ccccc4-c4ccccc43)ccc2n1

Procedure:
9-[N-(2,4-Diaminoquinazolin-6-yl)amino]fluorene (Formula I: Ar=2,4-diaminoquinazolin-6-yl; W=NH; Z=CH; Z=chemical bond; m=n=0) is prepared similarly to N-(2,4-diaminopyrido[3,2-d]diamino]fluorene as disclosed above by using fluorenone (360 mg, 2.0 mmol), 2,4,6-triaminoquinazoline (350 mg, 2.0 mmol), and BH3.Et3N (75 mg, 6.6 mmol). The product can be purified by chromatography.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6](=[O:13])C(=O)[NH:8]2)=[CH:4][CH:3]=1.[OH-:14].[Na+].OO.Cl>>[NH2:8][C:9]1[C:10]([F:11])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[C:6]([OH:13])=[O:14]
Reactant: O=C1Nc2c(ccc(F)c2F)C1=O
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: Nc1c(C(=O)O)ccc(F)c1F
Temperature: 65 °C

Procedure:
6,7-Difluoroisatin (22.2 g) was added to a solution of sodium hydroxide (2N, 185 ml). Hydrogen peroxide (30%, 36 ml) was added at 40° C. or less over 20 minutes. After 1 hour the mixture was heated to 65° C. for 0.5 hours, cooled, poured onto water and acidified with concentrated hydrochloric acid. The resulting solid was filtered, washed with water and recrystallized from ethyl acetate/cyclohexane to give 2-amino-3,4-difluorobenzoic acid (1.3 g) as an orange solid, m.p. 207-208° C.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11](=O)[NH2:12])=[O:7])[CH2:2][CH2:3][CH3:4].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]#[N:12])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N[C@H](CC(N)=O)C(=O)O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCCCOC(=O)N[C@H](CC#N)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
N-Butyloxycarbonyl-D-asparagine (25 g, 108 mmol) was dissolved in 200 mL pyridine and 14 mL acetic anhydride and the solution was allowed to stir overnight at room temperature. After most of the pyridine was removed under reduced pressure, ethyl acetate was added and the solution was washed with citric acid and brine, dried (MgSO4), and concentrated to give 21 g (91%) oily product. ES-MS: calcd M+1 215.0; found 215.0.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>ClCCl.CO>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCOCC1

Procedure:
Prepared analogously to Example 1.1.c. from 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and morpholine. Yield: 0.3 g (39.4% of theory); C13H18N2O5 (M=282.29); calc.: molecular ion peak (M+H)+: 283; found: molecular ion peak (M+H)+: 283; Rf value: 0.6 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[CH:10]1)[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:7]([N:9]1[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[CH:10]1)[CH3:8]
Reactant: CCn1cnc(C=O)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1cnc(CO)c1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
To a mixture of lithium aluminum hydride (1.74 g) and tetrahydrofuran (100 mL) was added 1-ethyl-1H-imidazole-4-carbaldehyde (5.71 g) at 0° C. After stirring the reaction mixture for 1 hr, sodium sulfate decahydrate (15 g) was added and the mixture was further stirred at room temperature for 5 hrs. Insoluble materials were filtered off and the filtrate was concentrated to give (1-ethyl-1H-imidazol-4-yl)methanol as a colorless oil (5.83 g, yield 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:40])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[O:40])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)=[CH:11][C:10]=1[CH2:16][O:17][C:18](=[O:26])[NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COC(=O)NC1CCCCC1
Reactant: O=C(c1ccccc1)c1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCc1ccc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)cc1COC(=O)NC1CCCCC1
Temperature: 80 °C
Yield: 62.5 %

Procedure:
A mixture of 3-(2-cyclohexylcarbamoyloxymethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (50 mg, 0.13 mmol; Example 652 Step D), [4-(3-bromo-propoxy)-phenyl]-phenyl-methanone (64 mg, 0.2 mmol, Bull Chem. Soc. Jpn. 1990, 63, 1342) and potassium carbonate (53 mg, 0.39 mmol) in acetonitrile (6 mL) was heated at 80° C. overnight. Ethyl acetate (20 mL) and H2O (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. The crude mixture was purified by silica gel column chromatography (hexane/ethyl acetate 4/1) to give the title compound (50 mg, 62%). 1H-NMR (300 MHz, CDCl3): δ 7.74 (d, 2H, J=8.5), 7.68 (d, 2H, J=7.7), 7.48 (d, 1H, J=8.4), 7.40 (m, 2H), 7.05 (d, 1H, J=8.5), 6.90 (d, 2H, J=8.6), 6.85 (s, 1H), 6.74 (dd, 1H, J=8.5, 2.2), 5.04 (s, 2H), 4.68 (d, 1H, J=7.3), 4.17 (t, 2H, J=5.9), 4.09 (t, 2H, J=5.9), 3.43 (m, 1H), 2.82 (t, 2H, J=7.8), 2.40 (t, 2H, J=7.8), 2.21 (qn, 2H, J=5.9), 1.85 (m, 2H), 1.67-1.02 (m, 8H), 1.36 (s, 9H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([NH:47][CH3:48])[N:42]=[C:41]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=4)[S:54][CH:55]=3)[C:40]=2[C:63]#[N:64])=[CH:35][CH:34]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(OC(C)(C)C)=O)=O)(C)(C)C.[ClH:65]>ClCCl.C(OCC)C>[ClH:62].[ClH:65].[NH2:8][C@H:9]([C:22]([NH:24][C@H:25]([C:27]([O:29][CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[C:44]([C:45]#[N:46])=[C:43]([NH:47][CH3:48])[N:42]=[C:41]([S:49][CH2:50][C:51]3[N:52]=[C:53]([C:56]4[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=4)[S:54][CH:55]=3)[C:40]=2[C:63]#[N:64])=[CH:37][CH:38]=1)=[O:28])[CH3:26])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c1C#N
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCOC(=O)[C@H](C)NC(=O)[C@@H](N)CCCCN)cc2)c1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.00 g (1.071 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(methylamino)pyridin-4-yl)phenoxy}ethyl N2,N6-bis(tert-butoxycarbonyl)-L-lysyl-L-alaninate (Example 23A) were initially charged in 18.7 ml of dichloromethane. 10.71 ml of a 1N solution of hydrogen chloride in diethyl ether were added, and the reaction solution was stirred at RT for 18 h. Another 10.71 ml of a 1N solution of hydrogen chloride in diethyl ether were then added. After a reaction time of 18 h, the reaction mixture was treated in an ultrasonic bath for 90 min. The mixture was concentrated by evaporation. This gave 867 mg (100% of theory) of the target compound.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:43]([O:47][C:48](=[O:59])[NH:49][CH2:50][C:51](=[O:58])[N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.O>[C:43]([O:47][C:48](=[O:59])[NH:49][CH2:50][C:51]([N:52]1[CH2:53][CH2:54][N:55]([C:23](=[O:25])[C:22]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:21]=2[Cl:20])[CH2:56][CH2:57]1)=[O:58])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
HOBt (125 mg, 0.93 mmol) and DIPEA (207 mg, 2.2 mmol) were added to a stirred solution of 2,5-dichloro-benzoic acid (141 mg, 0.74 mmol) in DMF (2.5 mL). The mixture was then cooled to 10° C. and EDCI.HCl (178 mg, 0.93 mmol) followed by (2-oxo-2-piperazin-1-yl-ethyl)-carbamic acid tert-butyl ester (200 mg, 0.82 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification using column chromatography (silica gel (60-120 mesh) using 30% ethyl acetate in hexane as the eluent) afforded {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester as a solid in 91.2% yield. LC-MS purity: 99.48%.
Reaction SMILES: C([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=O)C1C=CC=CC=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1)[NH2:29].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:25][C:26]1[CH:27]=[C:28]([NH:29][C:22]2[C:23]3[N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][OH:9])[CH:16]=[CH:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: OCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (863 mg) and 1-methyl-2-pyrrolidone (10 mL) was stirred at 120° C. for 1.5 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50→100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (1.420 g) in methanol (30 mL) was added 1N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→5:95). The object fraction was concentrated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diethyl ether. The crude crystals were recrystallized from ethyl acetate-diisopropyl ether to give the title compound (933 mg) as a white powder.
Reaction SMILES: [CH:1]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14]#[CH:15])[CH3:12].C(N(CC)CC)C>C(OCC)C>[CH2:11]([O:13][CH:14]1[C:1]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8](=[O:9])[CH2:15]1)[CH3:12]
Reactant: C#COCC
Reactant: O=C(Cl)C1CCCCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC1CC(=O)C12CCCCCC2
Yield: 87.1 %

Procedure:
A solution of cycloheptyl carbonyl chloride (10.0 g, 0.062 mol) and ethoxyacetylene (40% w/w solution in hexanes, 6.0 g, 0.083 mol, 12 ml) in diethylether (50 ml) was treated dropwise with triethylamine (20 ml, 0.14 mol) and the reaction stirred for 5d at room temperature. Filtration and concentration of the filtrate in vacuo followed by chromatography (SiO2, 5:1 EtOAc:hexanes) gave the title compound as a pale yellow oil (10.5 g, 0.054 mol, 87%). δH (CDCl3, 300K) 4.78 (1H, s), 4.20 (2H, q J 7.1 Hz), 1.94-1.87 (2H, m), 1.83-1.77 (2H, m), 1.71-1.66 (2H, m), 1.63-1.52 (6H, m), 1.45 (3H, t J 7.1 Hz); m/z (ES+, 70V) 194.9 (MH+).
Reaction SMILES: OS(O)(=O)=O.[C:6]([NH:9][C@@H:10]([CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])=[O:17])[C:11]([OH:13])=[O:12])(=[O:8])[CH3:7].O.[CH3:44]O>>[C:6]([NH:9][C@H:10]([C:11]([O:13][CH3:44])=[O:12])[CH2:14][S:15][C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])=[CH:21][C:20]=1[C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])=[O:17])(=[O:8])[CH3:7]
Reactant: CO
Reactant: CC(=O)N[C@@H](CSC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H](CSC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCc1ccccc1)NC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
H2SO4 (0.020 mL, 0.343 mmol) was added to a solution of (R)-2-acetamido-3-((2′,4′-difluoro-3-(benzyloxycarbonyl)biphenyl-4-yloxy)carbonylthio)propanoic acid (54 mg, 0.102 mmol) in MeOH (10 mL). The reaction mixture was stirred at r.t. for 18 h, poured into H2O (30 mL) and extracted with CH2Cl2 (20 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was purified by flash chromatography on SiO2 (3% MeOH/CH2Cl2) to furnish (R)-benzyl 4-((2-acetamido-3-methoxy-3-oxopropylthio)carbonyloxy)-2′,4′-difluorobiphenyl-3-carboxylate (yellow-coloured solid, yield: 82%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Li]CCCC.CCCCCC.C(O[B:36]1[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]1)(C)C>O.C1(C)C=CC=CC=1.C1COCC1>[C:4]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][C:17]([B:36]3[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]3)=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccccc3)cc2)OC1(C)C
Temperature: -78 °C
Yield: 43.6 %

Procedure:
To a flame-dried 3-neck, round-bottomed 500 mL flask equipped with mechanical stirring and an addition funnel was added 4-bromotriphenylamine (12.5 g, 39.5 mmol) and THF (250 mL) by cannula. The solution was cooled to −78° C. and 1.6 M n-BuLi in hexane (26.5 mL, 42.4 mmol) was added by addition funnel over 15 min. After stirring for 30 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.8 mL, 48.2 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature overnight. Toluene and water were added, and the organic phase was further washed with water, dried with MgSO4, and concentrated. The crude product was purified by column chromatography eluting with hexane, 2/1 hexane/CH2Cl2, and finally 1/1 hexane/CH2Cl2 to give 6.4 g (45%) white crystals. 1H NMR (400 MHz, CDCl3) δ: 7.66 (m, 2H), 7.26 (m, 4H), 7.10 (m, 4H), 7.04 (m, 4H); GC-MS (m/z): 371 (M+), >97% purity. Anal. Calcd. for C24H26BNO2: C, 77.64%; H, 7.06%; B, 2.91%; N, 3.77%. Found: C, 77.78%; H, 7.21%; B, 2.70%; N, 3.53%.
Reaction SMILES: [C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:28][CH:27]2[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[C@H:21]1[C:29]([OH:31])=[O:30])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[CH2:28][CH:27]2[CH:22]([CH2:23][CH2:24][CH2:25][CH2:26]2)[C@H:21]1[C:29]([OH:31])=[O:30])=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CC2CCCCC2[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CC2CCCCC2[C@H]1C(=O)O

Procedure:
As described in Example 2 treat N-(1-carboethoxy-3-phenylpropyl-(S)-alanyl]octahydroisoindole-1(S)-carboxylic acid (prepared as described in Example 18) with sodium hydroxide to obtain the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH2:23])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([NH:31][CH2:32][C:33](O)=[O:34])=[O:30])=[CH:27][C:26]=1[C:38]([F:41])([F:40])[F:39]>>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([NH:23][C:33](=[O:34])[CH2:32][NH:31][C:29](=[O:30])[C:28]2[CH:36]=[CH:37][C:25]([F:24])=[C:26]([C:38]([F:39])([F:41])[F:40])[CH:27]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2ccc(F)c(C(F)(F)F)c2)C1

Procedure:
The title compounds were prepared as white solids from the EDCI coupling of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharma) and (4-fluoro-3-trifluoromethyl-benzoylamino)-acetic acid (analog synthesis by the procedure described in Organic Synthesis XII, 40-2, 1932) using the procedure described in Step F of Example 1.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:3]=1[CH2:9][CH:10]=[O:11].S(=O)(=O)(O)[OH:13].O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>CC(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])([CH3:8])[CH2:5][CH2:4][C:3]=1[CH2:9][C:10]([OH:13])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: CC1=C(CC=O)CCC1(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(CC(=O)O)CCC1(C)C
Temperature: 0 °C

Procedure:
A solution was made of β-campholenic aldehyde (150 g) in acetone (2 liters) and cooled to 0° C. Oxidizing agent was prepared from 169 ml conc. sulfuric acid, 736 ml water and 292 g of sodium dichromate (Na2Cr2O7.2H2O). The reagent (375 ml) was added to the solution at 0° C. over a period of 30 minutes. After an additional 15 minutes at 0° C. the acetone was removed by decantation and the residual chromium salts were washed with an additional 200 ml acetone. The combined acetone solution was concentrated, the residue taken up in 10% aqueous sodium hydroxide (1 liter) and the solution washed with CH2Cl2 (2×1 liter). The aqueous phase was acidified with 25% sulfuric acid followed by extraction with CH2Cl2 (2×1 liter). Concentration of the dried CH2Cl2 solution yielded an oil (73 g) which was distilled under reduced pressure to give 53 g of a yellowish liquid; bp 102° C. @ 1.1 mm Hg; crystallized upon standing; analysis: (CW 20M fused silica column, 190° C.) 96% β-campholenic acid.