Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[C:17]=1[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[Cl:32]N1C(=O)CCC1=O>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:32])[C:19]([NH2:22])=[C:18]([CH3:23])[C:17]=1[CH2:24][O:25][C:26](=[O:28])[CH3:27])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Solvent: CC#N
Product: COC(=O)[C@@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Yield: 57 %

Procedure:
(R)-3-(2-(acetoxymethyl)-4-amino-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate (15.00 g, 38.9 mmol) in acetonitrile (200. ml, 3829 mmol) was added N-chlorosuccinimide (5.72 g, 42.8 mmol). The reaction mixture was then heated to reflux for 2 min. The solvent was removed and the crude product was washed with aqueous NaHCO3. The crude product was purified by flash chromatography using 30% EtOAc in hexane to give (R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate in 57% yield. MS (ESI) 442 (M+H); Rf=2.42.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]([F:17])([F:16])C(OC)=O.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[F:16][CH:11]([F:17])[O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 0.3 h
Yield: 53.2 %

Procedure:
4-Cyanophenol (0.12 G, 1.0 mmol, Aldrich), methyl chlorodifluoroacetate (0.29 g, 2.0 mmol, Aldrich) and potassium carbonate (0.29 g, 2.1 mmol) were combined in dry DMF (0.5 mL) under an argon atmosphere. After stirring at 75°-80° C. for 0.3 h, the mixture was cooled to RT, ethyl acetate (20 mL) was added and the organic layer was washed twice with 10% NaOH. The organic extract was dried (MgSO4), filtered and evaporated. The residue was purified by flash chromatography (silica gel, 20% ether/hexanes) to provide the title compound as a colorless solid (0.09 g, 53%). mp 34°-35° C.
Reaction SMILES: C(C1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][CH:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)#N.[CH3:22][Mg]Br.[NH4+].[Cl-].C([O:29][CH2:30][CH3:31])C>C1C=CC=CC=1.C(OCC)(=O)C>[C:30]([C:31]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][CH:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)(=[O:29])[CH3:22]
Reactant: C[Mg]Br
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(CN3)C1
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCN(CCC)C1Cc2c(C(C)=O)ccc3c2C(CN3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of 0.5 g (1.8 mmol) of (+)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 75 mL of benzene was treated with 5 mL of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 2 days. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of a saturated NH4Cl solution. The benzene layer was separated and washed once with a saturated NaCl solution. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL of 5N HCl and the solution was stirred at room temperature for 30 min. The acidic solution was made alkaline with the addition of excess concentrated NH4OH solution. The basic mixture was extracted twice with CH2Cl2. The combined organic solution was washed once with a saturated NaCl solution and dried over MgSO4. The CH2Cl2 solution was evaporated to yield 0.5 g off an oil. Chromatography of this oil over silica gel with ethyl acetate as eluent gave 0.4 g (75%) of product an oil which upon standing solidified.
Reaction SMILES: O.Cl.Cl.NCC1(CC2C=CC=CC=2)CCN(CCCC2(C3C=CC([Cl:35])=C(Cl)C=3)CCCN([C:21](=[O:28])[C:22]3C=CC=C[CH:23]=3)C2)CC1.[NH2:44][CH2:45][C:46]1([CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH2:54][C:55]2([C:69]3[CH:74]=[CH:73][C:72]([Cl:75])=[C:71]([Cl:76])[CH:70]=3)[CH2:60][CH2:59][CH2:58][N:57]([C:61](=[O:68])[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)[CH2:56]2)[CH2:48][CH2:47]1.Cl.Cl.C(N(CC)CC)C.C(Cl)(=O)CC.Cl>C(Cl)Cl>[ClH:35].[C:61]([N:57]1[CH2:58][CH2:59][CH2:60][C:55]([CH2:54][CH2:53][CH2:52][N:49]2[CH2:50][CH2:51][C:46]([CH2:77][C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([CH2:45][NH:44][C:21](=[O:28])[CH2:22][CH3:23])[CH2:47][CH2:48]2)([C:69]2[CH:74]=[CH:73][C:72]([Cl:75])=[C:71]([Cl:76])[CH:70]=2)[CH2:56]1)(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: NCC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Agent: CCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NCC1(Cc2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Reaction time: 0.08 h
Yield: 121.4 %

Procedure:
A solution of 0.6 g of the compound obtained in EXAMPLE 9 and 0.18 ml of triethylamine in 10 ml of DCM is cooled to 0° C., 0.1 ml of propionyl chloride is added dropwise and the mixture is stirred for 5 minutes. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed twice with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (9515; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.37 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[C:10]([Cl:18])[N:9]=1)(C)(C)[CH3:2].C(OC(=O)CC1C=CC(C(F)(F)F)=C(Cl)N=1)(C)(C)C>CCO.Cl.CCOC(C)=O>[CH2:1]([O:5][C:6](=[O:19])[CH2:7][C:8]1[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:11]=[C:10]([Cl:18])[N:9]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)Cc1nc(Cl)ccc1C(F)(F)F
Agent: CC(C)(C)OC(=O)Cc1ccc(C(F)(F)F)c(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)Cc1nc(Cl)ccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A 1:2.5 mixture of (6-chloro-3-trifluoromethyl-pyridin-2-yl)-acetic acid tert-butyl ester and (6-chloro-5-trifluoromethyl-pyridin-2-yl)-acetic acid tert-butyl ester (semi-crude; 10.15 g, 34.33 mmol) is dissolved in EtOH (100 ml) previously saturated at 0° C. with HCl gas. The solution is heated to 90° C. After 30 minutes at 90° C., TLC analysis indicates full conversion of the starting material. The solvent is completely evaporated. The crude reaction product is dissolved in EtOAc, washed once with conc. aqueous NaHCO3 and once with H2O (backextracted with EtOAc). The organic layer is dried over Na2SO4 and concentrated. Careful purification by FCC (hexanes/EtOAc 100:0, 97:3, 95:5, 9:1, 85:15, 8:2 to 7:3) separates the two regioisomeric compounds, (6-chloro-3-trifluoromethyl-pyridin-2-yl)-acetic acid tert-butyl ester and (6-chloro-5-trifluoromethyl-pyridin-2-yl)-acetic acid ethyl ester. Analytical data for (6-Chloro-3-trifluoromethyl-pyridin-2-yl)-acetic acid ethyl ester: 1H NMR (CDCl3, 400 MHz) δ 1.28 (t, J=6.7 Hz, 3H), 3.95 (s, 2H), 4.12 (q, J=6.7 Hz, 2H), 7.32 (d, J=8.9 Hz, 1H), 7.85 (d, J=8.9 Hz, 1H); ES-MS: 268.2 [M+H]+.
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11](O)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH:34]([NH:38][C:11](=[O:12])[CH:10]([NH:9][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:8])[CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[CH:35]([OH:37])[CH2:36]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(O)C(NC(=O)C(CS(=O)(=O)Cc2ccccc2)NC(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (1 g, 2.8 mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 3.46 mmol) prepared as in Reference 1, EDC (1.5 g, 7.8 mmol), and HOBt (1.5 g, 9.6 mmol) were combined. Dichloromethane (10 mL) was added and then 4-methylmorpholine (1.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (200 mL) the solution was washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried with MgSO4 and evaporated under vacuum. 3-Hydroxy-4-{2-[(morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, 1.94 mmol) was obtained as yellowish foam and was dissolved in dichloromethane (6 mL). Trifluoroacetic acid (6 mL) was added and the mixture was stirred at ambient temperature for 1 hour. Evaporation under vacuum gave crude morpholine-4-carboxylic acid [1-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as TFA salt, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[N:24][O:25][CH:26]=2)(=[O:15])=[O:14])=[O:11])[N:3]=1.[CH3:27][O-:28].[Na+].Cl.[CH3:31][OH:32]>O>[CH3:27][O:28][C:2]1[N:7]=[C:6]([O:32][CH3:31])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[N:24][O:25][CH:26]=2)(=[O:15])=[O:14])=[O:11])[N:3]=1
Reactant: C[O-]
Reactant: CO
Reactant: O=C(Nc1nc(Cl)nc(Cl)n1)NS(=O)(=O)c1ccccc1-c1cnoc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccc2-c2cnoc2)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1 g of sulfonamide prepared in Example 15 in 10 ml of methanol is added portionwise 0.41 g of sodium methoxide. After an initial exotherm, the suspension is stirred at 25° to 50° C. for about 1 hour, then cooled to room temperature and diluted with excess water (about 30 ml). The solution is acidified to a pH of about 1 with concentrated HCl. The resulting mixture is filtered and suction dried to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH3:17])[C@@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1)=[O:10].C([Sn](CCCC)(CCCC)[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC.[C:49]([O-:52])([O-])=[O:50].[Cs+].[Cs+]>O1CCOCC1>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[O:10])[C@H:12]1[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1.[C:49]([OH:52])([C:26]([F:29])([F:28])[F:27])=[O:50]
Reactant: Cc1ccc(Br)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2CCC[C@H](C)[C@@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: O=C(O)C(F)(F)F
Temperature: 140 °C

Procedure:
The mixture of rac-cis-(2-bromo-5-methylphenyl)(3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)methanone (0.03 g, 0.0638 mmol), 2-(tributylstannyl)pyrimidine (0.028 g, 0.0766 mmol), P(PPh3)4 (0.011 g, 0.01 mmol), Cs2CO3 (0.42 g, 0.13 mmol) and dioxane (1 mL) was degassed for 5 min and heated overnight at 140° C. oil bath. The completion of reaction was monitored by analytical HPLC. The mixture was cooled and extracted with EtOAc. The combine organic layers were washed with saturated NaHCO3 and dried over Na2SO4. The solvent was removed in vacuo to obtain the crude, which was purified by preparative-HPLC to obtain the title compound as TFA salt. ESI-MS (m/z): 470, [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(C)c1F
Yield: 82 %

Procedure:
To a solution of 2-fluoro-3-methyl benzoic acid (3.57 g, 23 mmol) in MeOH (40 mL) was added concentrated sulfuric acid (2.3 mL), and the reaction mixture was heated at reflux for 12 h. The reaction mixture was cooled, the solvent was removed under reduced pressure, and the residue was dissolved in EtOAc. The organic solution was washed with a saturated solution of NaHCO3 and then brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford methyl 2-fluoro-3-methylbenzoate as a yellow oil (3.2 g, 82%): 1H NMR (300 MHz, CDCl3) δ 7.76-7.71 (m, 1H), 7.39-7.34 (m, 1H), 7.08 (t, J=8 Hz, 1H), 3.98 (s, 3H), 2.31 (d, J=3 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 57.4 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (1.19 g, 5.88 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.22 g, 6.47 mmol), HOAt (881 mg, 6.47 mmol), 4-methylmorpholine (1.42 mL, 12.95 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.24 g, 6.47 mmol) in DCM (30 mL) was stirred at RT for 21 h. The reaction mixture was then partitioned between additional DCM and an aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo and the resulting residue (2.40 g) was dissolved in AcOH (50 mL) and stirred for 48 h at 60° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) affording [(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as a yellow foam (1.20 g, 57%). LCMS: RT 3.50 min [M+H]+ 356.2
Reaction SMILES: F[C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5](F)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>>[NH2:21][CH2:20][CH2:19][NH:22][C:2]1[C:7]2[C:8](=[O:17])[C:9]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[C:15](=[O:16])[C:6]=2[C:5]([NH:21][CH2:20][CH2:19][NH2:22])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C1c2ccncc2C(=O)c2c(F)ccc(F)c21
Product: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O

Procedure:
The reported synthetic procedures use, as a key intermediate, 6,9-difluorobenzo[g]isoquinoline-5,10-dione. This compound is reacted with ethylene-diamine which produces the desired 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=4)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.[S:41]1[CH2:45][C:44](=[O:46])[NH:43][C:42]1=[O:47]>C(O)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:33]4[CH:40]=[CH:39][C:36]([CH:37]=[C:45]5[S:41][C:42](=[O:47])[NH:43][C:44]5=[O:46])=[CH:35][CH:34]=4)[CH:27]=[C:28]4[O:32][CH2:31][O:30][C:29]=34)[CH2:23][CH:18]3[CH2:17][CH:16]([CH2:22][CH:20]([CH2:19]3)[CH2:21]1)[CH2:15]2
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(-c2cc3c(c(C45CC6CC(CC(C6)C4)C5)c2)OCO3)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3cc4c(c(C56CC7CC(CC(C7)C5)C6)c3)OCO4)cc2)S1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A solution of toluene (10 mL), piperidine (10 μL), acetic acid (10 μL), 4-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-benzaldehyde (0.400 g, 1.11 mmol) and 2,4-thiazolidinedione (0.130 g, 1.11 mmol) was heated at reflux overnight under an argon atmosphere. The reaction mixture was cooled to room temperature, and the resulting crystalline compound was filtered, washed with toluene and ethanol. The yellow solid was dried under high vacuum to afford 0.390 g (76%) of 4-[3-(1-adamantyl)-4,5-methylenedioxyphenyl]-benzylidene-2,4-thiazolidinedione, mp 308° (dec). 1H NMR (500 MHz; DMSO-d6): 1.74 (s, 6H), 2.04 (s, 9H), 6.05 (s, 2H), 7.06 (d, J=1.5 Hz, 1H), 7.20 (d, J=1.5 Hz, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.81 (s, 1H), 12.5–12.7 (brs, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])C=C)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1CCC1>ClCCCl>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]3[NH:14][C:15](=[O:18])[CH:16]=[CH:17]3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C=CC(=O)NC(C=C)C1CCC2(CC1)OCCO2
Agent: C1CNC1
Solvent: ClCCCl
Product: O=C1C=CC(C2CCC3(CC2)OCCO3)N1
Temperature: 50 °C

Procedure:
A solution of N-(1-(1,4-dioxaspiro[4.5]decan-8-yl)allyl)acrylamide (560 mg, 2.23 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (95 mg, 0.11 mmol) in DCE (50 mL) was degassed and heated to 50° C. under argon for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM->0-5% MeOH/ethyl acetate) to afford the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@@H:12]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: CC(C)CBr
Reactant: Cc1cc(Cl)ccc1N=C1N[C@@H](CC(C)C)CS1
Product: Cc1cc(Cl)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Chloro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-Chloro-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-chloro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+]([O-])=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].[N:22]1(CCCN)CCC[CH2:23]1>>[C:23]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])#[N:22]
Reactant: CN(C)CCCN
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCCN1CCCC1
Product: CN(C)CCCNc1ccc(S(N)(=O)=O)cc1C#N

Procedure:
This example was prepared by substituting EXAMPLE 90A for 4-chloro-3-nitrobenzenesulfonamide and N1,N1-dimethylpropane-1,3-diamine for 3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[F:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30]>>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: Cc1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(Br)cc2)c(F)c1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(-c3ccc(C(=O)O)cc3)cc2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 166, from (E)-5-(3-(4-bromophenyl)-3-(2-fluoro-4-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one and 4-carboxyphenylboronic acid (CAS RN 14047-29-1). The compound was purified by silica gel chromatography using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Yellow solid. MS (ESI+): m/z=485.2 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl.C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:6]([C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[C:4]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: COc1cccc2c1C(=O)OC2=O
Reactant: COc1ccc(OC)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(OC)c(C(=O)c2cccc(OC)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
3-Methoxyphthalic anhydride (17.8 g, 0.1 mole) was suspended in 100 ml. dry methylene chloride (previously distilled over anhydrous potassium carbonate). To the suspension was added anhydrous aluminum chloride (30.5 g, 0.23 mole) in one portion. The suspension quickly became bright yellow and was stirred at room temperature for 2 hours. A solution of p-dimethoxybenzene (27.6 g, 0.2 mole) in methylene chloride (100 ml) was added slowly to the vigorously stirred solution. The reaction mixture was stirred overnight at 25° and poured onto ice (300 g) and concentrated hydrochloric acid (50 ml). The slurry was stirred for 30 minutes and extracted with chloroform (4 × 150 ml). A white precipitate suspended in the aqueous layer is collected by filtration. The organic extract was washed once with water (200 ml) and washed with saturated sodium bicarbonate (4 × 150 ml). The aqueous bicarbonate extract was washed once with chloroform (150 ml) and acidified with concentrated hydrochloric acid, the mixture cooled on an ice bath and filtered. The residue was washed well with water and dried under reduced pressure and combined with the white precipitate to yield 2-(2',5'-dimethoxybenzoyl)-6-methoxybenzoic acid (I) as a pale yellow solid (13 g, 41% yield), m.p. 180°-182° C (from ethanol); IR (KBr) 2.95, 5.72μ; NMR (CDCl3) δ, 7.60-6.80 (m, 6H), 6.10 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([N:14]2[CH2:21][CH:20]3[CH:16]([CH2:17][N:18]([C:22](=[O:35])[C:23]4[C:28]([N:29]5[N:33]=[CH:32][CH:31]=[N:30]5)=[CH:27][CH:26]=[CH:25][C:24]=4[F:34])[CH2:19]3)[CH2:15]2)[N:8]=1)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[NH3:8].[F:34][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([N:29]2[N:33]=[CH:32][CH:31]=[N:30]2)[C:23]=1[C:22]([N:18]1[CH2:17][CH:16]2[CH:20]([CH2:21][N:14]([C:9]3[N:10]=[C:11]([CH3:13])[CH:12]=[C:7]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[N:8]=3)[CH2:15]2)[CH2:19]1)=[O:35]
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)nc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1
Reactant: C1COCCN1
Product: Cc1cc(N2CCOCC2)nc(N2CC3CN(C(=O)c4c(F)cccc4-n4nccn4)CC3C2)n1
Product: N
Temperature: 25 °C
Reaction time: 14 h
Yield: 8 %
Yield: 78 %

Procedure:
A mixture of Intermediate 58 (137 mg, 0.254 mmol) and morpholine (1.3 mL) was stirred 14 h at room temperature. The mixture was concentrated in vacuo. Chromatography (DCM to 8% 2 M NH3 in MeOH/DCM) afforded the desired product as a pale yellow foam (95 mg, 78%). MS (ESI) mass calculated for C24H27FN8O2, 478.53; m/z found, 479.3. 1H NMR (500 MHz, CDCl3): 7.86-7.78 (m, 2H), 7.72 (s, 1H), 7.51-7.44 (m, 1H), 7.18-7.10 (m, 1H), 5.77-5.72 (m, 1H), 3.99-3.47 (m, 13H), 3.28-3.21 (m, 1H), 3.09-2.91 (m, 2H), 2.90-2.86 (m, 2H), 2.25 (s, 3H).