Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].N1C=CC=N[C:12]=1[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[CH3:26][O:27]C1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[O:17]1[CH2:12][CH2:26][O:27][C:25]2[CH:24]=[C:21]([C:22]3[NH:10][C:1](=[O:9])[C:2]4[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:4]=3)[CH:20]=[CH:19][C:18]1=2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Reactant: O=Cc1ccc(Oc2ncccn2)cc1
Reactant: NC(=O)c1ccccc1N
Product: O=c1[nH]c(-c2ccc3c(c2)OCCO3)nc2ccccc12
Yield: 72 %

Procedure:
2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-(pyrimidin-2-yloxy)-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)quinazolin-4(3H)-one (222 mg, 72%) was isolated as a light beige solid. Selected data: MS (m/z): 280.98; MP 267-268° C. (decomposed).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15](OC)=[O:16])[CH:11]=2)=[CH:6][CH:5]=1.[NH2:21][NH2:22].O>CCO>[F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]([NH:21][NH2:22])=[O:16])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
To a solution of methyl 5-(4-(trifluoromethoxy)phenyl)isoxazole-3-carboxylate (6.50 g, 22.6 mmol) in EtOH (200 mL) was added NH2NH2.H2O (80%, 7 mL, 113 mmol) and the mixture was stirred at RT for 3 h. The mixture was then concentrated under reduced pressure and purified by silica gel chromatography (Petroleum ether:EtOAc=1:2) to give the ttitle compound as a white solid (4.4 g, 67.8%). MS (ES+) C11H8F3N3O3 requires: 287. found: 288 [M+H]+.
Reaction SMILES: O=S(Cl)[Cl:3].[O:5]=[C:6]([C@H:8]([CH2:10][C:11]1[CH:18]=[C:16]([OH:17])[C:14]([OH:15])=[CH:13][CH:12]=1)[NH2:9])[OH:7].[CH3:19][CH2:20]O>>[NH2:9][CH:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:15])=[C:16]([OH:17])[CH:18]=1)[C:6]([O:7][CH2:19][CH3:20])=[O:5].[ClH:3]
Reactant: CCO
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)C(N)Cc1ccc(O)c(O)c1
Product: Cl
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To 30 mL of EtOH at −5° C. was added, with stirring, 0.37 mL of SOCl2 slowly. The clear colorless solution was cooled to −5° C. and 1 g of L-Dopa was added. After 5 min, the resulting solution was refluxed overnight. The solution was concentrated to afford 164 as HCl salt (1.30 g, 99%). 1H NMR (DMSO): δ 1.29 (t, 3H, J=7.4 Hz), 3.03 (m, 1H), 3.15 (m, 1H), 4.21 (m, 1H), 4.27 (m, 2H), 4.35 (sl, 3H), 6.60 (d, 1H, J=7.9 Hz), 6.74 (s, 1H), 6.82 (d, 1H, J=7.9 Hz), 8.63 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O-:10])=O)=[N:6][CH:7]=1.Cl[C:12]1[N:13]=[C:14]([S:23][CH3:24])[N:15]=[N:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CS(C)=O.C(OCC)(=O)C>[CH:25]1([NH:28][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:12]3[N:13]=[C:14]([S:23][CH3:24])[N:15]=[N:16][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=2)=[O:10])[CH2:27][CH2:26]1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: NC1CC1
Reactant: Nc1ccc(C(=O)[O-])nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc(C(=O)NC2CC2)nc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Aminopicolinate (44 mg) was added to a solution of ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (70 mg) in dimethylsulfoxide (1.5 ml), and the reaction solution was stirred at room temperature for 10 minutes. Thereafter, cyclopropylamine (0.017 ml), diisopropylethylamine (0.079 ml), and HATU (125 mg) were successively added, and the reaction solution was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain ethyl 5-(6-(cyclopropylcarbamoyl)pyridin-3-ylamino)-3-(methylthio)-1,2,4-triazine-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].ClS([N:15]=[C:16]=[O:17])(=O)=O.[C:18]([O-])(O)=O.[Na+]>ClCCl>[NH:1]([C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9][CH2:10][CH3:18])=[O:8])[C:16]([NH2:15])=[O:17]
Reactant: O=C([O-])O
Reactant: COC(=O)c1occc1N
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1occc1NC(N)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92 %

Procedure:
To a solution of methyl 3-aminofuran-2-carboxylate (100 mg, 1.0 eq) in dichloromethane (3 ml) at −78° C. was added chlorosulfonyl isocyanate (0.09 ml, 1.4 eq) dropwise. The reaction was slowly warmed to room temperature and stirred for 40 minutes. Reaction was concentrated. To the residue was added 6N HCl (3.5 ml) and mixture was heated to 100° C. for 20 minutes. Reaction mixture was allowed to cool down to room temperature, and was neutralized with saturated aq. NaHCO3. Solid was collected by filtration to yield ethyl 3-ureidofuran-2-carboxylate (120 mg, 92%) as a beige solid which was used in the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]([CH3:14])[C:3](=[N:9][O:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:18])(=O)=O>C(O)(=O)C>[Cl:18][CH2:14][C:2](=[O:1])[C:3](=[N:9][O:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCON=C(C(C)=O)C(=O)OCC
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCON=C(C(=O)CCl)C(=O)OCC
Temperature: 0 °C
Yield: 85.4 %

Procedure:
Ethyl 3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.) and sulfuryl chloride (10.6 g.) were dissolved in acetic acid (15.4 ml.), warmed at 35° to 40° C. for 10 minutes with stirring and then stirred at ambient temperature for additional 6 hours. The reaction mixture was poured into ice-water (200 ml.) and the resultant mixture was extracted twice with chloroform. The extract was washed with an aqueous solution of sodium chloride, twice a saturated aqueous solution of sodium bicarbonate and once with water in turn, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure to give ethyl 4-chloro-3-oxo-2-propoxyiminobutyrate (syn isomer, 15.4 g.), oil.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.CCCCCC.[F:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([C:39]3[CH:40]=[C:41]4[C:46]5=[C:47]([CH2:49][CH2:50][N:45]5[C:44](=[O:51])[CH2:43][CH2:42]4)[CH:48]=3)=[O:38])[CH2:31][CH2:30]2)[CH:25]=[CH:26][CH:27]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:62])(=O)=O)=CC=1>O1CCCC1.O>[F:62][CH:36]([CH2:35][CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([F:21])[CH:23]=2)[CH2:34][CH2:33]1)[C:37]([C:39]1[CH:40]=[C:41]2[C:46]3=[C:47]([CH2:49][CH2:50][N:45]3[C:44](=[O:51])[CH2:43][CH2:42]2)[CH:48]=1)=[O:38]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(CCC1CCN(Cc2cccc(F)c2)CC1)c1cc2c3c(c1)CCN3C(=O)CC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(c1cc2c3c(c1)CCN3C(=O)CC2)C(F)CC1CCN(Cc2cccc(F)c2)CC1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Into a nitrogen-flushed, three-necked flask, a solution of 1,1,1,3,3,3-hexamethyldisilazane (1.38 g, 8.60 mmol) in tetrahydrofuran (50 ml) was placed and the resulting mixture was cooled in a dry ice/acetone bath. Thereto was added dropwise a solution of n-butyl lithium in hexane (1.6 M)(5.4 ml, 8.6 mmol) and then the resulting solution was stirred at −20° C. for 10 minutes. To this solution, which was cooled again in a dry ice/acetone bath, was added dropwise a solution of 8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]quinolin-4-one (3.0 g, 7.1 mol), which was obtained in Example 1, in tetrahydrofuran (20 ml). The resulting mixture was stirred at −20° C. for 20 minutes and then cooled again in a dry ice/acetone bath. To this solution was added dropwise a solution of N-fluorobenzenesulfonimide (1.38 g, 8.6 mmol) in tetrahydrofuran (20) and the temperature was gradually raised to room temperature. The reaction mixture was mixed with water and was extracted with ethyl acetate. Then, the organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate, and concentrated to remove the solvent. The resulting residue was purified by column chromatography on silica gel (eluent: ethyl acetate) to obtain of the title substance as a colorless oily substance (42 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=O)[CH:5]=[CH:6][C:7]=1[F:8].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:38]2)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[S:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1snnc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)[Si](OCc1snnc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 160 °C
Yield: 75.2 %

Procedure:
A solution of N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thiadiazole-4-carboxamide (2.3 g, 0.0052 mol) in anhydrous THF (10 mL) was distributed equally into 2 microwave vials. 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (4.2 g, 0.010 mol) (Lawesson's reagent) was added to each vial. The reactions were each heated at 160° C. in a microwave for 15 minutes. The solutions were combined, concentrated and purified by flash chromatography to give the desired product (1.80 g, 76%). MF═C19H27ClFN3OS2Si; LCMS calculated for C19H28ClFN3OS2Si (M+H)+: m/z=460.1.
Reaction SMILES: S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(O)=O)N=1)CC2)=O.[NH2:39][C:40]1[N:44](C(OC(C)(C)C)=O)[N:43]=[C:42]([C:52]2[CH:53]=[C:54]([CH:103]=[CH:104][CH:105]=2)[O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([C:63]3[S:67][C:66]([N:68]4[CH2:77][CH2:76][C:75]5[C:70](=[C:71]([C:78](=[O:97])[N:79]([C:88]6[S:89][C:90]7[CH:96]=[CH:95][CH:94]=[CH:93][C:91]=7[N:92]=6)COCC[Si](C)(C)C)[CH:72]=[CH:73][CH:74]=5)[CH2:69]4)=[N:65][C:64]=3[C:98]([O:100]CC)=[O:99])=[CH:59][CH:58]=2)[C:41]=1[C:106]#[N:107]>>[NH2:39][C:40]1[NH:44][N:43]=[C:42]([C:52]2[CH:53]=[C:54]([CH:103]=[CH:104][CH:105]=2)[O:55][CH2:56][C:57]2[CH:58]=[CH:59][C:60]([C:63]3[S:67][C:66]([N:68]4[CH2:77][CH2:76][C:75]5[C:70](=[C:71]([C:78](=[O:97])[NH:79][C:88]6[S:89][C:90]7[CH:96]=[CH:95][CH:94]=[CH:93][C:91]=7[N:92]=6)[CH:72]=[CH:73][CH:74]=5)[CH2:69]4)=[N:65][C:64]=3[C:98]([OH:100])=[O:99])=[CH:61][CH:62]=2)[C:41]=1[C:106]#[N:107]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2cccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)c2)cc1
Agent: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(-c3ccc(CO)cc3)s1)CC2
Product: N#Cc1c(-c2cccc(OCc3ccc(-c4sc(N5CCc6cccc(C(=O)Nc7nc8ccccc8s7)c6C5)nc4C(=O)O)cc3)c2)n[nH]c1N

Procedure:
The title compound 37 was prepared in a similar manner to the synthesis of compound 34 by substituting compound 34D with compound 37A: 1H NMR (DMSO-d6): δ 8.02 (d, J=7.36 Hz, 1H), 7.78 (d, J=7.98 Hz, 1H), 7.33-7.49 (m, 11H), 7.05-7.08 (m, 1H), 5.15 (s, 2H), 4.91 (s, 2H), 3.78 (t, J=6.14 Hz, 2H), 3.08 (t, J=5.83 Hz, 2H). MS (ESI(+)): m/z 725 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].S([O:23][CH3:24])(OC)(=O)=O>>[CH3:12][O:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:23][CH3:24])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: [K+]
Product: COC(=O)c1ccc(C)cc1OC

Procedure:
2-Hydroxy-4-methylbenzoic acid was reacted with K2CO3 and dimethyl sulfate to give methyl 2-methoxy-4-methybenzoate (boiling point at 0.7 mm=100° C.). Hydrolysis with 2N sodium hydroxide solution provided 2-methoxy-4-methylbenzoic acid (melting point 103°-104° C.). Bromination to give the 4-bromomethyl compound (melting point 123°-125° C.) and reaction with potassium cyanide provided the 4-cyanomethyl compound (melting point 105°-107° C., from toluene), the catalytic hydrogenation of which with Ra--Ni and reaction with ethanolic hydrochloric acid provided the ethyl 4-(2-aminoethyl)-2-methoxybenzoate hydrochloride (melting point 86°-88° C.).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:18]1([N:13]2[C:12]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: FC(F)(F)c1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1
Yield: 21.8 %

Procedure:
The title compound (45.2 mg) was prepared as in Example 177, Steps C and D, using 269.2 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 359.2 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C19H22F3N3, 349.49; found, m/z 350.3 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.87 (d, J=7.9 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 4.48 (m, 1H), 3.43-3.40 (m, 2H), 3.21-3.17 (m, 2H), 2.81-2.77 (m, 2H), 2.07-1.86 (m, 6H), 1.66-1.57 (m, 2H).
Reaction SMILES: C(=O)([O-])O.[Na+].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>C(OCC)(=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=3)[CH:26]=2)(=[O:31])=[O:32])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: O=S(=O)(Cl)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a mixture of aqueous sodium hydrogen carbonate (10 ml) solution, 1-tert-butoxycarbonylpiperazine (1.0 g) and ethyl acetate (10 ml), was added 6-chloronaphthalene-2-sulfonylchloride (1.4 g) and the mixture was stirred at room temperature for 1 hour and extracted with dichloromethane. The extract was washed with water, dried and concentrated. The residue was crystallized from diisopropylether to give colorless crystals of 1-(tert-butoxycarbonyl)-4-(6-chloro-naphthalene-2-sulfonyl)piperazine (2.02 g).
Reaction SMILES: C([N:8]([CH2:30][C@@H:31]([C:33]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]2C=CC=CC=2)=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[OH:32])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)C1C=CC=CC=1.C([OH:54])C>C(O)(=O)C.[Pd]>[C:44]([OH:54])(=[O:43])[CH3:45].[OH:32][C@H:31]([C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](=[O:51])[NH:38]2)[CH2:30][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: CCO
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(OCc3ccccc3)c3[nH]c(=O)ccc23)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)c1

Procedure:
A solution of 3-(4-{[6-(Benzyl{(2R)-2-[8-(benzyloxy)-2-oxo-1,2-dihydroquinolin-5-yl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)benzenesulfonamide (10 mg) in ethanol (10 ml) and acetic acid (0.1 ml) was stirrer under hydrogen in the presence of palladium on charcoal (5 mg) for 2 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient from DCM to DCM-MeOH—NH3(aq) 100:10:1) and freeze-dried from water-acetic acid to give the title compound (5.8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:65]1[CH2:70][CH2:69][CH:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([N:65]2[CH2:70][CH2:69][CH:68]([CH2:71][C:72]([NH2:74])=[O:73])[CH2:67][CH2:66]2)=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)CC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N2CCC(CC(N)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (80 mg, 0.138 mmol) in methylene chloride (10 mL), HATU (Aldrich, 79 mg, 0.21 mmol) was added followed by the addition of DIPEA (0.145 mL, 0.83 mmol) and piperidin-4-yl-acetamide (Chembridge, 41 mg, 0.21 mmol). The mixture was stirred at rt for 3 hrs then overnight after the addition of 3 mL of DMF. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (12 g column, eluent, 20% EtOAc/methylene chloride) to give a white solid. 21 mg.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35](/[CH:38]=[CH:39]/[CH2:40][OH:41])=[CH:34][CH:33]=2)[CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:24][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:41][CH2:40]/[CH:39]=[CH:38]/[C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[CH:37][CH:36]=2)=[O:9])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/c1ccc(Cc2cccnc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccc(Cc3cccnc3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 225 mg (1 mM) of (E)-3-{4-(3-pyridylmethyl)phenyl)-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 481 mg (89%).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].[CH:12]1([C:15]([NH:17][C:18]2[CH:19]=[C:20]([O:24][C:25](Cl)=[O:26])[CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:14][CH2:13]1>C(#N)C>[CH:12]1([C:15]([NH:17][C:18]2[CH:19]=[C:20]([O:24][C:25](=[O:26])[N:5]([CH2:4][CH2:3][C:1]#[N:2])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:21]=[CH:22][CH:23]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: O=C(Cl)Oc1cccc(NC(=O)C2CC2)c1
Reactant: N#CCCNc1ccccc1
Solvent: CC#N
Product: N#CCCN(C(=O)Oc1cccc(NC(=O)C2CC2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
29.2 g N-(2-cyanoethyl)-aniline is dissolved in 200 ml acetonitrile and then reacted with 23.97 g chloroformic acid-[3-(cyclopropylcarbonylamino)-phenyl]-ester with stirring, with which the temperature of the solution rises to about 35° C. After standing overnight the solvent is removed under vacuum, the remaining oily residue is treated with water, the water is decanted and the oil brought to crystallization with a 1:1 mixture of isopropyl ether/isopropanol. The crystallizate is finally recrystallized from isopropanol.
Reaction SMILES: [OH2:1].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:10]O.C(O)C.[C:15]1(=O)[C:28]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH2:18][CH2:17][CH2:16]1>O>[C:15]1(=[N:10][OH:1])[C:28]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]=2[CH2:18][CH2:17][CH2:16]1
Reactant: NO
Reactant: O=C1CCCc2c1ccc1ccccc21
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCCc2c1ccc1ccccc21
Yield: 87.4 %

Procedure:
To a solution of sodium acetate trihydrate (7.07 g, 52 mmol) in water (30 ml) was added hydroxylamine hydrochloride (3.61 g, 52 mmol). Ethanol (75 ml) and 3,4-dihydro-2H-phenantren-1-one (5.0 g, 26 mmol) were added and the suspension was heated at reflux for 2h. The reaction mixture was cooled on an ice-bath and the precipitated solid was isolated by filtration, washed with cold water and dried in vacuo to afford 4.8 g of 3,4-dihydro-2H-phenanthren-1-one-oxime.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH2:22][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27]
Reactant: C1CCNC1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)c4)cc23)CCS1(=O)=O
Yield: 17.6 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid, and pyrrolidine (0.058 mL, 0.697 mmol) was added. Stirred for 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring overnight at 23° C. The mixture was quenched with water, extracted with DCM, the DCM solution was evaporated to dryness, and the resulting mixture was rerun through the same process: 1.5 mL of DMSO, 1 drop of glacial acetic acid, and 0.577 mL of pyrrolidine. Left stirring 30 min and then 299 mg of polymer bound sodium triacetoxyborohydride was added and the mixture was left stirring 16 h. The sodium triacetoxyborohydride polymer bound was removed by filtration. The mixture was dissolved in 1 mL of DMSO, and the product was purified by preparative HPLC (NH4OH buffer). The desired fractions were concentrated, giving 6 mg of the title compound.