Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][CH2:17]1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1>COCCOC.O.CCO>[Cl:37][C:38]1[CH:43]=[C:42]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9](=[O:14])[CH:8]=[C:7]3[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]=[CH:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)[CH:41]=[CH:40][CH:39]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Br)ccc2o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(-c3cccc(Cl)c3)ccc2o1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
Into a dry microwave vial under N2 was added 6-Bromo-4-[1-(3-phenyl-allyl)-piperidine-4-ylamino]-chromen-2-one (20 mg, 0.046 mmol), Pd(PPh3)Cl2 (about 1 mol %), and Cs2CO3 (17.8 mg, 0.0547 mmol) in DME/H2O/EtOH (7/3/2, 0.5 mL). 3-Chlorophenyl boronic acid (6.3 mg, 0.046 mmol) was added and the solution was heated in the microwave for 5 minutes at 160° C., filtered, and was purified by Prep HPLC to give 3 mg (11%) of the desired compound as the TFA salt. MS (ESI(+)Q1MS m/z 469 (M−H)+; 1H NMR (300 MHz, DMSO) δ ppm 1.84-1.91 (m, 2H), 2.25 (br d, 2H), 3.16-3.23 (m, 2H), 3.61 (br d, 2H), 3.84-4.01 (m, 3H), 5.43 (s, 1H), 6.37-6.43 (m, 1H), 6.89 (d, 1H), 7.34-7.94 (m. 12H), 8.41 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](O)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl.C(OCC)C>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:8][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Temperature: 0 °C

Procedure:
5.29 g (40.0 mmol) of (2,2-dimethyl-[1,3]dioxolan-4-yl)methanol (Solketal®) and 10 ml of pyridine are introduced into a round-bottomed flask under an argon atmosphere. The mixture is cooled to 0° C., 8.39 g (44.0 mmol) of para-toluenesulphonic acid are added and the mixture is stirred for sixteen hours at room temperature. The reaction medium is poured into a 1N HCl/ethyl ether mixture, extracted with ethyl ether, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with dichloromethane. After evaporation of the solvents, 9.70 g (85%) of the expected product are collected in the form of yellow crystals with a melting point of 45–47° C.
Reaction SMILES: [C:1](N)(=[O:5])C(C)=C.[C:7]([O:12][CH3:13])(=[O:11])[C:8]([CH3:10])=[CH2:9].C(N)=O>>[CH3:1][O:5][C:8]([CH3:10])([CH3:9])[C:7]([O:12][CH3:13])=[O:11]
Reactant: C=C(C)C(N)=O
Reactant: C=C(C)C(=O)OC
Solvent: NC=O
Product: COC(=O)C(C)(C)OC
Yield: 8 %

Procedure:
The reaction product was cooled, and analyzed by gas chromatography. This analysis showed that the conversion of methacrylic acid amide was 94%, the selectivity of methyl methacrylate based on methacrylic acid amide was 91%, and the selectivity of formamide was 98%. In addition, 8% of methyl α-methoxyisobutyrate was obtained in a yield of 8%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(C1C=C(C(C)(C)C)C=C(O)C=1O)(C)(C)C.Cl[C:51](C(O[Na])=O)([F:53])[F:52].[F-:58].[K+]>COCCOCCOC.O>[F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)[C:51]([F:53])([F:58])[F:52]
Reactant: [F-]
Reactant: C=Cc1ccc(C(=O)C(F)(F)F)cc1
Reactant: O=C(O[Na])C(F)(F)Cl
Agent: CC(C)(C)c1cc(O)c(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOCCOC
Solvent: O
Product: C=Cc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by a modification of the procedure of Klabunde and Burton, described in Journal of American Chemical Society (1972, 94, 820), herein incorporated by reference. To a solution of 2,2,2-trifluoro-1-(4-vinylphenyl)ethanone (8.27 g, 41.32 mmol) in diglyme (80 mL) was added PPh3 (21.67 g, 82.62 mmol) plus a few crystals of 3,5-di-tert-butylcatechol. The reaction mixture was heated in an oil bath to 150° C., then a solution of ClCF2CO2Na (12.60 g, 82.64 mmol) in diglyme (40 mL) was added in portions over 1 h. The reaction mixture was kept at 150° C. for 1 h, allowed to cool to 95° C., then KF (5.28 g, 90.88 mmol) in H2O (1.65 mL, 91.56 mmol) was added in one portion. The reaction mixture was kept at 95° C. overnight, allowed to cool to room temperature, diluted with H2O, and extracted with hexane. The combined extracts were washed with brine, dried (Na2SO4), and concentrated to provide 24.75 g of a reddish oil. This material was purified by filtration chromatography on silica gel using hexane to provide 5.56 g of a pale yellow oil, followed by vacuum distillation to provide 4.62 g (44%) of a colorless oil: bp 43-4° C. (1.3 mm); 1H NMR (CDCl3) δ 7.42 (d, 2ArH), 7.34 (d, 2ArH), 6.68 (dd, CH═), 5.77 (dd, ═CHH), 5.30 (dd, ═CHH), 4.00 (septet, CH).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]([NH2:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:19][C:20]([CH3:23])([O-])[CH3:21].[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:18]([CH2:2][CH2:1][CH2:5][CH2:6][CH2:7][CH3:8])[C:12]2[CH:17]=[CH:16][C:15]([C:20]([CH3:23])([CH3:21])[CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CCCCCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCN(c1ccc(C(C)(C)C)cc1)c1ccc(C(C)(C)C)cc1
Yield: 99.6 %

Procedure:
According to the general procedure B, 4-tert-butylbromobenzene (214 mg, 1.00 mmol) reacted with n-hexylamine (66 μl, 0.50 mmol) using 1 mol % of Pd(OAc)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (116 mg, 1.21 mmol) in toluene at 100° C. for 4 h to give the title compound (182 mg, 99%) as an oil: 1H-NMR (400 MHz, CDCl3): δ 7.17 (d, 4H, J=8.4Hz), 6.82 (d, 4H, J=8.8 Hz), 3.55 (t, 2H, J=7.2 and 8.0 Hz), 1.57 (m, 2H), 1.22 (s, 18H), 0.79 (t, 3H, J=6.4 and 6.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 145.68, 143.41, 125.93, 120.20, 52.38, 34.06, 31.67, 31.49, 27.55, 26.78, 22.70, 14.05. GC/MS(EI): m/z 365 (M+). Anal. Calcd for C26H39N: C, 85.42; H, 10.75; N, 3.83. Found: C,85.22; H, 10.82; N, 3.86.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.[CH3:20][O:21][CH2:22][CH2:23]Br>>[CH3:20][O:21][CH2:22][CH2:23][NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1
Reactant: Cc1cccc(Nc2ncnc3ccc(N)cc23)c1
Reactant: COCCBr
Product: COCCNc1ccc2ncnc(Nc3cccc(C)c3)c2c1
Yield: 20 %

Procedure:
Using an analogous procedure to that described in Example 16, 6-amino-4-(3'-methylanilino)quinazoline was reacted with 2-bromoethyl methyl ether to give 6-(2-methoxyethylamino)-4-(3'-methylanilino)quinazoline in 20% yield, m.p. 163°-167° C.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([C:30]4[C:21](=[CH:22][C:23]5[O:28][CH2:27][CH2:26][O:25][C:24]=5[CH:29]=4)[O:20][CH2:19]3)[C:11]2=[O:31])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl>[O:31]=[C:11]1[C:12]2([C:30]3[C:21](=[CH:22][C:23]4[O:28][CH2:27][CH2:26][O:25][C:24]=4[CH:29]=3)[O:20][CH2:19]2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]1[CH2:9][C:4]1[C:3]([NH:2][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccnc1CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.5 %

Procedure:
A 50 mL round-bottom flask was charged with 1′-[(3-aminopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one hydrobromide (0.56 g, 1.0 mmol), methanesulfonyl chloride (0.12 g, 1.1 mmol), pyridine (0.25 g, 3.0 mmol) and dichloromethane (20 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 16 h and diluted with dichloromethane (50 mL). The organic phase was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 0% to 100% gradient of ethyl acetate in dichloromethane, followed by recrystallization from methanol (10 mL) to afford N-{2-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]pyridine-3-yl}methanesulfonamide (0.18 g, 38%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.27 (dd, J=4.6, 1.2 Hz, 1H), 7.78 (dd, J=8.0, 1.4 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 7.21-7.10 (m, 2H), 6.96 (t, J=7.4 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 5.17 (ABq, 2H), 4.73 (ABq, 2H), 4.18-4.05 (m, 4H), 3.14 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 154.9, 151.0, 147.1, 144.5, 143.2, 138.1, 134.5, 132.6, 132.2, 132.1, 129.0, 123.8, 123.2, 122.2, 112.3, 109.4, 99.0, 79.6, 64.6, 64.1, 57.8, 41.8, 40.6; MS (ES+) m/z 479.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:19]2[S:23][CH:22]=[C:21]([C:24]([O:26]C)=[O:25])[CH:20]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][C:9]3([CH3:18])[CH3:17].[OH-].[Li+].CO.O>C1COCC1>[CH3:1][C:2]1([C:19]2[S:23][CH:22]=[C:21]([C:24]([OH:26])=[O:25])[CH:20]=2)[CH2:6][O:5][C:4]2[CH:7]=[C:8]3[C:13](=[CH:14][C:3]1=2)[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][C:9]3([CH3:17])[CH3:18]
Reactant: COC(=O)c1csc(C2(C)COc3cc4c(cc32)C(C)(C)CCC4(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)OCC3(C)c1cc(C(=O)O)cs1

Procedure:
A mixture of methyl [5-(3,5,5,8,8-pentamethyl-2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-3-yl)-thiophene-3-yl]carboxylate (2.1 g, 5.4 mmol), lithium hydroxide (2g, 48 mmol), methanol (1 ml) and water (1 ml) in 30 ml of THF was heated under reflux for 6 h. After concentrating in a rotary evaporator under vacuum at 40° C., adding water, ethyl ether and acidifying with a concentrated hydrochloric acid solution to pH 1, the organic phase was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator under vacuum at 40° C. The solids obtained were washed with heptane.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:20])[CH3:21])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc(Cl)c4Cl)c3)cnc2c1F
Yield: 2 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 2,3-dichlorobenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2′,3′-dichloro-2-fluorobiphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (3 mg, 2%): m/z (ES+) 434 [MH+].
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:29][NH2:30]>C1COCC1.C1(C)C=CC=CC=1.CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:16]=[CH:17][C:18]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:19][CH:20]=4)[C:13]([NH:30][CH3:29])=[CH:12][C:11]3=[O:28])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1C=C(O)C(c2ccc(N3CCOCC3)cc2)N1c1ccc2[nH]cnc2c1
Reactant: CN
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNC1=CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(N2CCOCC2)cc1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-(4-morpholinophenyl)-1H-pyrrol-2(5H)-one (0.50 g, 1.32 mmol) and saturated methylamine solution in THF (1 ml) in toluene/DMF (2:1; 5 ml) according to method 8b described above.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][C:16]([N:25]([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl.O>[C:1]1([O:7][C:8](=[O:9])[NH:11][CH2:12][CH:13]2[CH2:14][CH2:15][C:16]([N:25]([CH3:27])[CH3:26])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C1(c2ccccc2)CCC(CN)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The chloroformic acid phenyl ester (1.32 ml, 10.5 mmole) dissolved in abs. DCM (25 ml) was slowly added dropwise while cooling with iced water to a solution of (4-aminomethyl-1-phenylcyclohexyl)-dimethylamine (2.32 g, 10 mmole) in abs. DCM (25 ml) and pyridine (888 μl, 11 mmole). The reaction mixture was then stirred for 20 hours at RT. The reaction mixture was worked up by extraction with water (3×10 ml), with 1M HCL (3×10 ml) and with 1M NaOH (2×10 ml). The organic phase was dried with Na2SO4 and then concentrated by evaporation. The residue was the diastereoisomer mixture of (4-dimethyl-amino-4-phenylcyclohexylmethyl)-carbamic acid phenyl ester. This was obtained as a colourless solid in a yield of 3.18 g (m.p. 108°-124° C., 90%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:9][C:10]1[CH:11]=[C:12]([C:14](I)=[CH:15][CH:16]=1)[NH2:13]>>[F:9][C:10]1[CH:11]=[C:12]2[C:14]([CH:2]=[C:1]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=3)[NH:13]2)=[CH:15][CH:16]=1
Reactant: Nc1cc(F)ccc1I
Reactant: C#Cc1cccnc1
Product: Fc1ccc2cc(-c3cccnc3)[nH]c2c1

Procedure:
3-Ethynylpyridine and 3-fluoro-6-iodoaniline are processed according to the method described in Example 86 to give 6-fluoro-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 213.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[C:17]1([CH:27]=O)[C:26]2[C:20]([CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1.N1CCCC1>C(O)C>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:17]1[C:26]2[C:20]([CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:19][CH:18]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2cccccc1-2
Solvent: CCO
Solvent: C1CCNC1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3cccccc1-3)C(=O)N2
Yield: 6.9 %

Procedure:
0.504 g 2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (0.0021 mole) and 0.323 g azulene aldehyde (0.0021 mole) were dissolved in 30 mL dried ethanol. 1.5 mL pyrrolidine (1M) was then added and uniformly stirred at reflux temperature for two hours. After removal of dried ethanol, the results were extracted by dichloromethane and citric acid aqueous solution. The organic layer was collected, dried with anhydrous magnesium sulfate, filtered, concentrated under vacuum, and separated by silica gel column chromatography to give Compound 050 (E-form (0.0548 g), Z-form (0.1376 g)).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][N:6]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:23]([NH:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)=[CH:5][N:6]=1)(=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 0 °C
Yield: 78.7 %

Procedure:
To a mixture of 2-amino-5-(4-nitrophenylthio)thiazole (2.6 g) and pyridine (1 g) in N,N-dimethylformamide (30 ml) was added dropwise the propionylchloride (1.1 g) at 5° C. under ice cooling with stirring. The mixture was stirred at 5° C. for 3.5 hours. The reaction mixture was poured into ice water and the mixture was adjusted to pH 8 using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-propionylamino-5-(4-nitrophenylthio)thiazole (2.5 g, yield: 78.7%). mp: 227°-229° C. (dec.)
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]1[CH2:41][OH:42]>>[C:28]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:34][C@@H:35]2[CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:41][OH:42])=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: N[C@@H]1CCCC[C@@H]1CO
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N[C@@H]2CCCC[C@@H]2CO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-carbonyl chloride, and [(1S,2R)-2-aminocyclohexyl]methanol, the title compound was obtained in 63% purity by HPLC. MS(ESI+): m/z=450.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][NH:30][S:31]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=2)(=[O:33])=[O:32])=[CH:20]1>>[OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[C:3]=1[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[NH:19][C:27]2[C:22]([C:21]=1[CH2:28][CH2:29][NH:30][S:31]([C:34]1[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=1)(=[O:32])=[O:33])=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: O=Cc1ccccc1
Reactant: O=S(=O)(NCCc1c[nH]c2ccccc12)c1ccc2ccccc2c1
Reactant: CC(C)C1NC(=O)C=C1O
Product: CC(C)C1NC(=O)C(C(c2ccccc2)c2[nH]c3ccccc3c2CCNS(=O)(=O)c2ccc3ccccc3c2)=C1O

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with benzaldehyde and naphthalene-2-sulfonic acid [2-(1H-indol-3-yl)-ethyl]-amide (Lit. 1) to give the title compound as an orange solid. MS: 580.3 ([M+H]+).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9]([O-:12])(=[O:11])[CH3:10].[K+]>C(O)(=O)C>[CH2:6]([CH:7]1[O:12][C:9](=[O:11])[CH2:10][CH2:8]1)[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCCCCC1CCC(=O)O1
Temperature: 138 °C
Reaction time: 4 h

Procedure:
About 1.69 g. (0.015 mole) octene-1 and 8.1 g. (0.03 mole) manganic acetate were added to 73 ml. glacial acetic acid and the mixture sealed in a tube. No potassium acetate was used. The tube was placed in an oil bath maintained at 138° C., and after 4 hours the characteristic dark brown color due to manganic ion disappeared. The reaction was stopped and the reaction mixture worked up by extracting with ether and water. Gamma-n-hexyl-butyrolactone was obtained in a yield of 2.0 g., comprising 78% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[S:21][C:22]1[S:23][C:24]([CH:27]=O)=[CH:25][N:26]=1.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:27]([C:24]3[S:23][C:22]([S:21][C:13]4[NH:12][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=5[N:14]=4)=[N:26][CH:25]=3)[C:30]3[C:31](=[O:35])[CH2:32][CH2:33][CH2:34][C:29]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1cnc(Sc2nc3ccccc3[nH]2)s1
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1cnc(Sc2nc3ccccc3[nH]2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
A suspension of 308.3 mg (2.0 mmol) of 3-amino-2-ethoxycarbonylpyrrole and 522.7 mg (2.0 mmol) of 2-(1H-benzimidazol-2-ylsulfanyl)-thiazole-5-carbaldehyde (obtained from step 1) in 10 mL of n-butanol under argon is stirred at room temperature for 0.5 hour. 1,3-Cyclohexanedione (224.3 mg, 2.0 mmol) is then added and the reaction mixture is heated at reflux temperature for 2 h. The mixture is then cooled to room temperature and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 70 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate; rate: 40 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is triturated in ethanol, filtered, washed with diethylether and dried under reduced pressure. 313 mg of 9-[2-(1H-benzimidazol-2-ylsulfanyl)-thiazol-5-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester are obtained as a yellow powder. mp: 194° C. LCMS: m/z 492: [M+H]+ (base peak); m/z 490: [M−H]− (base peak).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8](Cl)(Cl)Cl)[NH:5][C:6]=1[Cl:7].[NH3:12]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]#[N:12])[NH:5][C:6]=1[Cl:7]
Reactant: N
Reactant: Clc1nc(C(Cl)(Cl)Cl)[nH]c1Cl
Solvent: CCO
Product: N#Cc1nc(Cl)c(Cl)[nH]1
Yield: 90 %

Procedure:
25.4 g (0.1 mol) of 4,5-dichloro-2-trichloromethyl-imidazole were introduced in small portions into 200 ml of ethanol saturated with ammonia, whilst cooling with ice and stirring vigorously. The mixture was stirred for a further 30 minutes at 50° C., the constituents which had not dissolved were then filtered off and the filtrate was evaporated under reduced pressure. The combined residues were dissolved in hot water. On acidifying the solution with dilute hydrochloric acid, the reaction product precipited out. This was filtered off, washed with water and dried. In this way 14.6 g (90% of theory) of 4,5-dichloro-2-cyano-imidazole were obtained and after recrystallization from toluene this had a melting point of 187°-189° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([N:15]([CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C(O)=O>CSC.C(S)(S)C>[NH2:1][C@@H:2]([C:13]([N:15]([CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH2:31])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(N)=O
Agent: CC(S)S
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Yield: 74 %

Procedure:
Condensation of BocMeLeuOH (5.0 g.) and HMetNH2 (3.7 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocMeLeu-MetNH2 in 67% yield. De-t-butoxycarbonylation of BocMeLeu-MetNH2 (5.2 g.) using hydrogen chloride in ethyl acetate gave HMeLeu-MetNH2 in 90% yield. Condensation of BocDTrpOPFP (5.60 g.) and HMeLeu-MetHN2 (3.70 g.) by the activated ester method gave BocDTrp-MeLeu-MetNH2 in 55% yield. De-t-butoxycarbonylation of BocDTrp-MeLeu-MetNH2 (3.38 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HDTrp-MeLeu-MetNH2 in 74% yield.