Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])C=CC=CC=1>ClCCl.C(N(CC)CC)C>[CH3:1][C@H:2]([O:9][C:10]([CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:18]=2)[CH2:13]1)=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: CCCCCC[C@H](C)OC(=O)C1CCc2cc(O)ccc2C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC[C@H](C)OC(=O)C1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution 6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (1S)-1-methylheptyl ester (37) (1 equi.), and N-phenyl trifluoromethanesulfonamide (1 equi.) in dichloromethane (10 mL/mmole), triethylamine (1.5 equi.) was added at −78 C. The reaction mixture was stirred at that temperature for 1 h and at room temperature for 24 h, quenched with water, extracted with ethyl acetate:hexane(1:1), washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by chromatography on silica gel (5% EtOAc/hexanes) gave 6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (1S)-1-methylheptyl ester (45), as a colorless oil (92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([C:15]([OH:17])=O)[CH:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:18][C:19]1(C)OC(=O)CC(=O)[O:20]1.S([O-])(O)(=O)=O.[K+]>CN(C1C=CN=CC=1)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19](=[O:20])[CH:18]=[C:15]([OH:17])[CH:11]2[CH:12]([CH3:13])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C1C(O)=CC(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
To a solution of N-(3-chloro-4-cyanophenyl)valine (5.66 g), Meldrum's acid (3.39 g) and 4-(N,N-dimethylamino)pyridine (4.11 g) in tetrahydrofuran (70 mL) was added N,N′-carbonyldiimidazole (4.36 g) at 0° C., and the mixture was stirred at room temperature overnight. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium hydrogen sulfate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (70 mL), and the mixture was refluxed for 45 min. After allowing to room temperature, the organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate-isopropyl ether to give the title compound as colorless crystals (yield: 653 mg, 11%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:52])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[O:33][CH:34]([CH:36]([CH3:39])C=C)[CH3:35])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]>ClCCCl.[Cu]I.C1(C)C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C>[C:48]([O:47][C@@H:41]([C:12]1[C:13]([CH3:40])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:52])([O:4][CH2:1][CH:2]=[CH:3][CH:36]([CH3:39])[CH:34]([CH3:35])[O:33][C:27]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:42]([O:44][CH2:45][CH3:46])=[O:43])([CH3:51])([CH3:49])[CH3:50]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(-c4cccc(-c5cc(C)ccc5OC(C)C(C)C=C)c4)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Solvent: ClCCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CC(C)C(C)Oc1ccc(C)cc1-c1cccc-3c1

Procedure:
To a mixture of (2S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methyl-2-(5′-methyl-2′-((3-methylpent-4-en-2-yl)oxy)-[1,1′-biphenyl]-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (250 mg, 0.353 mmol) and CuI (67.2 mg, 0.353 mmol) in DCE (200 mL) at 70° C. was added (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride (22.10 mg, 0.035 mmol) and the resulting mixture was refluxed for 2 h. At this point LCMS indicates completion of reaction. Mixture was then concentrated and used as is in the next step without further purification. LCMS (M+H)=681.4.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[N+](C1C=CC=CC=1)([O-])=O>[C:13]1([C:12]2[NH:1][C:2]3[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][C:10]=3[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1cccc2nc(-c3ccccc3)[nH]c12
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of methyl ester of 2,3-diaminobenzoic acid (4.00 g, 24.07 mmol) and benzaldehyde (2.56 g, 24.07 mmol) in nitrobenzene (60 ml) was stirred at 155-160° C. for 3 hrs. After being cooled to room temperature, the reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate=20 and 4) to give methyl ester of 2-phenylbenzimidazole-4-carboxylic acid (3.89 g, 64%) as a pale yellow crystals.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([NH:14][CH:15]1[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]1[CH2:17]4)[CH2:21]3)=S)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>C1(C)C=CC=CC=1.C(O)(C)(C)C.C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1)=[N:14][CH:15]1[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]1[CH2:17]4)[CH2:21]3)[CH2:8]2
Reactant: C1COCCN1
Reactant: S=C(NC1C2CC3CC(C2)CC1C3)NC1C2CC3CC(C2)CC1C3
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C1CN(C(=NC2C3CC4CC(C3)CC2C4)NC2C3CC4CC(C3)CC2C4)CCO1

Procedure:
A mixture of 3.45 g. (0.01 mole) of N,N'-di-2-adamantylthiourea, 3.15 g. (0.012 mole) of triphenylphosphine, 1.55 g. (0.01 mole) of carbon tetrachloride and 1.0 g. (0.01 mole) of triethylamine in 25 ml. of methylene chloride is stirred at 40°-45° for 2.5 hr. The solvent is evaporated and the residue which contained N,N'-di-2-adamantylcarbodiimide is reacted with 10 ml. of morpholine in 10 ml. of tert-butyl alcohol on a steam-bath for 16 hrs. The mixture is diluted with toluene and evaporated in vacuo to remove excess morpholine. The residue is partitioned between 10 percent hydrochloric acid and ether. Some solid insoluble in both phases is filtered off and discarded. The acid layer is combined with the water extracts of the ether layer. The acid layer is basified with 20 percent sodium hydroxide to pH 13-14 and nitrogen bubbled through the solution to remove ether. The solid which separated is collected, washed with water, airdried and recrystallized from isopropanol-water: 1.6 (40 percent), m.p. 123-124.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[C:13]([CH3:19])=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[Cl:11][C:12]1[C:13]([CH3:19])=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1c(N)cccc1Cl
Product: Cc1c(Cl)cccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6.3 g. (0.04 mole) of 2-chloro-3-nitropyridine and 16.9 g. (0.12 mole) of 3-chloro-2-methylaniline was heated in an oil bath to 170° C. when the temperature spontaneously rose to 185° C. After an additional 10 minutes at 180° C., the mixture was cooled to 50° C. and extracted with a solution of 75 ml. of water and 25 ml. of acetic acid. The insolubles were collected, air dried, dissolved in methylene chloride, and the solution was dried over magnesium sulfate. The solution was concentrated to a small volume and diluted with 50 ml. of ether which caused crystallization of 6.6 g. of 2-(3-chloro-2-methylanilino)-3-nitropyridine, m.p. 134°-135° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[Si:42]([O:49][CH2:50][CH2:51]O)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[O:30]1[C@H:31]2[O:32][CH2:33][CH2:34][C@H:35]2[C@@H:28]([O:27][C:26](=[O:36])[NH:25][C@@H:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:51][CH2:50][O:49][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])=[CH:20][CH:19]=2)[C@H:15]([OH:37])[CH2:14][N:13]([S:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:29]1
Reactant: CC(C)(C)[Si](C)(C)OCCO
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCO[Si](C)(C)C(C)(C)C)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
(3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate was treated with 2-{[tert-butyl(dimethyl)silyl]oxy}-1-ethanol (J. Org. Chem. 1986, 51, 3388-3390)/triphenyl phosphine/diisopropyl azodicarboxylate as described above to provide the title compound as solid foam. 1H NMR (DMSO-d6): 0.0 (6H, s), 0.78 (3H, d), 0.82 (3H, d), 0.84 (9H, s), 1.2 (1H, dd), 1.37 (1H, quintuplet), 1.9-2.0 (1H, m), 2.37 (1H, dd), 2.6-2.8 (2H, m), 2.9 (1H, d), 2.98 (1H, dd), 3.2-3.3 (1H, m), 3.4-3.5 (1H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 3.88 (2H, dd), 3.93 (2H, dd), 4.8 (1H, dt), 5.0 (1H, d), 5.45 (1H, d), 6.18 (2H, s), 6.78 (2H, d), 7.0-7.1 (3H, m), 7.18 (1H, d), 7.2 (1H, s), 7.28 (1H, d); MS: 751 (MH+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#N.[Na+].[C:22]([CH:29]([NH2:32])[CH:30]=O)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[CH2:1]([O:8][C:9](=[O:13])[C@H:10]([CH3:12])[NH:11][CH2:30][CH:29]([NH2:32])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(N)C=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: C[C@H](NCC(N)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 143.1 %

Procedure:
Alanine benzyl ester (10, 8.82 g, 49 mmol, 1 eq) was dissolved in MeOH (100 ml) and glacial acetic acid (10.34 g, 172 mmol, 3.5 eq) was added. The mixture was stirred at 0° C. under nitrogen and sodium cyanoborohydride (10.82 g, 172 mmol, 3.5 eq) was added. Boc-aminoacetaldehyde (15.67 g, 98 mmol, 2 eq) in MeOH (200 ml) was added dropwise during 2 h. The reaction mixture was stirred at 0° C. for 35 min. and then at 4-5° C. overnight. Water (300 ml) was added to the reaction mixture and the pH was adjusted to 9 by addition of solid sodium carbonate. The saturated solution was filtered and subsequently extracted with ether (3×500 ml). The organic phase was washed with a 1:1 mixture of saturated aqueous solutions of sodium chloride and sodium bicarbonate (1×450 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give 22.60 g of crude N-(2-Boc-amino-ethyl)alanine benzyl ester as a slightly golden oil. The crude product was dissolved in dry ether (500 ml) and stirred at 0° C. HCl in ether (60 ml) was then added to the solution, and the resulting precipitate was collected by filtration and washed with cold dry ether (3×20 ml) affording 7.21 g (41%) of 11 as white crystals. A second crop of 2.12 g (12%) could be collected as a white semicrystalline material by keeping the mother liquor in the freezer overnight. This second crop was slightly less pure than the first crop. 1H-NMR (D2O/TMS): δ 1.36 (s, 9H, Boc); 1.52 (d, J=7.2 Hz, 3H, Me); 3.16 (m, 2H, NCH2); 3.35 (m, 2H, NCH2); 4.17 (q, J=7.2 Hz, 1H, CH); 5.26 (s, 2H, CH2Ph); 7.40 (s, 5H, Ph). 13C-NMR (D2O/TMS): δ 13.5 (Me); 27.3 (Box); 36.4 (CH); 45.5 (NCH2); 55.2 (NCH2); 68.4 (CH2Ph); 128.3, 128.7, 128.8 (Ph). MS(FAB+) m/z (%): 323 (100, M-HCl+H) Anal. Calcd for C17H27CIN2O4 : C, 56.90; H, 7.58; N, 7.81; Cl, 9.88. Found: C, 55.11; H, 7.52; N, 7.93; Cl, 10.45.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](O)=[O:19])=[CH:12][C:11]=1[C:21]([F:24])([F:23])[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(O)C2N=NNC=2C=1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C.[F:57][C:58]([F:72])([F:71])[CH:59]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[CH:62]=1)[NH2:60]>ClCCl>[O:19]=[C:18]([NH:60][CH:59]([C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:68])([F:69])[F:70])[CH:62]=1)[C:58]([F:71])([F:72])[F:57])/[CH:17]=[CH:16]/[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(/C=C/C(=O)O)cc1C(F)(F)F
Reactant: NC(c1cccc(C(F)(F)F)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cc(Cl)cc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 130.1 %

Procedure:
To a solution of 980 mg (1 eq, 2.84 mmol) of (2E)-3-[4-{[(tert-butoxycarbonyl)amino]methyl}-3-(trifluoromethyl)phenyl]acrylic acid in 10 ml of dichloromethane were added 481 mg (1 eq, 2.84 mmol) of 6-chlorohydroxybenzotriazole and 707 mg (1.3 eq, 3.70 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 733 mg (2 eq, 5.68 mmol, 989 μl) of Huenig's base. The reaction mixture was stirred at room temperature for 20 min. Then 1.04 g (1.5 eq, 4.26 mmol) of 2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethanamine as a solution in 1 ml of CH2Cl2 were added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and partitioned between saturated Na2CO3 solution and ethyl acetate. After drying and concentrating the solvent, 2.108 g of tert-butyl {4-[(1E)-3-oxo-3-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}amino)prop-1-en-1-yl]-2-(trifluoromethyl)benzyl}carbamate were obtained as an oil, which was converted in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26]>>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:4]1[CH:3]=[C:2]([NH:22][CH2:23][CH:24]([OH:27])[CH2:25][OH:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Clc1cc(N2CCc3ccccc3C2)nc2ccccc12
Reactant: NCC(O)CO
Product: OCC(O)CNc1cc(N2CCc3ccccc3C2)nc2ccccc12

Procedure:
The title compound, MS: m/e=349 (M+), was prepared from 4-chloro-2-(3,4-dihydro-1H-isoquinolin-2-yl)-quinoline and (RS)-3-amino-1,2-propanediol.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([OH:20])=O)[N:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C1C=C2N=NN(O)C2=CC=1.O.Cl.[CH2:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][CH2:36][N:35]([CH2:33][CH3:34])[C:18](=[O:20])[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])=[N:7]1
Reactant: COc1ccc2c(C(=O)C(C)C)nn(CC(=O)O)c2c1
Reactant: CCNCCC(C)(C)C
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: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(=O)C(C)C)c2ccc(OC)cc21
Reaction time: 8 h

Procedure:
Charge a 13×100 mm screw-capped tube with 27.6 mg (3-isobutyryl-6-methoxy-1H-indazol-1-yl)acetic acid, 23.0 mg HOBt hydrate, 18.6 mg N-ethyl-3,3-dimethylbutan-1-amine hydrochloride, and 89 μL DIEA. Dissolve the mixture in 1 mL anhydrous DMF. Add 38.3 mg EDC HCl salt and let the mixture sit at room temperature overnight. The title compound was isolated from the reaction mixture using RP-HPLC with 65-100% MeCN gradient with 0.1% TFA. LC-MS: 3.89 min. (m/Z=388.2, 410.1)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33](I)[CH3:34]>C(#N)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:33][CH3:34])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCI
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Solvent: CC#N
Product: CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Yield: 66.6 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (102 mg, 0.2 mmol) in acetonitrile (10 mL) was treated with ethyl iodide (34 mg, 17.4 μL, 0.2 mmol). The reaction mixture was heated for 24 h at 50° C., until analysis (TLC/LCMS) showed complete consumption of starting material. The reaction mixture was allowed to cool to ambient temperature and was then concentrated in vacuo. The resultant residue was partitioned between ethyl acetate (10 mL) and 1M sodium carbonate solution (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by chromatography (silica, Si-SPE, EtOAc) to afford the title compound as a white solid (72 mg, 60%). 1H NMR (CDCl3, 400 MHz,): 9.56 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.65 (s, 1H), 8.25-8.22 (m, 2H), 7.67-7.62 (m, 1H), 7.54-7.49 (m, 2H), 5.15 (s, 1H), 2.96 (s, 2H), 2.48 (s, 2H), 2.23 (s, 4H), 2.02 (d, J=16.9 Hz, 2H), 1.18-1.04 (m, 3H). LCMS (Method G): RT=3.5 min, M+H+=541.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.[C:22](=O)([O-])[O-].[Na+].[Na+].CI>CN(C)C=O>[CH3:22][N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCOC(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 134A (158 mg) in anhydrous N,N-dimethylformamide (4 mL) was added sodium carbonate (64 mg) and methyl iodide (78 mg). After stirring overnight at room temperature, the mixture was evaporated to dryness. The crude product was then absorbed on silica gel (6 g) and purified on a silica gel column eluting with 10% methanol in dichloromethane to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Br:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23]>COC(O)C.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Reactant: Nc1ccc(F)c(Br)c1
Agent: COC(C)O
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Br)c3)c2cc1[N+](=O)[O-]
Yield: 74.1 %

Procedure:
A mixture of 3.52 g (9.7 mmol) of 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile and 2.0 g (10.7 mmol) of 3-bromo-4-fluoro aniline in 150 ml of methoxyethanol was refluxed under nitrogen for 5.5 hours. The reaction mixture was diluted with ethyl acetate and wash with sodium bicarbonate solution and sodium chloride solution. The organic layer was dried with sodium sulfate and then solvent was removed under vacuum. The residue was chromatographed on silica gel eluting with mixture of ethyl acetate and methanol to give 3 g of yellow solid: mass spectrum (electrospray, m/e): 416.8 and 418.8.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3S(C3C=CC(C)=CC=3)(=O)=O)=[C:15]([C:32]3[O:33][C:34]([CH2:37]Cl)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[OH-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[C:15]([C:32]3[O:33][C:34]([CH2:37][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cc(-c2cc(-c3nnc(CN4CCOCC4)o3)c3cn[nH]c3c2)cnc1Cl
Temperature: 90 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
N-(2-Chloro-5-{4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-[(4-methylphenyl)sulfonyl]-1H-indazol-6-yl}-3-pyridinyl)methanesulfonamide (30 mg, 0.051 mmol) and morpholine (1 ml, 11.48 mmol) were placed a vial and heated in a microwave at 90° C. for 15 mins. The morpholine was blown off under a stream of nitrogen and the residue suspended in isopropanol (2 ml) and 2M sodium hydroxide (1 ml) added. The mixture was stirred at room temperature for 2 h. The solvent was blown off and the residue purified by chromatography on a silica gel (20 g) cartridge, eluting with 0-25% methanol in dichloromethane over 30 mins. The solvent was removed in vacuo and the residue loaded onto a SCX (10 g) cartridge and eluted with methanol and then 2M ammonia in methanol. The residue was purified by Mass Directed Automated Preparative HPLC (Method B) to give the title compound as a white solid (5 mg).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2(O)[C:14]3[C:15]([CH3:35])=[C:16]([N:21]4[CH2:26][CH2:25][N:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)[CH2:23][CH2:22]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:37])[CH3:36])=[CH:6][CH:5]=1>C(O)C>[F:40][C:2]([F:1])([F:39])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:35])=[C:16]([N:21]4[CH2:22][CH2:23][N:24]([C:27]5[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=5)[CH2:25][CH2:26]4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:37])=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(OC(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(OC(F)(F)F)cc3)C(C)(C)O4)CC2)cc1
Yield: 70 %

Procedure:
Using 3-(4-(trifluoromethyl)phenyl)-5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 65, the title compound was synthesized in the same manner as in Example 46. Yield 70%. mp. 147–148° C. (ethanol).