Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH2:20][C:21]([OH:23])=O)(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.[N:25]1([CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH2:20][C:21]([N:35]2[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:37][CH2:36]2)=[O:23])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)O)c(C)c1
Reactant: C1CCN(CCC2CCNCC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N2CCCC2COCC(=O)N2CCC(CCN3CCCC3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (71 mg, 0.441 mmol) was added to a solution of 2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)pyrrolidin-2-yl)methoxy)acetic acid (150 mg, 0.420 mmol) in dichloromethane (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(2-(pyrrolidin-1-yl)ethyl)piperidine (76 mg, 0.420 mmol) in dichloromethane (3 ml) was then added, and the reaction mixture was stirred for 15 h at room temperature. Saturated sodium hydrogen carbonate solution (10 ml) was then added to the reaction mixture, and then the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography using ethyl acetate/methanol/ammonia solution (25% aq.) (400:100:5).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(C)(=O)=O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (50 mg, 0.075 mmol) and methane sulfonamide (9.3 mg, 0.098 mmol) as described in the general procedure above to give [18-(isoquinolin-1-yloxy)-4-methanesulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (300 MHz, CD3Cl3) δ 1.18 (s, 9H), 1.25–1.96 (m, 11H), 2.26 (m, 1H), 2.54 (m, 1H), 2.71 (m, 2H), 3.18 (s, 3H), 4.08 (m, 1H), 4.26 (m, 1H), 4.64 (m, 2H), 5.00 (m, 2H), 5.73 (m, 1H), 6.01 (s, 1H), 6.73 (s, 1H), 7.28 (d, J=5.5 Hz, 1H), 7.50 (t, J=7.3 Hz, 1H), 7.65–7.76 (m, 2H), 7.98 (d, J=5.9 Hz, 1H), 8.19 (d, J=7.7 Hz, 1H), 10.28 (s, 1H). LC-MS (Method A, retention time: 3.57 min), MS m/z 670 (M++1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[N:5]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:4]=1.[NH:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:5]2[C:6]([C:8]3[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=3)=[CH:7][C:3]([CH2:2][N:27]3[CH2:33][CH2:32][CH2:31][N:30]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=5)[N:5]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[N:4]=4)[CH2:29][CH2:28]3)=[N:4]2)[CH:22]=1
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2cccnc2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5cccnc5)n4)CC3)nn2Cc2cccnc2)cc(OC)c1OC

Procedure:
3-Chloromethyl-1-(3-pyridylmethyl)-5-(3,4,5-trimethoxyphenyl)pyrazole (110 mg) and homopiperazine (13 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Si:18]([O:25][CH2:26][CH:27]1[C:31]([CH2:32]Br)=[CH:30][CH2:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:18]([O:25][CH2:26][CH:27]1[C:31]([CH2:32][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])=[CH:30][CH2:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC=C1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CCCC2CO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.16 g, 0.66 mmol) and (5-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide (0.20 g, 0.66 mmol) in dimethylformamide (10 ml) were heated at 50° C. for overnight in the presence of sodium bicarbonate (66 mg, 0.79 mmol). After the concentration of dimethylformamide, [(5-t-butyldimethylsilyloxymethyl cyclopent-1-en-1-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF (10 ml) was reacted with n-tetrabutylammoniumfluoride at room temperature for 1 hr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product (35 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[C:21](N)[C:4]=2[N:3]=1.N([O-])=[O:30].[Na+].C([O-])(O)=O.[Na+]>O.CO.OS(O)(=O)=O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:20]=[C:21]([OH:30])[C:4]=2[N:3]=1
Reactant: Cc1nc2c(N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nc2c(O)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-amine (842 mg) in H2O (20 mL), MeOH (1 mL) and conc. H2SO4 (3 mL) was added aqueous NaNO2 (344 mg) solution drop-wise at 0° C. The mixture was stirred at 0° C. for 15 min and then stirred at reflux temperature for 1 h. The mixture was cooled to room temperature and the pH neutralized with aqueous NaHCO3 solution. It was extracted with DCM (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in-vacuo. The residue was then purified by silica gel chromatography eluted with MeOH:DCM=1:60 and then by Prep-HPLC to afford crude desired product LC-MS: m/e=374 [M+1]+ containing an impurity that was removed by the two-step sequence described below.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:14]=12)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:19]([N:15]1[C:14]2[C:9](=[O:8])[NH:10][N:11]=[CH:12][C:13]=2[CH:17]=[C:16]1[CH3:18])[CH:20]([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: Cc1cc2c(Cl)nnc(OCc3ccccc3)c2n1CC(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cc2cn[nH]c(=O)c2n1CC(C)C
Yield: 52 %

Procedure:
4.5 g (13.6 mmol) of 7-benzyloxy-4-chloro-1-isobutyl-2-methylpyrrolo[2,3-d]pyridazine (contaminated with about 40% of the isomeric 4-benzyloxy compound), 4 ml of triethylamine and 0.5 g of palladium (5%)/carbon catalyst are hydrogenated with hydrogen for 5 h in 500 ml of methanol. Purification: chromatography on silica gel (eluent: toluene/dioxane 4:1). Yield: 52%, m.p.: 188°-191° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To 300 ml. of DMF were added 107 grams of phenyl p-hydroxybenzoate and 26 grams of sodium hydride (50 percent in oil). The mixture was heated at 60° C. for two hours. To the mixture then were added 67 grams of 1-chloro-2-pyrrolidinoethane, and the mixture was stirred overnight at 85° C. The bulk of the DMF then was evaporated from the mixture. Water was added to the residue, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was concentrated, and the residue was dissolved in a 1:1 mixture of ether and ethyl acetate. The organic solution then was extracted with 2 N hydrochloric acid, and the acid extract was added dropwise to 2 N sodium hydroxide. The resulting mixture was extracted with ethyl acetate, and the ethyl acetate extract was washed and then dried over magnesium sulfate. The ethyl acetate was concentrated to obtain 110 grams of crude phenyl p-(2-pyrrolidinoethoxy)benzoate.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Reactant: Fc1ccc(CBr)cc1
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(Cc3ccc(F)cc3)CC1)O2

Procedure:
Compound 156 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-fluorobenzene and conditions outlined in general procedure W. M.p.=210-211° C.; 400 MHz 1H NMR (CDCl3) δ: 7.91-7.88 (m, 1H), 7.84-7.83 (m, 1H), 7.65-7.62 (m, 1H), 7.30-7.26 (m, 3H), 7.05-7.00 (m, 2H), 3.58 (s, 2H), 2.93 (s, 2H), 2.76-2.72 (m, 2H), 2.50-2.46 (m, 2H), 2.13-2.05 (m, 2H), 1.94-1.83 (m, 2H); LCMS: 488 [M+H].
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23]2.[CH2:35]([O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48]O)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]([O:42][C:43]([NH:45][CH2:46][CH2:47][CH2:48][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:23]2)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: COC(=O)CCc1cc2cc(O)ccc2[nH]1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)CCc1cc2cc(OCCCNC(=O)OCc3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (370 mg, 1.5 mmol) was added to the solution of methyl 3-(5-hydroxyindolyl)propanoate (220 mg, 1.0 mmol), as prepared in step g of Example 5, 3-(benzyloxycarbonylamino)propanol (230 mg, 1.1 mmol) and tri-n-butylphosphine (305 mg, 1.5 mmol) in tetrahydrofuran (20 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (0–2% ethyl acetate in methylene chloride) to give the title compound as an off white solid (310 mg, 76%). 1H-NMR (400 MHz, CDCl3) δ 7.35 (m, 5H), 7.22 (d, J=8.9 Hz, 1H), 7.09 (d, J=3.1 Hz, 1H), 7.07 (d, J=2.1 Hz, 1H), 6.86 (dd, J=8.8, 2.4 Hz, 1H), 6.38 (d, J=2.9 Hz, 1H), 5.11 (br s, 3H), 4.41 (t, J=6.8 Hz, 2H), 4.07 (t, J=5.9 Hz, 2H), 3.66 (s, 3H), 3.44 (q, J=6.3 Hz, 2H), 2.81 (t, J=6.8 Hz, 2H), 2.02 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC1CCCC(=O)C1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: C1CCNC1
Solvent: CO
Product: CC1CCCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reaction time: 8 h
Yield: 124.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), 3-methylcyclohexanone (10.5 g, 93.4 mmol) and pyrrolidine (6.3 g, 88.8 mmol) in methanol (200 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, and then H2O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-3′-methylspiro[chroman-2,1′-cyclohexan]-4-one (18 g, 100%). 1HNMR (CDCl3): 0.86 (m, 3H), 0.91 (m, 2H), 1.02 (m, 2H), 1.30 (m, 2H), 1.52 (m, 2H), 1.65 (m, 4H), 1.80 (m, 7H), 2.01 (m, 4H), 2.22 (m, 1H), 2.48 (m, 1H), 2.60 (s, 2H), 2.72 (t, 3H), 6.81 (m, 1H), 7.50 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:33][C:30]3[S:31][CH:32]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[N:29]=3)=[O:18])=[CH:15][CH:14]=2)(=[O:11])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: COc1ccc(NS(=O)(=O)c2ccc(C(=O)Nc3nc(-c4ccccn4)cs3)cc2)cc1

Procedure:
4-(N-(4-methoxyphenyl)sulfamoyl)benzoic acid (10) (104 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-methoxyphenyl)sulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 29 mg (25%). 1H-NMR: 10.08 (s, 1H), 8.63-8.60 (m, 1H), 8.21 (d, J=8.5 Hz, 2H), 8.04-7.87 (m, 3H), 7.82 (d, J=8.5 Hz, 2H), 7.34 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.01-6.90 (m, 3H), 6.82 (d, J=9.0 Hz, 2H), 3.66 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22](O)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:23])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)O
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
To a mixture of 8.2 mg of 7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid, 3.8 mg of 1-(2-aminoethyl)piperidine, 13.1 μL of DIPEA, and 0.4 mL of DMF was added a mixture of 9.8 mg of HATU and 0.1 mL of DMF, followed by stirring at room temperature overnight. The reaction mixture was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 3.6 mg of 7-methyl-4-oxo-N-[2-(piperidin-1-yl)ethyl]-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxamide.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([S:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=34)[CH:7]=[C:6]([NH2:30])[C:5]=2[CH:4]=[N:3]1.N1C=CC=CC=1.[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43](Cl)=[O:44])[N:42]=1>C(Cl)Cl>[CH3:37][C:38]1[S:39][CH:40]=[C:41]([C:43]([NH:30][C:6]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]4[N:17]([S:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[CH:18]=[CH:19][C:12]=34)[CH:9]=[C:10]3[C:5]=2[CH:4]=[N:3][N:2]3[CH3:1])=[O:44])[N:42]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(N)c5cnn(C)c5c4)ccnc32)cc1
Reactant: Cc1nc(C(=O)Cl)cs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(NC(=O)c5csc(C)n5)c5cnn(C)c5c4)ccnc32)cc1
Temperature: 25 °C

Procedure:
1-Methyl-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-indazol-4-amine (75 mg) and pyridine (0.029 ml) were added to DCM (5 ml) under stirring at RT under nitrogen. 2-Methyl-1,3-thiazole-4-carbonyl chloride (38 mg) was added into the reaction mixture. The reaction mixture was partitioned between water (20 ml) and DCM (20 ml).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:38]1[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]([CH3:53])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:42]=1>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:38]3[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]([CH3:53])[CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:42]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CN(CCn1cc(Br)cn1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)Cc4ccccc4)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (300 mg, 0.721 mmol, for a preparation see Intermediate 52), potassium carbonate (149 mg, 1.081 mmol) and 2-(4-bromo-1H-pyrazol-1-yl)-N-methyl-N-(phenylmethyl)ethanamine (317 mg, 1.078 mmol, for a preparation see Intermediate 53) were stirred in ethanol (3 mL) and toluene (3.00 mL). The mixture was degassed, tetrakis(triphenylphosphine)palladium(0) (41.6 mg, 0.036 mmol) added, the mixture degassed again and heated to reflux (90° C.) under nitrogen for 4.5 hours. The mixture was cooled to room temperature, loaded on to a 5 g SCX cartridge, eluted with MeOH (50 ml), 2M methanolic ammonia (25 ml) and the basic fractions evaporated to dryness. The residue was loaded on to a 12+M Biotage silica column and eluted with a gradient of 0 to 5% 2M methanolic ammonia in DCM. The product containing fractions were evaporated to a colourless gum (223 mg).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)=[N:12]1)[CH2:8]2.B(I)(I)I.O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[N:12]1)[CH2:8]2
Reactant: COc1cccc(C2=NC(=C3C4CC5CC(C4)CC3C5)C(C)(C)O2)c1
Agent: IB(I)I
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC(c2cccc(O)c2)=NC1=C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 7 mmol 4-adamantylidene-2-(3'-methoxyphenyl)-5,5-dimethyl-oxazoline in 20 ml absolute methylene chloride is added dropwise to a solution of 14 mmol boron triiodide while stirring at -25° C. with the exclusion of air and water. The mixture is heated to room temperature within one hour and stirred for a further 4 h. After admixing with 50 ml water the organic phase is separated and dried over sodium sulfate. The solvent is removed by distillation. The oily residue is separated by column chromatography (silica gel: ethyl acetate/petroleum ether 1:3).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]#[C:13]Br.C(N(CC)CC)C>CC(C)=O>[O:6]=[C:4]1[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:11])[N:5]1[C:13]#[N:12]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CBr
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: N#CN1C(=O)c2ccccc2C1=O
Reaction time: 0.25 h
Yield: 76.7 %

Procedure:
To a 25 mL round-bottomed flask was added phthalimide (1.47 g, 10.0 mmol), cyanogen bromide (1.27 g, 12.0 mmol), and 10 mL of reagent grade acetone. The resulting mixture was cooled using an ice/salt bath while triethylamine (1.8 mL, 12.8 mmol) was added dropwise over a 2 minute period. After 15 minutes, the mixture was transferred to a separatory funnel and partitioned between ethyl acetate and water. The organic phase was washed with water, saturated brine, dried (MgSO4), and filtered. The solution was decolorized with activated charcoal, and concentrated to give a brown solid. This material was recrystallized from ethyl acetate to give 1.32 g (77%) of a brown crystalline solid, mp 189°-191° C. (reported in Zh. Org. Khim. 1977, 13, 968 as 190° C.): IR (nujol) 2258 (nitrile), 1755 (carbonyl) cm-1 ; 1H NMR (200 MHz, DMSO) δ 8.05-8.15 (m, 4); 13C NMR (50 MHz, DMSO) δ 162.61, 136.35, 130.76, 125.03, 102.86.
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:31])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:14][C:13]=1[CH3:30].CI>>[CH3:9][O:10][C:11](=[O:31])[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])=[N:14][C:13]=1[CH2:30][CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(C)n1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)c(CC)n1
Temperature: 78 °C
Reaction time: 0.5 h

Procedure:
LDA (19 mg, 89 μL of 2 M solution in THF, 0.18 mmol) at −78° C. is added to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-nicotinic acid methyl ester (27 mg, 0.086 mmol). The mixture is stirred for 30 minutes at 78° C. Methyl iodide (15 μL, 0.24 mmol) is added and the resulting yellow mixture is stirred for 10 minutes at −78° C. After quenching with saturated NH4Cl the mixture is extracted with EtOAc. The combined extracts are dried, concentrated, and purified by flash-chromatography to give 6-(2,6-diethyl-phenyl)-2-ethyl-4-methoxy-nicotinic acid methyl ester.