Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH3:2].O1C[CH2:19][CH2:18][CH2:17]1.C([Mg]Br)CC.[Cl-].[NH4+]>O1CCCC1>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH2:17][CH2:18][CH3:19])=[CH:7][CH:6]=1)[CH3:15]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: C1CCOC1
Agent: CCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCCC(O)c1ccc(C(OCC)OCC)cc1
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
A solution of 4-(diethoxymethyl)benzaldehyde (10.4 g, 50.0 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature under a nitrogen atmosphere, 2 M n-propylmagnesium bromide tetrahydrofuran solution (27.5 mL, 55.0 mmol) was added dropwise. After 30 min, aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-20:80) to give 1-[4-(diethoxymethyl)phenyl]butane-1-ol (6.39 g, 25.3 mmol) as a colorless oil. The oil was dissolved in a mixture of tetrahydrofuran (75 mL) and water (25 mL) and p-toluenesulfonic acid monohydrate (0.500 g, 2.63 mmol) was added. The mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:90-40:60) to give the title compound (4.51 g, yield 51%, 2 step) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH2:23])=[O:22]>>[C:9]1([C@H:20]2[C@H:20]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[F:13])[C:21](=[O:22])[NH:23][C:21]2=[O:22])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccccc1F
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccccc1F

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2-fluorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2-fluorophenylacetamide. Yield 30.6 mg, 8.8%. 1H NMR (DMSO-d6) 400 MHz δ: 11.64 (s, 1H), 7.36 (m, 3H), 7.17 (m, 3H), 6.84 (m, 2H), 4.44 (d, 1H, J=7.2 Hz), 4.40 (d, 1H, J=7.6 Hz), 4.10 (s, 2H), 2.88 (s, 2H), 2.09 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9](O)[CH:10]=3.[C:27](=O)([O-])[O-:28].[K+].[K+].BrC[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:10]=3[O:28][CH3:27]
Reactant: O=C([O-])[O-]
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Reactant: CC(C)(C)OC(=O)CBr
Agent: [K+]
Solvent: CS(C)=O
Product: COc1c(C(=O)OC(C)(C)C)cc2c(=O)c(Cc3cccnc3)cn3c4cc(Br)ccc4c1c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) produced in Example 102 was suspended in dimethyl sulfoxide (8 ml). After adding potassium carbonate (136 mg), the mixture was stirred at room temperature for 30 minutes, and t-butyl bromoacetate (0.09 ml) was added. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water (20 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (144 mg, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:13]>>[ClH:11].[N:14]1([C:12]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=2[F:10])=[O:13])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Reactant: OCc1ccc(Br)cc1F
Product: Cl
Product: O=C(OCc1ccc(Br)cc1F)N1CCNCC1

Procedure:
4-Bromo-2-fluorobenzyl piperazine-1-carboxylate hydrochloride was prepared from 4-bromo-2-fluorobenzyl alcohol and 1-chlorocarbonyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 52 and 54 to give the product as a white solid (26.5%); melting point 209.5–209.6° C.; NMR δH (400 MHz, DMSO-d6) 3.078(4H, bt), 3.594(4H, bt), 5.118(2H, s), 7.455(2H, m), 7.592(1H, m) and 9.147(2H, bs).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:26][CH:27]1[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1.C(=O)([O-])[O-]>C(Cl)Cl>[NH:29]1[CH2:30][CH:27]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)NC3CNC3)ccc1OCC2
Reaction time: 1.5 h

Procedure:
Following the procedure for 126, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 1,1-dimethylethyl 3-aminoazetidine-1-carboxylate then the crude product was suspended in DCM and treated with MP carbonate resin and stirred for 1.5 h. The mixture was filtered, the filtrate concentrated in vacuo and the resultant residue triturated in diethyl ether to give 156 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.11 (d, J=6.84 Hz, 1H); 8.46 (d, J=2.18 Hz, 1H); 8.05 (t, J=0.64 Hz, 1H); 7.90-7.85 (m, 1H); 7.37-7.30 (m, 1H); 6.92 (s, 1H); 5.62-5.53 (m, 1H); 4.82-4.73 (m, 1H); 4.57 (t, J=5.76 Hz, 2H); 3.95-3.81 (m, 4H); 3.25 (t, J=5.78 Hz, 2H); 1.50 (d, J=6.58 Hz, 6H). LCMS RT=6.45 min, M+H+=394
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[CH:15]([OH:16])[N:14]2[CH:6]3[CH:7]4[N:23]([CH3:24])[C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:8]54[C@H:12]([OH:13])[CH:11]([CH:4]1[CH2:5]3)[CH:10]2[CH2:9]5.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[CH3:1][CH2:2][C@H:3]1[CH:4]2[CH:11]3[C@@H:12]([OH:13])[C:8]45[C:17]6[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=6)[N:23]([CH3:24])[C@H:7]4[C@H:6]([CH2:5]2)[N+:14]([O-:37])([C@H:10]3[CH2:9]5)[C@@H:15]1[OH:16]
Reactant: CCC1C2CC3C4N(C)c5ccccc5C45CC(C2[C@H]5O)N3C1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC[C@H]1C2C[C@H]3[C@@H]4N(C)c5ccccc5C45C[C@@H](C2[C@H]5O)[N+]3([O-])[C@@H]1O

Procedure:
200 mg of ajmaline were put in solution in an organic solvent such as chloroform or a mixture of chloroform and methanol (5 ml). A solution of 200 mg of metachloroperbenzoic acid in 5 ml of the same solvent was slowly added, with stirring, the mixture being cooled in ice. The kinetics of the reaction were followed by thin layer chromatography (alkaline Kieselgel plate; solvent CHCl3 90-MeOH 10). At the same time as the N-oxy-ajmaline, there were formed more polar secondary products, already in a important amount whereas the whole of the ajmaline was not yet transformed. The solution was diluted with chloroform, washed with an 15% aqueous solution of KHCO3, dried, filtered and dry distilled. The residue obtained, chromatographed on a silica column of activity V, gave 104 mg of N-oxyajmaline (Yield 49.5%).
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[O:20])[CH:14]=3)[CH2:10][C:8]=2[N:9]=1)=O.CS(C1[N:37]=CC2CN(C3C=CN=C(C(NC4C=CC=C(C(F)(F)F)C=4)=O)C=3)CC=2N=1)(=O)=O.[OH-].[NH4+]>O1CCOCC1>[F:29][C:28]([F:31])([F:30])[C:24]1[CH:23]=[C:22]([NH:21][C:19]([C:15]2[CH:14]=[C:13]([N:11]3[CH2:12][C:7]4[CH:6]=[N:5][C:4]([NH2:37])=[N:9][C:8]=4[CH2:10]3)[CH:18]=[CH:17][N:16]=2)=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)c1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Reactant: CS(=O)c1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 90 °C

Procedure:
A mixture of 4-(2-(Methylsulfinyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-N-(3-(trifluoromethyl)phenyl)picolinamide and 4-(2-(methylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-N-(3-(trifluoromethyl)phenyl)picolinamide was suspended in 1,4-dioxane (7 mL). Ammonium hydroxide (30%, 1.5 mL) was added and the reaction was heated at 90° C. for 16 hours. TLC indicated only partial conversion to the desired amine. The solvent was reduced with a nitrogen stream and then additional ammonium hydroxide (1 mL) was added. The reaction was sealed in a tube and heated at 100° C. for 17 h. The solvent was evaporated in vacuo. The resulting solid was triturated with water and then methanol. The solid was chromatographed on silica gel (4 g) eluted with ethyl acetate:methanol (9:1) to give the title compound (10.6 mg, 0.026 mmol).
Reaction SMILES: CS(C)=O.[OH-].[K+].[CH2:7]([NH:14][C:15](=[O:39])[C@@H:16]([CH2:37][OH:38])[NH:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:40]I>C1(C)C=CC=CC=1.O>[CH2:7]([NH:14][C:15](=[O:39])[C@@H:16]([CH2:37][O:38][CH3:40])[NH:17][C:18]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of DMSO (8 g) and pulverized KOH (0.308 g), Example 5 product (i.e., N-benzyl-N2-trityl-D-serinamide, 2 g) was added in one lot. It was stirred for 3 hours at ambient temperature. Methyl iodide (0.97 g) was slowly added to the mixture for 15 minutes at ambient temperature and stirred for 30 minutes. The reaction mixture was cooled to 0° C., water was added to it and the product was isolated with toluene. Oily product was recovered under vacuum at 35-40° C. from the organic layer. Hexane (100 ml) was added to the oily product and the solution formed is stirred for 15 minutes, filtered and dried to get the titled product of Formula Va. Yield=1 gm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](C(=O)COC)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Mg]Br.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>C(Cl)(Cl)Cl.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22]([CH3:23])([CH3:19])[CH2:26][O:25][CH3:24])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: C[Mg]Br
Reactant: C1CCOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COCC(C)(C)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(4-benzyl-piperazin-1-yl)-2-methoxy-ethanone (6.14 g) in dry THF (80 mL) at −10° C. was added zirconium chloride (5.76 g). After 30 minutes methyl magnesium bromide (3.0M solution in ether, 49.6 mL) was added in a dropwise manner. The reaction mixture was allowed to warm to room temperature. After stirring for 1 day, the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the was solvent removed in vacuo. The resulting residue was purified using flash chromatography to yield 1-benzyl-4-(2-methoxy-1,1-dimethyl-ethyl)-piperazine. Subsequent transfer hydrogenation, using ammonium formate and 10% palladium on carbon in MeOH, furnished the desired compound.
Reaction SMILES: [Al:1].[S:2](=[O:6])(=[O:5])([OH:4])[OH:3]>O>[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Al+3:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Al+3:1]
Reactant: O=S(=O)(O)O
Reactant: [Al]
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: [Al+3]

Procedure:
With additional reference to FIG. 2, the aluminum-containing residue or char from the kiln is introduced into a batch or continuous reactor 26 as by conveyor 29 and mixed therein with a sulfuric acid solution, as from vessel 27, heated water, as from vessel 28, direct steam, as from source 30 and preferably using thermal energy recovered from the hot gases in steam boiler 22 by various heat exchangers associated with vessels 27 and 28 and steam source 30 in a manner well-known to those of ordinary skill in the art. Mixing of the components in the reactor 26 is preferably accomplished by mechanical agitation, as by stirrer 32. The temperature of the aqueous streams entering the reactor 26 is preferably in the range of from about 80° C. to about 100° C. Reaction of the components in the reactor is believed to produce an aqueous solution of aluminum sulfate by the reaction:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:46]N(C=O)C.[H-].[Na+].IC>O>[CH3:46][N:16]1[C:14]2=[N:15][C:10]([S:7]([NH:6][C:35]3[S:39][N:38]=[CH:37][N:36]=3)(=[O:8])=[O:9])=[CH:11][CH:12]=[C:13]2[C:18]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][C:20]=2[C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)=[CH:17]1
Reactant: CN(C)C=O
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3n2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2nc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.75 h
Yield: 84 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (Intermediate J) (77.2 mg, 0.118 mmol) and DMF (1 mL) to give a clear solution. Sodium hydride (60% in mineral oil) (7.06 mg, 0.177 mmol) was added in one portion to give a bright yellow mixture. The mixture was stirred for 45 min, then iodomethane (14.72 μl, 0.235 mmol) was added. After stirring for an additional 1 h, the mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was taken up in DCM (0.9 mL) and TFA (0.18 mL), and the resulting mixture was stirred for 1.5 h. The mixture was diluted with MeOH (5 mL), then filtered through Celite® (diatomaceous earth) with the aid of methanol. The filtrate was concentrated, and the crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to afford 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (51.42 mg, 0.099 mmol, 84% yield) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ=8.48 (s, 1 H), 7.97-7.85 (m, 3 H), 7.83-7.78 (m, 1 H), 7.61 (d, J=8.3 Hz, 1 H), 7.53 (s, 1 H), 7.38 (d, J=1.9 Hz, 1 H), 6.35 (d, J=1.9 Hz, 1 H), 3.75 (s, 3 H), 3.28 (s, 3 H). m/z (ESI) 520.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[C:15](Cl)(=[O:17])[CH3:16].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:15](=[O:17])[CH3:16])=[CH:20]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: c1ccc2[nH]ccc2c1
Reactant: CC(=O)Cl
Product: CC(=O)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
1-[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-ethanone was prepared from phenanthridine, acetyl chloride, and indole according to GP 2. Yield, 30%. 1H-NMR (CDCl3): δ=2.25 (s, 3H), 6.16 (d, J=1.6 Hz, 1H), 7.10 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.12-7.17 (m, 2H), 7.18-7.25 (m, 2H), 7.31-7.48 (m, 3H), 7.50 (s, 1H), 7.73 (s, br., 1H), 7.81 (d, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 1H), 7.93-8.00 (m, 1H); (+)-ESI-MS: m/z=339 [M+H]+, 222 [M-indole+H]+.
Reaction SMILES: CCN(CC)CC.[CH2:8]([O:10][C:11](=[O:36])[CH2:12][CH2:13][NH:14][C:15]([C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])=[CH:19][CH:18]=1)=[O:16])[CH3:9].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:25]([C:24]3[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:35])[F:33])=[CH:31][C:23]=3[C:20]3[CH:19]=[CH:18][C:17]([C:15]([NH:14][CH2:13][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:36])=[O:16])=[N:22][CH:21]=3)=[O:26])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Temperature: 25 °C

Procedure:
Neat Et3N (0.28 mL, 2.0 mmol) was added to a DCM mixture (3 mL) of 2-(6-((3-ethoxy-3-oxopropyl)carbamoyl)pyridin-3-yl)-4-(trifluoromethyl)benzoic acid (˜40% pure) (616 mg, 0.6 mmol), 4′-chloro-2′-methyl-[1,1′-biphenyl]-4-amine (109 mg, 0.5 mmol), and EDCI (383 mg, 2.0 mmol) and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture was directly purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(Cl)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(Cl)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
4-Chloroaniline (0.150 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.115 g, 0.238 mmol, 44%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][N:6]([CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=O)[C:4]=2[O:3]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:31][CH:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1>C(OCC)(=O)C>[CH3:16][C:2]1([CH3:1])[CH2:7][N:6]([CH3:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([NH:31][CH:32]3[CH:37]4[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]4)[CH2:33]3)=[O:15])[C:4]=2[O:3]1
Reactant: CN1CC(C)(C)Oc2c(C(=O)O)cccc21
Reactant: NC1CN2CCC1CC2
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN1CC(C)(C)Oc2c(C(=O)NC3CN4CCC3CC4)cccc21
Temperature: 25 °C

Procedure:
To a solution of 1.0 g of 2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.2 ml of triethylamine, and 0.55 g of pivaloyl chloride was added dropwise thereto at -10° to -5° C. under cooling. After stirring for 15 minutes at the same temperature, 0.57 g of 3-aminoquinuclidine was added at -10° to -5° C. and the mixture was stirred at room temperature for an hour. The resultant mixture was washed with water, dried over magnesium sulfate and concentrated. The precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl ether and ethanol to give 2,2,4-trimethyl-N-(3-quinuclidinyl)-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 114°-116° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH3:15][Mg]Cl.O.CC(O)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH3:15]
Reactant: C[Mg]Cl
Reactant: O=Cc1sc(-c2cccnc2)nc1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(O)c1sc(-c2cccnc2)nc1Cl
Temperature: -10 °C
Reaction time: 18 h

Procedure:
4-Chloro-2-(3-pyridyl)thiazole-5-carbaldehyde (1.4 g, 6.25 mmol) was dissolved in dry THF (28 ml) and cooled to −10° C. A 3 M solution of methyl magnesiumchloride in THF (2.08 ml, 6.25 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 18 hours. Water (1.7 ml) was added, followed by CH3COOH (1 ml). The reaction mixture was extracted with ethyl acetate, the organic layer was separated, dried, filtered, and the solvent was evaporated to dryness to get 1-[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanol as a brown solid. 1H NMR (300 Mz, DMSO-d6): δ: 9.07 (s, 1H), 8.68 (dd, 1H, J=1.5 Hz), 8.26 (m, 1H), 7.53 (m, 1H), 5.92 (t, 1H, J=6 Hz), 4.67 (d, 3H, J=5.4 Hz).