Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([S:27]([NH:30][C:31]1[C:32](=[O:42])[N:33]([CH2:38][CH2:39][CH2:40]O)[C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:29])=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:44]>CN(C=O)C>[CH2:20]([S:27]([NH:30][C:31]1[C:32](=[O:42])[N:33]([CH2:38][CH2:39][CH2:40][Br:44])[C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:29])=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
A solution of triphenylphosphine (0.46 g, 1.75 mmol) in DMF (5 mL) was added to a mixture of 1-5 (0.49 g, 1.46 mmol) and carbon tetrabromide (0.68 g, 2.05 mmol) in DMF (5 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and allowed to stir for 12 hours. The mixture was then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate and hexane (3:1 to 2:1 gradient) as eluants to afford the title compound 1-6 (0.38 g, 66% yield) as a yellow solid. MS (m/e): 399. TLC: Rf (0.35) (EA/Hex); 1H NMR (400 MHz, CDCl3): δ 2.23 (m, 2H), 2.4 (s, 3H), 3.5 (t, 2H), 4.2 (t, 2H), 4.3 (s, 2H), 6.0 (d, 1H), 7.2(d, 1H), 7.3(m, 5H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:45][C:46](=[O:50])[C@H:47]([CH3:49])[NH2:48])C>CCOCC>[F:33][C:30]([F:31])([F:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:48][C@H:47]([C:46]([OH:50])=[O:45])[CH3:49])=[O:11])=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCC(F)(F)F)C(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of 4-[N-trifluoroacetyl-15-(trifluoromethyl)pentadecylamino]benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:18]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(Cc2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A heterogeneous mixture of methyl 2-oxo-2H-pyran-3-carboxylate (2.0 g, 13 mmol, 1.0 eq, Aldrich) and 4-fluorobenzylamine (1.5 mL, 13 mmol, 1.0 eq) in DMF (10 mL) was stirred at room temperature for 3 h. The reaction mixture was treated with EDCI (3.4 g, 18 mmol, 1.4 eq) and DMAP (0.11 g, 9.91 mmol, 0.07 eq) at room temperature and the resulting solution was stirred for 12 h. The reaction mixture was quenched with 1 N aqueous HCl and the solution was extracted with ethyl acetate (4×50 mL). The combined organic extracts were washed with 10% aqueous LiCl (3×70 mL), dried (Na2SO4), filtered and the filtrate concentrated in vacuo to afford the product (2.5 g, 73%) as a solid, which was used without further purification. 1H NMR (DMSO-d6) δ 8.17-8.20 (m, 1H), 8.03-8.05 (m, 1H), 7.38-7.46 (m, 2H),7.16-7.22 (m, 2H), 6.37 (dd, 1H, J=6.94 Hz), 5.13 (s, 2H), 3.73 (s, 3H); HRMS(ESI): calcd.: 262.0879, found: 262.0885.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][CH2:34][CH2:35][NH:36][C:37]1[S:41][N:40]=[C:39]([CH3:42])[CH:38]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:32][O:33][CH2:34][CH2:35][N:36]([C:37]1[S:41][N:40]=[C:39]([CH3:42])[CH:38]=1)[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: COCCNc1cc(C)ns1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1cc(C)ns1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid and (2-methoxy-ethyl)-(3-methyl-isothiazol-5-yl)-amine with triethylamine and diethyl cyanophosphonate in dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1.Cl.[CH2:15]([O:17][C:18](=[O:29])[CH:19](CC)[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][NH:22]1)[CH3:16].C(N(CC)CC)C>ClCCl>[CH2:15]([O:17][C:18](=[O:29])[CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[S:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=1[CH3:13])(=[O:11])=[O:10])[CH3:16]
Reactant: CCOC(=O)C(CC)CC1CCCCN1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC1CCCCN1S(=O)(=O)c1cc(C)c(Cl)cc1C
Temperature: 0 °C
Yield: 50 %

Procedure:
4-Chloro-2,5-dimethyl-benzenesulfonyl chloride (1 g, 3.8 mmol) was added to a solution of ethyl 3-(piperidin-2-yl)propionic acid ethyl ester hydrochloride (1.1 g, 4.6 mmol) in dichloromethane (15 ml) while stirring, the mixture was cooled to 0° C., and triethylamine (1.6 ml, 11.5 mmol) was added dropwise over 15 min. The mixture was stirred for 4 h at 0° C., then diluted with dichloromethane, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated to small volume under vacuum. The crude product was purified with ethyl acetate/hexane (9:1) by column chromatography. Yield: 50%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].[CH3:25][O:26][C:27]([N:29]1[C:37]2[C:32](=[CH:33][C:34]([S:38](Cl)(=[O:40])=[O:39])=[CH:35][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:38]([C:34]1[CH:33]=[C:32]3[C:37](=[CH:36][CH:35]=1)[N:29]([C:27]([O:26][CH3:25])=[O:28])[CH2:30][CH2:31]3)(=[O:39])=[O:40])[C:6](=[O:11])[C:5]2([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[NH:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: COCCCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Product: COCCCNC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)OC)c2ccc(Cl)cc21
Yield: 69.8 %

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 222 from 1.3 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-[(3-methoxypropyl)amino]indol-2-one and 0.980 g of 1-(methoxycarbonyl)-indoline-5-sulfonyl chloride. 1.5 g of the expected product are obtained after crystallization from a DCM/ iso ether/hexane mixture. M.p.=98° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)=[O:8]>C(O)(=O)C>[Br:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([N+:1]([O-:4])=[O:2])[C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)=[O:8]
Reactant: COc1cc(C(=O)CBr)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C(=O)CBr)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
A solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid is added dropwise while stirring and within 30 minutes at 20°-25° to a solution of 112.5 g of 2-bromo-4'-hydroxy-3'-methoxyacetophenone in 560 ml of glacial acetic acid. Yellow-brown crystals thereby separate. After 90 minutes the reaction mixture is poured on to 300 g of ice. The crystals are filtered under suction, washed with 1000 ml of water and dissolved in 1000 ml of methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate is evaporated at 50° in a water-jet vacuum until crystallization begins. The crystallizate, cooled to room temperature, is removed by filtration under suction and washed with a small amount of methylene chloride. There is obtained 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone of m.p. 147°-149°.
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15](Cl)(=[O:17])=[O:16])=[O:5]>O1CCCC1>[CH3:2][N:3]([CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([NH2:1])(=[O:17])=[O:16])=[O:5]
Reactant: N
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O

Procedure:
37 ml of concentrated ammonia solution (33% strength) are added dropwise at 5° C. and with stirring to a mixture of 77.8 g of 2-dimethylaminocarbonyl-5-nitrobenzenesulfonyl chloride and 780 ml of tetrahydrofuran. The mixture is subsequently stirred until the end of the reaction. The reaction mixture is concentrated under reduced pressure and the residue is stirred with a little water. Drying gives 66.9 g of the desired product. m.p.: 159-160° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N+:3]=1[O-:9].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:7]=[C:6]([N+:15]([O-:17])=[O:16])[C:5]([F:8])=[CH:4][N+:3]=1[O-:9]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cc(F)ccc1Br
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1F

Procedure:
Prepared analogously to example 83b from 2-bromo-5-fluoropyridine 1-oxide, conc. sulphuric acid and conc. nitric acid
Reaction SMILES: [H-].[Na+].[C@@H:3]1([OH:9])[CH2:7][CH2:6][CH2:5][C@H:4]1[OH:8].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[N:12]=1>CN(C=O)C.CCOCC>[Br:10][C:11]1[N:12]=[C:13]([CH2:17][O:8][C@@H:4]2[CH2:5][CH2:6][CH2:7][C@H:3]2[OH:9])[CH:14]=[CH:15][CH:16]=1
Reactant: BrCc1cccc(Br)n1
Reactant: O[C@@H]1CCC[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O[C@@H]1CCC[C@H]1OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.48 mg, 11.96 mmol) was suspended in DMF (12.0 mL) and cooled to 0° C. (1R,2R)-Cyclopentane-1,2-diol (1.22 g, 11.96 mmol) was added and the reaction was stirred for 30 minutes. 2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.30 g, 1.20 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. The reaction was then diluted with ether and quenched with water. After layer separation, the organic layer was dried over magnesium sulfate, filtered and concentrated. Purification of the crude residue by silica gel chromatography afforded the title compound.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[C@@H:32]12[NH:47][C@@H:36]([CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]1)[CH2:35][O:34][CH2:33]2>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([N:47]5[C@H:32]6[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[CH2:37][C@@H:36]5[CH2:35][O:34][CH2:33]6)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2COC[C@@H](C1)N2
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4[C@@H]5COC[C@H]4CN(C(=O)OC(C)(C)C)C5)cn3)nc2n1C1CCCC1
Yield: 85 %

Procedure:
Following general amide formation method 2, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid with 5 equiv LiCl and (1R,5S)-tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate were combined and gave (1R,5S)-tert-butyl 9-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate (115 mg) in 85% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (s, 1H), 8.60 (d, J=9.09 Hz, 1H), 8.44 (d, J=2.02 Hz, 2H), 7.85 (dd, J1=8.59 Hz, J2=2.02 Hz, 1H), 6.49 (s, 1H), 4.82 (m, 1H), 4.59-3.75 (m, 6H), 3.17 (s, 4H), 3.02 (s, 2H), 2.95 (s, 2H), 2.81 (m, 4H), 2.57 (m, 1H), 2.09 (m, 4H), 1.75 (m, 1H), 1.49 (m, 9H) LCMS m/z 604.9 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([N:23]2[CH2:37][C:26]3=[C:27]4[N:32]([N:33]=[C:25]3[CH2:24]2)[C:31]([CH3:34])=[C:30]([Cl:35])[C:29]([CH3:36])=[N:28]4)=[O:22])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:35][C:30]1[C:29]([CH3:36])=[N:28][C:27]2[N:32]([N:33]=[C:25]3[CH2:24][N:23]([C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[O:22])[CH2:37][C:26]3=2)[C:31]=1[CH3:34]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CC1CCN(C(=O)OC(C)(C)C)CC1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1CC1CCNCC1)C3
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-benzyl]-piperidine-1-carboxylic acid tert-butyl ester (210 mg; 0.4 mmol; 1 eq.) and TFA (2 mL) in DCM (2 mL) was stirred at room temperature for 2 hours then concentrated in vacuo. The residue was taken up in water, the pH made basic with 5M NaOH and extracted with DCM (2×). The combined organic layer was dried over magnesium sulfate and concentrated in to afford the title compound (131 mg, 77%) as an off-white solid. 1H NMR (CDCl3) δ 7.38-7.24 (m, 4H), 5.04-5.01 (m, 2H), 4.51 (s, 1.3H), 4.48 (s, 0.7H), 3.04-2.96 (m, 2H), 2.91 (s, 2H), 2.85 (s, 1H), 2.70 (s, 1H), 2.61-2.57 (m, 4H), 2.53-2.43 (m, 2H), 1.80-1.57 (m, 4H), 1.19-1.06 (m, 2H). HPLC (max plot) 100%, Rt 2.75 min. UPLC/MS: (MS+) 424.4 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Reactant: O=S(=O)(Cl)c1cccs1
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)c3cccs3)c2c1C
Yield: 68 %

Procedure:
3-Methyl-4-(thiophene-2-sulfonylamino)-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1), and 2-thiophenesulfonyl chloride according to the procedure of Example 68, Step 1. Yield: 68%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.6 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 6.7 (dd, J=7.8, 0.8 Hz, 1 H) 7.2 (dd, J=4.9, 3.7 Hz, 1 H) 7.4 (m, 2 H) 7.6 (dd, J=8.3, 0.8 Hz, 1 H) 8.0 (dd, J=4.9, 1.4 Hz, 1 H) 10.2 (s, 1 H)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-[3,3′-bipyridin]-2-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 437 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reaction time: 6 h
Yield: 75 %

Procedure:
To a suspension of 16.0 g N-benzyloxycarbonyl-L-aspartic acid (Z-Asp) in 24 ml toluene, was added 7.7 g of acetic anhydride, and the reaction was continued at room temperature for six hours to form N-benzyloxycarbonyl-L-aspartic anhydride (Z-Asp O).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:12][O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 30.5 %

Procedure:
A mixture of (4-nitro-phenyl)-methanol (3.0 g, 19.6 mmol), potassium carbonate (3.9 g, 28.1 mmol), acetonitrile (100 ml), and iodomethane (11 ml, 176 mmol) was heated at 50° C. for 48 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with hexane-dichloromethane (1:1 followed by 1:2) to yield 1-methoxymethyl-4-nitro-benzene (1.0 g, 31% yield).
Reaction SMILES: [CH:1]([C:9]1[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:11][NH:12][CH:13]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:20]SC1C(C2C=NC=CC=2)=NNC=1>>[CH:1]([C:9]1[C:10]([C:14]2[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][CH:19]=2)=[N:11][NH:12][CH:13]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC=Cc1c[nH]nc1-c1cccnc1
Reactant: CSc1c[nH]nc1-c1cccnc1
Product: CCCCCCC=Cc1c[nH]nc1C1=CCCN(C)C1

Procedure:
3-(4-Oct-1-enyl-1H-pyrazol-3-yl)-pyridine was converted to the title compound 47C, using the methodology described for the conversion of 21A to 22A (see Scheme 3). Yield: 95% (amorphous). 1H-NMR (400 MHz, CDCl3): δ 7.58 (s, 1H), 6.24 (bd, J=16 Hz, 1H), 6.07-6.02 (m, 1H), 5.98-5.89 (m, 1H), 3.29-3.25 (m, 2H), 2.63 (bt, J=7 Hz, 2H), 2.46 (s, 3H), 2.44-2.38 (m, 2H), 2.18-2.12 (m, 2H), 1.46-1.38 (m, 2H), 1.38-1.24 (m, 6H), 0.91 (t, J=7 Hz, 3H).
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=[CH:4][N:3]=C1.[NH:32]1C=CN=N1.N1C=CN=C1>>[N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:5]=[CH:4][N:3]=[N:32]1
Reactant: COc1cc(C(=O)c2c(-n3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reactant: c1c[nH]nn1
Agent: c1c[nH]cn1
Product: COc1cc(C(=O)c2c(-n3ccnn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
This material was prepared according to the procedure outlined above for 2-(N-imidazolyl)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (entry 27, Table 1), above, except the 1,2,3-triazole was used as the nucleophile in place of imidazole. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, 1H, J=1.21 Hz), 7.75 (d, 1H, J=1.20 Hz), 7.27 (d, 1H, J=8.60 Hz), 7.18 (d, 1H, J=8.66 Hz), 7.05 (s, 2H, benzoyl Hs), 3.94 (s, 3H, OMe), 3.74 (s, 6H, 2×OMe), 3.73 (s, 3H, OMe).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3]C.[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:31])=[C:13]([C:29]=1[CH3:30])[C:14]([C:16]1[C:21](C)=[CH:20][C:19]([O:23][CH3:24])=[C:18]([O:25][CH3:26])[C:17]=1[O:27][CH3:28])=[O:15]>C(COC)OC>[Br:8][C:9]1[C:29]([CH3:30])=[C:13]([C:12]([CH3:31])=[CH:11][CH:10]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:23][CH3:24])=[C:18]([O:25][CH3:26])[C:17]=1[O:27][CH2:28][CH2:1][CH2:2][CH3:3])=[O:15]
Reactant: COc1cc(C)c(C(=O)c2c(C)ccc(Br)c2C)c(OC)c1OC
Reactant: CCCCO
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCOc1c(C(=O)c2c(C)ccc(Br)c2C)ccc(OC)c1OC
Temperature: 90 °C

Procedure:
A mixture of n-butanol (5 ml) and sodium hydride (60% in oil, 20 mmol) is stirred until the formation of H2 gas ceases. A mixture of 1C (2.0 g, 5.0 mmol) and dimethoxyethane (15 ml) is added to the resulting reaction mixture. Subsequently, the reaction mixture is heated to 90° C. with stirring for 14 hours and dimethoxyethane is distilled off. A mixture of water and ethyl acetate (1:1 v/v; 100 ml) is then slowly added at room temperature. The organic phase is separated, concentrated and the residue is purified by column chromatography (petrol ether: ethyl acetate, 90:10 v/v) yielding the pure product as a yellow oil, 1.7 g (78.3%).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:28]3[CH:27]=[C:26]4[C:31](=[CH:30][CH:29]=3)[N:23]([CH3:22])[CH:24]=[CH:25]4)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
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: O
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc4c(ccn4C)c3)CCC2)CCN(C)C1
Temperature: 90 °C

Procedure:
To a degassed solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 1-methylindole-5-boronic acid pinacol ester (149 mg, 0.579 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was heated at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(1-methyl-1H-indol-5-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR, (CD3OD, TFA salt) δ (ppm): 7.21-7.38 (m, 2H), 7.2 (s, 1H), 7.04 (m, 2H), 6.9 (d, 1H), 6.8 (d, 1H), 6.21 (s, 1H), 4.62 (m, 1H), 4.35 (m, 1H), 3.65 (s, 3H), 3.58 (m, 2H), 3.01 (s, 3H), 2.81 (m, 2H), 2.6 (m, 4H), 2.41 (s, 3H), 2.21 (m, 2H).