Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22]Cl)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.FC1C=CC(C2CCCN2)=CC=1.BrCC1C=CC(S(Cl)(=O)=O)=CC=1.[CH3:48][O-:49].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][O:49][CH3:48])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(CCl)cc1)N1CCCC1c1ccc(F)cc1
Reactant: C[O-]
Agent: Fc1ccc(C2CCCN2)cc1
Agent: O=S(=O)(Cl)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
Reaction of (RS)-2-(4-fluoro-phenyl)-1-(4-chloromethyl-benzenesulfonyl)-pyrrolidine (0.50 g, 1.41 mmol), which was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-bromomethyl-benzenesulfonyl chloride, with sodium methanolate in MeOH for 80 h at 50° C. yielded after crystallization from EE/hexane 0.28 g (52%) of the title compound as a white solid, m.p. 115° C., and MS: m/e=349 (M+).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:12][C@:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:15][C@H:14]1[CH:16]=[CH2:17].[CH:22]1[N:26]=[CH:25][N:24]([C:27](N2C=NC=C2)=[O:28])[CH:23]=1>C1COCC1>[N:24]1([C:27]([NH:12][C@:13]2([C:18]([O:20][CH3:21])=[O:19])[CH2:15][C@H:14]2[CH:16]=[CH2:17])=[O:28])[CH:23]=[CH:22][N:26]=[CH:25]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)n1ccnc1)C(=O)OC

Procedure:
Compound BT was prepared according to Scheme 12. To a suspension of (1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate tosylate salt (25.0 g, 1 eq.) in THF (150 mL) at 50° C. were added CDI (14.24 g, 1.1 eq.) and TEA (12.27 mL, 1.1 eq.). The reaction mixture was then refluxed overnight. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc, and washed with water. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated in Et2O to afford compound BT (15.24 g, purity 80%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1.63 (dd, J=5.8 and 9.7 Hz, 1H), 1.96 (dd, J=5.8 and 8.4 Hz, 1H), 2.30 (q, J=8.9 Hz, 1H), 3.73 (s, 3H), 5.16 (d, J=10.0 Hz, 1H), 5.28 (d, J=17.0 Hz, 1H), 5.69-5.81 (m, 1H), 7.03 (s, 1H), 7.50 (s, 1H), 8.24 (s, 1H), 8.57 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH2:3][OH:4].[N:16]#[C:17]Br>>[CH3:8][C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:15])[CH2:6][CH2:5][C@H:2]1[CH2:3][O:4][C:17]([NH2:16])=[N:1]1
Reactant: CC(C)(CC[C@H](N)CO)c1ccccc1
Reactant: N#CBr
Product: CC(C)(CC[C@H]1COC(N)=N1)c1ccccc1

Procedure:
In analogy to example 1d (S)-2-amino-5-methyl-5-phenyl-hexan-1-ol was reacted with cyanogen bromide to give (S)-4-(3-methyl-3-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine. White solid. MS (ISP): 233.1 ([M+H]+))
Reaction SMILES: Br[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:14][C:15]1[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([CH3:21])[CH:20]=1>>[CH3:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[NH:14][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Reactant: Cc1ccc(C)c(N)c1
Product: Cc1ccc(C)c(Nc2c(C(=O)O)cccc2[N+](=O)[O-])c1
Yield: 65 %

Procedure:
Reaction of 2-bromo-3-nitrobenzoic acid and 2,5-xylidine gave 2-(2,5-dimethyl phenylamino)-3-nitro benzoic acid (65%): mp (benzene/acetone) 215-217° C. 1H NMR [(CD3)2SO] δ 2.10 (s, 3 H, CH3), 2.23 (s, 3 H, CH3), 6.53 (s, 1H, H-6'), 6.79 (d, J=7.4 Hz, 1 H, H-4'), 7.02 (t, J=8.0 Hz, 1 H, H-5), 7.11 (d, J=7.7 Hz, 1 H, H-3'), 8.03 (dd, J=8.1, 1.4 Hz, 1 H, H-6), 8.22 (dd, J=7.7, 1.5 Hz, 1 H, H-4), 9.84 (br s, 1 H, NH), 13.8 (br s, 1 H, CO2H). Anal. (C15H14N2O4) C, H, N.
Reaction SMILES: CC1NC2C[CH:9]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:10][C:11](=[O:12])[C:5]=2C(C2C=CC=C(O)C=2)C=1C(OCCOC)=O.C(O)(=O)C.N.COC1C=CC=CC=1C=O.C(OCC)(=O)CC([O-])=O>CC(C)=O>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:9]=[CH:10][C:11](=[O:12])[CH3:5]
Reactant: COCCOC(=O)C1=C(C)NC2=C(C(=O)CC(c3ccccc3OC)C2)C1c1cccc(O)c1
Agent: CCOC(=O)CC(=O)[O-]
Agent: COc1ccccc1C=O
Agent: N
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: COc1ccccc1C=CC(C)=O

Procedure:
Synthesis of HPIs of the disclosure can be performed by any means by one of skill in the art. However, an example of synthesis of HPI-1 is provided. HPI-1 can be readily prepared in a one-pot synthesis using the Hantzsch reaction (Loev et al., J. Pharm. Pharmacol. (1972) 24:917-918) (see also FIG. 10 panel A-B). This synthetic transformation generates the dihydropyridyl pharmacophore from an aldehyde, two 1,3-diones, and ammonia acetate in high yields. First, one of the 1,3-diones was prepared in two synthetic steps (FIG. 10, panel A). 4-(2-methoxyphenyl)but-3-en-2-one was synthesized by an aldol condensation of 2-methoxybenzaldehyde and acetone, followed by dehydration. Reaction of the α,β-unsaturated ketone product with ethyl malonate generated an ester intermediate, which yielded the desired aryl-substituted 1,3-dione upon decarboxylation. HPI-1 was then synthesized by heating a mixture of the aryl-substituted 1,3-dione, 3-hydroxybenzaldehyde, 2-methoxyethyl acetoacetate, ammonium acetate, and the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM.BF4) (FIG. 10, panel B). Purification by silica gel chromatography yielded the final product as a mixture of four diastereomers in 63% overall yield. Using this procedure, it is possible to synthesize gram quantities of HPI-1, which would be sufficient for both research and clinical applications. HPI-1 derivatives set forth in Table II were similarly prepared.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:6]=[C:5]([CH3:17])[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29]>CN(C=O)C>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:13]1[CH:14]=[C:9]([C:8]2[C:3]([F:2])=[N:4][C:5]([CH3:17])=[CH:6][CH:7]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: Cc1ccc(-c2c[nH]c(=O)[nH]c2=O)c(F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2ccc(C)nc2F)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.8 %

Procedure:
A mixture of 5-(2-fluoro-6-methyl-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep 15, 667 mg, 2.59 mmol), and K2CO3 (358 mg, 2.59 mmol) in DMF (25 ml) was stirred 30 minutes at room temperature. Then 90% 3-Bromo-1,1dimethoxy-propane (432 μl, 2.85 mmol) was added in three portions during 3 days. Solvent was then removed under vacuum at 40° C. and the residue washed with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98-2-0.2) to give 291 mg of the title compound as a white solid (35% yield).
Reaction SMILES: [CH2:1]=O.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].N>CO.ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:30])=[N:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:29])=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:1])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: C=O
Reactant: Cc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Agent: N
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn(C2CCN(C)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
37% Aqueous formaldehyde (0.042 ml) at 0° C. was added to a stirred solution of 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (178 mg) dissolved in methanol (2 ml) and dichloromethane (2 ml) over a period of 5 minutes under argon. The resulting solution was stirred at 0° C. for 5 minutes. Then sodium triacetoxyhydroborate (121 mg) was added and the mixture was stirred for 5 minutes at 25° C. A solution of ammonia in methanol 7N (2 ml) was added and the mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 5% methanolic ammonia (7 N) in dichloromethane. The solvent was evaporated to dryness, then the resulting solid was stirred in acetonitrile overnight, filtered and dried to afford 3-(1,3-benzoxazol-2-yl)-5-[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (125 mg) as a solid; NMR Spectrum: (DMSOd6) 1.88-2.11 (m, 6H), 2.21 (s, 3H), 2.33 (s, 3H), 2.81-2.93 (m, 2H), 3.97-4.11 (m, 1H), 7.38-7.50 (m, 2H), 7.65 (bs, 2H), 7.79 (d, 1H), 7.84 (d, 1H), 8.07 (s, 1H), 8.28 (s, 1H), 8.35 (s, 1H); Mass spectrum: M+H+: 389
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11]C)=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:13]([CH2:17][CH3:18])[CH2:14][O:15][CH3:16])[CH:3]=1.[C:19]([CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH3:16][O:15][CH2:14][CH:13]([N:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]=2[C:2]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][C:19]#[N:20])=[CH:23][CH:24]=2)=[CH:3]1)[CH2:17][CH3:18]
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: CCC(COC)n1cc(I)c2c(OC)nccc21
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: CN(C)C=O
Solvent: O
Product: CCC(COC)n1cc(-c2ccc(CC#N)cc2)c2c(=O)[nH]ccc21
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a solution of 3-iodo-4-methoxy-1-(1-methoxybutan-2-yl)-1H-pyrrolo[3,2-c]pyridine (50.0 mg) obtained in Step A-2 of Example 17 in DMF (2 mL)/water (0.20 mL) were added (4-(cyanomethyl)phenyl)boronic acid (33.8 mg), tetrakis(triphenylphosphine)palladium(0) (15.9 mg) and potassium carbonate (38.3 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (20.2 mg).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH3:20][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)n1nc(O)c2cc(C(=O)OC)ccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)n1c2ccc(C(=O)OC)cc2c(=O)n1C

Procedure:
1-Ethyl 5-methyl 3-hydroxy-1H-indazole-1,5-dicarboxylate (1.75 g, 6.62 mmol) was suspended in acetone (85 mL). Cesium carbonate (2.27 g, 6.95 mmol) and methyl iodide (1.3 mL, 20 mmol) were added and the reaction was stirred at reflux for 22 hours. The reaction was concentrated to dryness and the residue was partitioned between dichloromethane (60 mL) and water (100 mL). The layers were separated and the aqueous was extracted again with dichloromethane (60 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (7-60% ethyl acetate/heptanes) gave two regioisomeric products.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])/[CH:10]=[CH:12]/[N:13]([CH3:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(F)c(F)c1
Yield: 84 %

Procedure:
The title compound was prepared in 84% yield from 1-(3,4-difluorophenyl)ethanone and DMF-DMA according to the procedure for the preparation of Example 12, part A. 1H NMR (400 MHz, CDCl3): δ 2.93 (3H, s), 3.16 (3H, s), 5.62 (1H, d, J=12.0 Hz), 7.13-7.20 (1H, m), 7.63-7.76 (2H, m), 7.83 (1H, d, J=12.0 Hz).
Reaction SMILES: C(C1C=C(NC(=O)C[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)C=CC=1S(CC)(=O)=O)#N.BrC1C=CC(C[CH2:35][N:36](C)[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]#[N:47])[CH:41]=2)=[O:38])=CC=1>>[C:46]([C:42]1[CH:41]=[C:40]([NH:39][C:37](=[O:38])[N:36]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=2)[CH3:35])[CH:45]=[CH:44][CH:43]=1)#[N:47]
Reactant: CN(CCc1ccc(Br)cc1)C(=O)Nc1cccc(C#N)c1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Product: CN(CCc1ccc(B(O)O)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 91 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 23C (200 mg, 0.70 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 23D (165 mg, 91%) as a yellow oil. MS (ESI) m/z 324.03 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)=[O:2].S(=O)(=O)([OH:31])N.Cl([O-])=O.[Na+]>O1CCCC1.O>[CH3:28][O:27][C:25]([CH2:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:1]([OH:31])=[O:2])[CH:4]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:22][CH:21]=1)=[O:26]
Reactant: NS(=O)(=O)O
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C=O)c3)c2)cc1
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCc1ccc(OCc2cccc(-c3cccc(C(=O)O)c3)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a solution of methyl 4-[(3′-formyl-[1,1′-biphenyl]-3-yl) methoxy]benzenepropanoate (0.48 g, 1.3 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was added sulfamic acid (0.15 g, 1.3 mmol), and a solution of sodium chlorite (0.17 g, 1.5 mmol) in water (1.5 mL) was added. The mixture was stirred at room temperature for 15 hrs., and water was added. The mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure to give the title compound 0.50 g (quantitative).
Reaction SMILES: C1C2C(COC([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:48])[CH2:26][C:27]([C:30]3[C:35](=[O:36])[C:34]([CH3:37])=[C:33]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:32](=[O:46])[C:31]=3[CH3:47])([CH3:29])[CH3:28])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C>[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:48])[CH2:26][C:27]([C:30]1[C:35](=[O:36])[C:34]([CH3:37])=[C:33]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH:44]=[CH2:45])=[O:41])[C:32](=[O:46])[C:31]=1[CH3:47])([CH3:29])[CH3:28]
Reactant: C=CCOC(=O)CCC1=C(C)C(=O)C(C(C)(C)CC(=O)OCCCCCNC(=O)OCC2c3ccccc3-c3ccccc32)=C(C)C1=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C=CCOC(=O)CCC1=C(C)C(=O)C(C(C)(C)CC(=O)OCCCCCN)=C(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound J (250 mg, 0.38 mmol) dissolved in 10 mL of DMF was added piperidine (0.5 mL). The solution was stirred 10 min at room temperature. The solvent was evaporated and the residue was purified by flash chromatography using a gradient solvent system 10% MeOH/CH2Cl2 to 100% MeOH. After evaporation of the solvent 53 mg (33%) of the compound K was isolated as a yellow oil. 1H NMR 500 MHz (CD3OD) δ5.87 (m, 1H), 5.22 (m, 2H), 4.54 (dt, J=5.6 Hz, 1.2 Hz, 2H), 3.93 (t, J=7 Hz, 2H), 2.92 (s, 2H), 2.72 (t, J=8 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.45 (t, J=8 Hz, 2H), 210 (s, 3H), 1.96 (s, 3H), 1.58-1.42 (br, 4H), 1.38 (s, 6H), 1.30 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:38]=[CH:37][C:20]2[N:21]([CH2:25][C:26]3[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=3[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:38]=[CH:37][C:20]3[N:21]([CH2:25][C:26]4[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1ccccc1CN1CCOc2cc(N)ccc21
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1CN1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Yield: 77.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.14 g, 0.8 mmol), thionyl chloride (3 mL), ethyl 2-[(7-amino-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methyl]benzoate obtained in Example (104b) (0.35 g, 1.12 mmol) and pyridine (5 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) to obtain 0.29 g of the title compound as a yellow solid (77%).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:30](Br)[C:31]#[CH:32].C1(C)C=CC=CC=1>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:32][C:31]#[CH:30])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:26]=[CH2:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccccc1-c1[nH]c2cc(C(=O)OC)ccc2c1C1CCCCC1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCn1c(-c2ccccc2C=C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Yield: 84 %

Procedure:
Methyl 3-cyclohexyl-2-(2-vinylphenyl)-1H-indole-6-carboxylate was dissolved in DMF (0.277 M) and sodium hydride (1.2 eq.) was added. After the evolution of gas had ceased, a solution of propargylbromide in toluene (80% solution, 1.6 eq.) was added. After 3 h all volatiles were evaporated in vacuo. The residual material was purified by flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents, the product was obtained as a colourless foam (84%). MS (ES+): 398.4 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].ClCCl.[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:30][C@@H:31]([CH3:35])[C:32]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1CC2=C(CCCC2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 107 ml of triethylamine and then 162 g of (2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3-dihydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]2[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[NH:9][C:8]=2[C:22]([F:25])([F:24])[F:23])[CH:3]=1.[Br:26]Br.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[NH:9][C:8]([C:22]([F:23])([F:24])[F:25])=[C:7]([C:4]3[C:3]([Br:26])=[C:2]([Br:1])[S:6][CH:5]=3)[C:11]=2[N+:12]([O-:14])=[O:13])=[CH:20][CH:19]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1-c1csc(Br)c1Br

Procedure:
A solution of 3-(5-bromo-3-thienyl)-5-(p-chlorophenyl)-4-nitro-2-(trifluoromethyl)pyrrole (0.50 g, 1.1 mmol), bromine (0.20 g, 1.3 mmol) and sodium acetate (0.11 g, 1.3 mmol) in acetic acid (10 mL) is heated overnight at 50° C. and poured into water. The solids are collected and recrystallized from 1,2-dichloroethane to give the title product as a yellow solid, mp 241°-242° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>O.CC(C)=O>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:11][CH2:10][CH:9]([O:12][CH3:13])[O:8][CH3:7])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COC(CN)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(CNC(=O)c1ccc(Br)cc1)OC
Temperature: 25 °C

Procedure:
Potassium carbonate (8.0 g) was added to a solution of 2,2-dimethoxyethylamine in water (90 ml) and acetone (40 ml) at rt. The reaction mixture was cooled in an ice-water bath and 4-bromobenzoyl chloride (16.4 g) dissolved in acetone (70 ml) was added drop-wise over 90 min. The stirred reaction mixture was allowed to warm to rt. After a further 2 h the reaction mixture was extracted into EtOAc (3×75 ml), the combined organics were washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated to give the amide as an off white solid (18.5 g). LCMS electrospray (+ve) 289 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]>ClCCl.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:13](=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:8][CH:7]=1
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)CCCCC(=O)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 15 h

Procedure:
A suspension of 2.59 g (19.4.10−3 mol) of aluminum chloride in 4 ml of dichloromethane is prepared. It is cooled to −5° C. and a mixture of 0.97 ml (10.3.10−3 mol) of fluorobenzene and 1.31 ml (8.4.10−3 mol) of methyl 6-chloro-6-oxohexanoate in 3 ml of dichloromethane is added gradually, the temperature being maintained between −4 and −7° C. The temperature is then allowed to rise to 20° C. and, after 15 hours, the mixture is hydrolyzed in acidified iced water. It is extracted with dichloromethane and the organic phase obtained is washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The 2 g of crude product recovered in this way are purified by chromatography on silica gel using a petroleum ether/ethyl acetate mixture (96/4) as the eluent to give 1.26 g of the expected product in the form of a white powder (yield=63%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>CCO>[CH2:17]([N:19]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1)[CH2:20][CH3:21])[CH3:18]
Reactant: CCNCC
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCN(CC)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-ethylethanamine (0.50 ml, 4.8 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 87 (6), 86 (bp), 77 (4), 58 (6).