Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[C:7](=[O:16])[C@:6]3([CH3:22])[C@H:17]([CH3:21])[O:18][CH2:19][CH2:20][N:5]3[C:4]=2[N:3]=1.[CH3:23][NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)=[O:26].C([O-])(O)=O.[Na+].[Na+].[Cl-]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH:13]1([CH2:12][N:8]2[C:7](=[O:16])[C@:6]3([CH3:22])[C@H:17]([CH3:21])[O:18][CH2:19][CH2:20][N:5]3[C:4]3[N:3]=[C:2]([C:31]4[CH:30]=[CH:29][C:28]([NH:27][C:25]([NH:24][CH3:23])=[O:26])=[CH:33][CH:32]=4)[N:11]=[CH:10][C:9]2=3)[CH2:15][CH2:14]1
Reactant: C[C@@H]1OCCN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@]12C
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2ncc3c(n2)N2CCO[C@@H](C)[C@@]2(C)C(=O)N3CC2CC2)cc1
Yield: 5.3 %

Procedure:
A microwave vial equipped with a magnetic stirrer was added crude (6aS,7S)-2-chloro-5-(cyclopropylmethyl)-6a,7-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (98 mg, 0.304 mmol), 1,4-dioxane (1.5 ml), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (126 mg, 0.455 mmol), saturated NaHCO3 (0.500 mL), and PdCl2(dppf) (11.11 mg, 0.015 mmol). The reaction was irradiated in the microwave at 100° C. for 40 minutes. The reaction solution was poured into saturated NaCl and extracted with ethyl acetate three times. The organic layers were collected, dried over Na2SO4, filtered and concentrated in-vacuo to give a brown residue. The residue was purified by preparative HPLC (eluting with 20-30% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to afford the title compound (6.8 mg, 0.016 mmol, 5.13% yield) as a light brown solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.46 (m, 2 H) 0.60 (m, 2 H) 1.20-1.25 (m, 1 H) 1.41 (d, J=6.6 Hz, 3 H) 1.92 (s, 3 H) 2.81 (s, 3 H) 3.53-3.67 (m, 1 H) 3.79-3.87 (m, 1 H) 3.91 (d, J=7.0 Hz, 2 H) 3.99-4.11 (m, 1 H) 4.27 (d, J=6.6 Hz, 1H) 4.87-5.00 (m, 1 H) 7.65 (d, J=8.8 Hz, 2 H) 7.97 (s, 1 H) 8.11 (d, J=8.8 Hz, 2 H). MS [M+H] found 437.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28]O[CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[CH2:32](O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:30][CH3:31])=[N:20][S:21]([N:24]3[CH2:29][CH2:28][CH2:32][CH2:26][CH2:25]3)(=[O:23])=[O:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CNC(=NS(=O)(=O)N1CCOCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: CCO
Product: CNC(=NS(=O)(=O)N1CCCCC1)N1C[C@H](c2ccccc2)C(c2ccc(Cl)cc2)=N1

Procedure:
(−)-(4S)-3-(4-Chlorophenyl)-N-methyl-N′-((morpholin-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine ([α25D]=−144°, c=0.01, MeOH). (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of ethanol. Amorphous.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH3:11])[C:6]=2[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.[CH3:20][C:21]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=1[NH2:23].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:11][N:10]1[C:6]2[C:5]([C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[CH:27][C:21]=3[CH3:20])[C:7]=2[CH:8]=[CH:9]1
Reactant: Cc1cc(C(F)(F)F)ccc1N
Reactant: Cn1ccc2c(Cl)ncc(C(=O)N3CCOCC3)c21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)ccc1Nc1ncc(C(=O)N2CCOCC2)c2c1ccn2C
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-1-methyl-7-(4-morpholinylcarbonyl)-1H-pyrrolo[3,2-c]pyridine (100 mg), 2-methyl-4-trifluoromethylaniline (60 μl), cesium carbonate (163 mg), tris(dibenzylideneacetone)dipalladium (0) (7 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5 mg) in 1,4-dioxan (2 ml) was heated to 100° C. under argon overnight. The reaction mixture was diluted with dichloromethane and washed with water followed by saturated sodium chloride solution, then dried (MgSO4), filtered and evaporated. Purification and salt formation was as described in Example 101 to afford the title compound as a white solid (52 mg).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:15][CH:16]([CH2:18]O)O>>[CH3:13][S:10]([CH2:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:18][CH:16]=[CH:15]2)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cc1ccc(N)c(Br)c1
Reactant: OCC(O)CO
Product: CS(=O)(=O)Cc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-(methylsulfonylmethyl)aniline and glycerol can be combined to form 6-(methylsulfonylmethyl)-8-bromoquinoline.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([CH2:20][C:21]1[N:26]=[C:25]([CH2:27][C:28]([OH:30])=O)[CH:24]=[CH:23][CH:22]=1)([OH:19])=O>CO.CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:17](=[O:19])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([CH2:27][C:28]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:30])[N:26]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(CC(=O)O)n1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cccc(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)n1
Yield: 7.8 %

Procedure:
Using General Procedure A with 9.7 g (40 mmol) D-Proline benzyl ester hydrochloride and 3.9 g (20 mmol) (6-carboxymethyl-pyridin-2-yl)-acetic acid afforded, after flash chromatography (gradient: 0-10% MeOH/EtOAc), 890 mg (8%) of the title compound as a yellow oil. MS m/e (%): 570 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]1[N:12]=[N:11][C:10]([C:13]2[N:14]([CH3:26])[S:15](=[O:25])(=[O:24])[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]=2[OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:19][C:18]1[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[S:15](=[O:25])(=[O:24])[N:14]([CH3:26])[C:13]=1[C:10]1[N:11]=[N:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CN1C(c2nnn(Cc3ccccc3)n2)=C(O)c2ccccc2S1(=O)=O
Product: CC(=O)OC1=C(c2nnn(Cc3ccccc3)n2)N(C)S(=O)(=O)c2ccccc21
Yield: 90.5 %

Procedure:
A mixture of compound (a) above (0.30 g) and acetic anhydride (5 ml) was refluxed for 4 hours and then concentrated. The residual oil solidified upon addition of n-hexane. After removal of the solvent by decantation, the solid was crystallized from toluene, filtered off and dried in vacuo to give 0.275 g (90.5%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[H-].[Na+].Br[CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O>[C:19]([Si:16]([CH3:18])([CH3:17])[O:15][CH2:14][CH2:13][O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][OH:8])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(CCO)CCO
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CCO)CCOCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.4 %

Procedure:
Step A To the solution of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) prepared in Example 116a Step A. in anhydrous dimethylformamide (15 mL) was added NaH (60%, 0.68 g, 17 mmol). The mixture was stirred at room temperature for 15 min, then (2-bromoethoxy)-tert-butyldimethylsilane (3.3 g, 14 mmol) was added. The mixture was stirred at room temperature for 1 h. Water was added. The mixture was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3) to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol as a yellow oil (0.3 g, 9%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:22]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH:27]=[CH:26][CH:25]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: N
Product: CC(C)(C)OC(=O)Nc1cccc(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(tert-butoxycarbonylamino)benzoic acid (Aldrich). 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9H), 6.71 (s, 1H), 7.39-7.58 (m, 2H), 7.68 (d, J=7.9 Hz, 1H), 7.89 (d, J=9.1 Hz, 1H), 8.24 (s, 1H), 8.45 (d, J=7.9 Hz, 1H), 8.77 (d, J=4.8 Hz, 1H), 9.40 (s, 1H) ppm; MS (DCI/NH3) m/z 339 (M+H)+, 356 (M+NH4)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:11]1[CH:10]=[CH:9][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:12][C:13]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:14]=3[CH:15]=[O:16])[C:4]=12
Reactant: ClCc1cccn2ccnc12
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccn3ccnc23)c(C=O)c1
Temperature: 87.5 °C
Yield: 45 %

Procedure:
To a solution of the crude 8-(chloromethyl)imidazo[1,2-a]pyridine (6.8 mmol, 1 eq) and 2-hydroxy-5-methoxybenzaldehyde (1.3 g, 8.1 mmol, 1.2 eq) in DMF (20 mL) was added potassium carbonate (2.8 g, 20.4 mmol, 3 eq) and the reaction mixture was heated at 85-90° C. for 5 h. DMF was removed under vacuum and the residue was taken in ethyl acetate and filtered. The solid was washed with additional ethyl acetate, and then dried and evaporated to give the crude, which was purified by column chromatography (EtOAc/Hexane) to yield the desired compound in 45% yield. NMR (400 MHz, CDCl3): δ 3.80 (s, 3H), 5.60 (s, 2H), 6.85 (d, 1H), 7.12 (d, 2H), 7.36 (m, 2H), 7.66 (m, 2H), 8.14 (m, 1H), 10.58 (s, 1H); MS: exact mass calculated for C16H14N2O3, 282.10; m/z found, 283 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10][CH3:11])[CH2:3][CH3:4].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][O:1][CH:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[S:10][CH3:11])[CH2:3][CH3:4]
Reactant: CCC(O)c1ccsc1SC
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(OCOCCOC)c1ccsc1SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
To a stirred solution of 3-(1-hydroxypropyl)2-methylthiothiophene (17.7 g, 0.094 mol) in dry methylene chloride (100 ml) was added methoxyethoxymethyl chloride (20.6 g, 0.165 mol) followed by N,N,-diisopropylethylamine (21.3 g, 0.165 mol). The mixture was stirred at room temperature overnight. The mixture was washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo at room temperature to give 24.4 g of amber oil (94% yield). NMR confirmed the structure and mass spectral analysis confirmed the molecular weight at 276.09.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S:26](Cl)(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1>>[Cl:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([S:26]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:28])=[O:27])=[C:21]([CH3:30])[CH:20]=1
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)cc1Cl
Product: Cc1cc(S(=O)(=O)Nc2cccc(COCc3ccc(F)cc3)n2)c(C)cc1Cl

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.058 g) and 4-chloro-2,5-dimethyl-benzenesulfonyl chloride (0.066 g) as a light yellow gum (0.089 g). MS (ESI−): 433.2. ([M−H]−)
Reaction SMILES: C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[O:15]=[C:16]1[NH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)[NH:18][CH:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1>[O:15]=[C:16]1[NH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=2)[N:18]=[C:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(c1ccccc1)N2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DDQ (21.25 g, 93.6 mmol, 2.62 equiv) was added to a stirred solution of methyl 3-oxo-2-phenyl-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (10.07 g, 35.7 mmol, 1.00 equiv) in dioxane (750 mL) and allowed to react, with stirring, overnight at room temperature. The solids were collected by filtration. The filter cake was washed with 2×500 mL of aqueous K2CO3 (saturated). This resulted in 7.29 g (crude) of methyl 3-oxo-2-phenyl-3,4-dihydroquinoxaline-6-carboxylate as an off-white solid. LC-MS (ES, m/z): 281 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][O:5]1)[CH:2]=[CH2:3].[OH2:16].[OH-].[Na+].OO>C1COCC1>[C:10]1([C:4]2([CH2:1][CH2:2][CH2:3][OH:16])[CH2:9][CH2:8][CH2:7][CH2:6][O:5]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O
Reactant: C=CCC1(c2ccccc2)CCCCO1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCCCC1(c2ccccc2)CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-allyl-2-phenyltetrahydro-2H-pyran (700 mg, 3.46 mmol) in THF (7 mL) at 0° C. was added 1M borane tetrahydrofuran complex (1.730 mL, 1.730 mmol) dropwise, and the mixture was stirred overnight at room temperature. After cooling to 0° C., water (0.07 ml) was added to destroy the excess borane. After stirring for 10 mins, 3M NaOH (0.42 mL, 1.260 mmol) was added and stirred for 10 mins. Then 30% H2O2 (0.42 mL, 4.11 mmol) was added and the cooling bath was removed. It was refluxed for 1.5 hrs and cooled to room temperature. It was extracted with EtOAc (2×), and the combined extracts were washed with brine, dried over Na2SO4 and evaporated to give 3-(2-phenyltetrahydro-2H-pyran-2-yl)propan-1-ol as oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.11-7.44 (5 H, m), 3.66-3.81 (2 H, m), 3.48-3.59 (2 H, m), 2.22-2.37 (2 H, m), 1.35-1.89 (8 H, m).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1O.S(=O)(=O)(O)O.B(O)(O)O>CS(C)=O.C1(C)C(C)=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:18]2[CH:17]=[CH:16][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: Oc1ccc2ccccc2c1
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: CS(C)=O
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2ccc3ccccc3c2)CC1

Procedure:
A suspension of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride(1.8 g), β-naphtol(1.44 g), sulfuric acid(0.05 g) and boric acid(0.03 g) in a mixture of dimethylsulfoxide(10 ml) and xylene(50 ml) was heated under reflux conditions for 20 hours. The resulting water was removed by azeotropy with xylene. Following concentration of the reaction mixture, the residue was chromatographed on a column of silica gel with chloroform/methanol as eluent to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: c1ccc(C2CCCCN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCCCC2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
To a solution of 2 g of 1-(tert-butoxycarbonyl)-3-piperidinecarboxylic acid (commercially available) (8.72 mmol) in 15 mL of DMF: DCM (3:1) was added 1.39 g 2-phenylpiperidine (commercially available) (8.72 mmol) and 3.04 mL DIPEA (17.4 mmol). The mixture was stirred at room temperature for 10 minutes. 2.5 g EDCI (13.1 mmol) and 2.04 g HOBT (13.1 mmol) was added. The mixture was stirred for 6 h at room temperature, diluted with brine (50 mL) and extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain the crude product, which was further purified by column chromatography on silica eluting with 30-35% ethyl acetate in hexane to yield 1 g (31%) of the title compound. (MH+) 372.18.
Reaction SMILES: [F: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=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=O)=[O:22])[C:16]=1[CH3:32].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[F:62][C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[C:65]([NH2:70])[CH:64]=1>[Cl-].[Na+].O.CN(C=O)C>[F: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=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:69][C:66]2[CH:67]=[CH:68][C:63]([F:62])=[CH:64][C:65]=2[NH2:70])=[O:31])=[O:22])[C:16]=1[CH3:32]
Reactant: Nc1ccc(F)cc1N
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccc(F)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
6-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (441 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 4-fluoro-o-phenylenediamine (151 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (417 mg, 76% yield) as a red solid. 1H NMR (DMSO-d6)δ1.35 (m, 2H, CH2), 1.53 (m, 2H, CH2), 1.62 (m, 2H, CH2), 2.30 (t, J=8.0 Hz, 2H, CH2CO), 2.33 (s, 3H, pyrrole-CH3), 2.43 (s, 3H, pyrrole-CH3), 3.21 (m, 2H, NCH2), 5.12 (s, 2H, benzene-NH2), 6.28 (m, 1H, Ar—H), 6.47 (dd, J=4.0 and 8.0 Hz, 1H, Ar—H), 6.85 (dd, J=4.0 and 8.0 Hz, 1H, Ar—H), 7.07 (td, J=4.0 and 8.0 Hz, 1H, Ar—H), 7.20 (td, J=4.0 and 8.0 Hz, 1H, Ar—H), 7.64 (t, J=4.0 Hz, CONH), 8.33 (dd, J=4.0 and 8.0 Hz, 1H, Ar—H), 8.63 (s, 1H, vinyl-H), 9.02 (s, 1H, benzene-NH), 10.72 (s, 1H, indolinone-NH), 11.82 (s, 1H, pyrrole-NH). LC-MS (m/z) 550 (M+1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][N:19]([C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1)[CH2:20][CH2:21][NH:22][CH3:23].CCOP(O)N(C(C)C)C(C)C>ClCCl>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:22]([CH3:23])[CH2:21][CH2:20][N:19]([CH3:18])[C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH3:30])[CH:29]=1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CNCCN(C)c1cncc(C)c1
Agent: CCOP(O)N(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cncc(N(C)CCN(C)C(=O)/C=C/C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.5 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml containing one drop of dimethyl formamide), oxalyl chloride was added (16 μl, 0.18 mmol) and the solution was stirred at room temperature for 10 minutes. This solution was added to a solution of N,N′-dimethyl-N-(5-methyl-3-pyridyl)ethane-1,2-diamine dihydrochloride (36 mg, 0.13 mmol) and EDIPA (132 μl, 0.75 mmol) in anhydrous dichloromethane (1.5 ml) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 24 mg of a solid (0.08 mmol, 53%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O[K])(C)(C)C.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])([O-:13])=[O:12]>CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[NH:17][C:16]2[C:15]([CH:4]=1)=[C:14]([N+:11]([O-:13])=[O:12])[CH:20]=[CH:19][CH:18]=2
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CC(C)=O
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetone (1.0 mL) and tert-butoxy potassium (2.7 g) were added to a solution of 3-nitroaniline (1.38 g) in dimethylsulfoxide (20 ml), and the reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, and washed successively with an aqueous ammonium chloride solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 2-methyl-4-nitro-1H-indole.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4]([CH3:31])=[C:5]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH:45]=O)[CH3:44])[CH2:33][CH2:34][CH3:35].C1OC1CC>>[CH2:32]([O:36][C:37](=[O:48])[CH:38]=[C:39]([CH3:47])[CH:40]=[CH:41][CH:42]=[C:43]([CH3:45])[CH:44]=[CH:6][C:5]1[C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:3]([Cl:2])[C:4]=1[CH3:31])[CH2:33][CH2:34][CH3:35]
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Reactant: CCCCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: CCC1CO1
Agent: [Cl-]
Product: CCCCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(C)c(Cl)c1C

Procedure:
16 g of 3-chloro-2,4,6-trimethyl-benzyl-triphenylphosphonium chloride and 10 g of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid butyl ester are heated to boiling with stirring after the addition of 40 g of 1,2-butylene oxide. The 1,2-butylene oxide is slowly distilled off. The reaction mixture is stirred for 30 minutes at 80°-82° C, then cooled and thoroughly extracted with hexane. The hexane extract is shaken out 5 times with 50 ml of methanol/water 70:30 parts by volume each time, then dried over sodium sulphate and evaporated under reduced pressure to produce 9-(3-chloro-2,4,6-trimethyl-phenyl),3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid butyl ester as a residue.