Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]([S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:31][C:27]1[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1cccc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(C)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 83.1 %

Procedure:
To a solution of 1.00 g (2.985 mmol) of the product of Example 3 in 7.5 mL of DMF was added 0.514 g (3.134 mmol) of 3-picolyl chloride hydrochloride and 1.30 g (9.50 mmol) of potassium carbonate. The rection was stirred for 18 h at room temre and then an additional 0.051 g of 3-picolyl chloride hydrochloride and 0.130 g of potassium carbonate was added and the reaction was steeed for 18 h at room temperature. The reaction was then diluted with water and extracted with ether. The combined organic layers were extrated with 6N HCl solution and the aqueous acid layer was then basified with 6N NaOH solution and then extracted with ether. The resulting ether layer was dried over sodium sulfate, filtered and concentrated in vacuo. Trituration of the residue with ether provided 1.058 g (83%) of the desired product as a white solid. Electrospray Mass Spec: 427.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>CS(C)=O.O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10](=[CH:13][O:14][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@H](CCSC)NC(=O)C1=C(c2ccccc2)CC(=COCc2cccnc2)C=C1

Procedure:
The resultant compound from Example 16D (1.0 equivalent) is treated with sodium hydride (2.0 equivalents) in DMSO, then 3-chloromethylpyridine hydrochloride (1.0 equivalent) is added. When judged complete by TLC analysis, the reaction is diluted with water and ethyl acetate, the organic layer is dried and concentrated, and the crude title compound is purified by chromatography on silica gel.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH:13]1[O:15][CH2:14]1)[CH2:7][CH2:6][CH2:5]2.[CH2:19]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([OH:15])[CH2:14][N:26]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1c(OCC2CO2)cc2c(c1[N+](=O)[O-])CCC2
Reactant: c1ccc(CNCCOc2ccccc2OCc2ccccc2)cc1
Product: Nc1c(OCC(O)CN(CCOc2ccccc2OCc2ccccc2)Cc2ccccc2)cc2c(c1[N+](=O)[O-])CCC2

Procedure:
The condensation of 5-amino-6-(2,3-epoxypropoxy)-4-nitroindane and N-benzyl-2-(2-benzyloxyphenoxy)-ethylamine gives 5-amino-6-{3-[N-benzyl-2-(2-benzyloxyphenoxy)-ethylamino]-2-hydroxypropoxy}-4-nitroindane in the form of an oil. This compound, in the form of its hydrochloride, is hydrogenated and hydrogenolytically debenzylated in methanolic solution in the presence of 10% palladium-charcoal to give 4,5-diamino-6-{2-hydroxy-3-[2-(2-hydroxyphenoxy)-ethylamino]-propoxy}-indane hydrochloride; m.p. 193°-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:15](=O)[CH2:16]Br>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:15]2[N:1]=[C:2]3[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]3[CH:16]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccnc(N)c1
Reactant: COc1ccc(C(=O)CBr)cc1OC
Product: COc1ccn2cc(-c3ccc(OC)c(OC)c3)nc2c1

Procedure:
The title compound, pale yellow solid, m.p. 142° C. and MS: m/e=284.1 (M+), was prepared in accordance with the general method of example 1 from 2-amino-4-methoxy-pyridine and 3,4-dimethoxy-phenacylbromide.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]([NH:28][CH3:29])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][CH:19]([N:28]([CH3:29])[C:8](=[O:10])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:1])([CH3:12])[O:6]2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:30][CH:31]=1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Reactant: CNC(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C(=O)C=C1OC(C)(C)OC1=O)C(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A mixture of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid (0.936 g, 5.43 mmol) in dry acetonitrile (10 ml) was treated successively with [1-(4-chlorobenzyl)-2-(4-chlorophenyl)-ethyl]-methylamine (1.60 g, 5.43 mmol), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP®) (3.11 g, 5.98 mmol) and triethylamine (0.83 ml, 5.98 mmol). After 3 h at 22° C., the clear solution was diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 7:3) gave 2.35 g (97% yield) of the title amide as white needles; mp 109° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): mixture of rotamers; 1.62 and 1.69 (6H, 2 s, CH3), 2.75 and 2.97 (3H, 2 s, NCH3), 2.8-2.9 (4H, m, CH2), 4.15 (1H, m, CH), 5.44 and 5.89 (1H, 2 s, CH), 7.05-7.3 (8H, m, aromatics). Anal. calcd for C23H23C12NO4: C, 61.62; H, 5.17; N, 3.12. Found: C, 61.39; H, 5.25; N, 3.22.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].FC1C=C(NC2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1>>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1F
Agent: CC(C)(C)OC(=O)N1CCC(Nc2cccc(F)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2F)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 2-fluoroaniline using a method similar to that described for D3 in Description 3.
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].C(O)(=O)C.[CH3:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]>>[CH3:12][O:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1]
Reactant: C=CCCCCCCCCOCOC
Reactant: CO[SiH](OC)OC
Solvent: CC(=O)O
Product: COCOCCCCCCCCCC[Si](OC)(OC)OC

Procedure:
Under a nitrogen atmosphere at 80° C., a mixture of 64 g of trimethoxysilane and 0.57 g of acetic acid was dropped in a mixture of 100 g of 10-(methoxymethoxy)-1-decene and a catalytic amount of a solution of tetrahydrofuran chloroplatinate. The resultant mixture was stirred for 3 hours at 80° C., and then the reaction mixture was distilled under reduced pressure, to obtain 131 g of an intended substance.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[N:9]=[CH:8]2.[F:38][C:39]([F:44])([CH3:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:38][C:39]([F:44])([CH3:43])[C:40]([NH:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:36]=[CH:35][C:30]2[O:31][CH2:32][CH2:33][O:34][C:29]=2[CH:28]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:18])[N:9]=[CH:8]2)=[O:41]
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)N)ccc32)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCCO5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl 3-(5-((1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate (I4b) (0.5 g, 1.00 mmol), 2,2-difluoropropanoic acid (0.16 g, 1.45 mmol) and HBTU (0.567 g, 1.50 mmol) in DCM (4 mL) was treated with DIEA (0.696 mL, 3.99 mmol), the mixture was stirred at ambient temperature for 1 hour. The reaction was quenched by addition 10% NaHSO4 (aq), brine was added to help phase separation. The lower red DCM phase was separated, the waterphase was extracted with one portion of EtOAc, the combined organic solutions were dried over MgSO4 and filtered, solvents was removed by evaporation. Obtained a crude product as red oil. The crude material was further purified by flashchromatography using an 70 g prepacked silica column, an gradient of 0% to 50% EtOAc in Heptane was applied. Fractions with product was combined and solvents was removed by evaporation. An slightly yellow sticky oil was obtained after final evaporation from DCM. Yield 540 mg (91%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH:12]([CH2:14][N:15](CC2C=CC=CC=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:13])=[CH:4][C:3]=1[Cl:38].CCCCCC>C(O)C.Cl.C(O)C.[Pd]=O>[NH2:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]([CH:12]([CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[OH:13])=[CH:4][C:3]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C(O)CN(CCCCCCOCCc2ccccn2)Cc2ccccc2)cc1C(F)(F)F
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: Nc1c(Cl)cc(C(O)CNCCCCCCOCCc2ccccn2)cc1C(F)(F)F
Yield: 69.4 %

Procedure:
A solution of 4-amino-3-chloro-α-[[(phenylmethyl)[6-(2-pyridinylethoxy)hexyl]amino]methyl]-5-(trifluoromethyl)benzenemethanol (1.50 g) in absolute ethanol (10 ml) and conc. hydrochloric acid/ethanol (1:9 v/v, 2.48 ml) was hydrogenated over pre-reduced 10% palladium oxide on charcoal (50% aqueous, 300 mg) in absolute ethanol (10 ml). The mixture was filtered through hyflo and evaporated in vacuo to give an oil. Purification by FCC eluting with toluene-ethanol- triethylamine (95:5:1) gave a pink oil. Trituration with hexane afforded the title compound as a pale orange solid (0.87 g), m.p. 51.5°-53°.
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][Si](C(C)(C)C)(C)C)=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[CH3:1][C:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC1(CN2CCN(C(=O)OCc3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(CN2CCN(C(=O)OCc3ccc(O)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 0.33 h
Yield: 30.3 %

Procedure:
To a mixture of 4-(tert-butyldimethylsilanyloxy)benzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (400 mg, 0.75 mmol) and THF(10 ml), a 1M solution of tetrabutylammonium fluoride in THF (0.8 ml, 0.8 mmol) was added followed by stirring for 20 minutes with cooling on ice-bath. To the reaction mixture, ethyl acetate was added, and the solution was washed with a saturated ammonium chloride solution, water and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added, and the precipitates were filtered off to afford 4-hydroxybenzyl 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (95 mg, yield 30%) as a light yellow powder.
Reaction SMILES: [NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([N:17]1[CH2:61][CH2:60][CH2:59][C@H:18]1[C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([NH:47][CH2:48][C:49]([O:51]CC1C=CC=CC=1)=[O:50])=[O:46])[CH:42]([CH3:44])[CH3:43])=[O:39])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])=[O:20])=[O:16])[CH:12]([CH3:14])[CH3:13])=[O:9])=[O:5])[CH3:3].N(C(OC(C)(C)C)=O)[C@H](C(NCC(O)=O)=O)C>>[NH:1]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([NH:10][C@H:11]([C:15]([N:17]1[CH2:61][CH2:60][CH2:59][C@H:18]1[C:19]([NH:21][CH2:22][C:23]([NH:25][C@H:26]([C:34]([NH:36][CH2:37][C:38]([NH:40][C@H:41]([C:45]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:46])[CH:42]([CH3:43])[CH3:44])=[O:39])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])=[O:20])=[O:16])[CH:12]([CH3:13])[CH3:14])=[O:9])=[O:5])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)C(=O)NCC(=O)O

Procedure:
The nonapeptide benzylester (IX) was hydrogenated as described under VIII to obtain the acid in quantitative yield. Rf3 0.24. Anal. calcd. for C40H61N9O12 ·H2O: C 55.09, H 7.16, N 14.3%. Found: C 54.69, H 7.16, N 13.81%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH:11]([CH3:23])[C:12](=[O:22])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=O)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][C:12](=[O:22])[C:11]=2[CH3:23])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOc1cccc(C(=O)C(C)C(=O)CC(=O)c2ccccc2)c1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: CCOc1cccc(-c2c(C)c(=O)cc(-c3ccccc3)n2-c2ccccc2)c1

Procedure:
In 500 ml of xylene were dissolved 15.0 g (0.046 mole) of 1-(3-ethoxyphenyl)-2-methyl-5-phenyl-1,3,5-pentanetrione, 43.0 g (0.47 mole) of aniline and 8.8 g (0.092 mole) of methanesulfonic acid. The reaction mixture was heated under reflux for 30 minutes in a reactor fitted with a Dean-Stark apparatus. After cooling, the reaction mixture was filtered to remove solid matter, followed by removal of the solvent by distillation. The residue was extracted with chloroform and the resultant solution in chloroform (the extract) was washed first with 100 ml of 10% hydrochloric acid and then with 100 ml of a 10% aqueous solution of sodium hydroxide. The chloroform solution was washed further with water and was then dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to chromatography on a silica gel column (eluent: ethyl acetate). Upon recrystallization of the resultant crystals from acetone, 5.3 g of 2-(3-ethoxyphenyl)-3-methyl-1,6-diphenyl-4-(1H)-pyridinone having a melting point of 146°-149° C. was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl[CH2:14][CH:15]=O>C1(C)C=CC=CC=1>[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:14]=[CH:15][N:12]=2)[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: O=CCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2nccn2c1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 2-amino-5-pyridine carboxylic acid ethyl ester (4.5 g, 27.1 mmol), chloroacetaldehyde (5.7 ml, 40.6 mmol, 45% w/w in water) and toluene (125 ml) was heated to reflux and water was collected in a Dean Stark trap. After 3 hours at reflux the reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with ether. The solid was dissolved in water and the solution was neutralized by the addition of concentrated aqueous ammonium hydroxide. The aqueous layer was extracted with chloroform, the organic layer was washed with brine and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, treated with charcoal and passed through a plug of silica. Removal of the solvent in vacuo afforded 3.1 g (60%) of 6-carboethoxy imidazo[1,2-a]-pyridine as an off-white solid, m.p. 93°-94° C. when recrystallized from tert-butylmethyl ether and dried for 16 hours at 50° C. in high vacuum.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: BrCC1CC1
Reactant: Cc1ccc(O)c(Br)c1
Product: Cc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-methyl-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:10])=[O:9].[H-].[Na+].IC.[CH2:35](Cl)Cl>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH3:35])[C:12]1[C:13]([C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:9])=[O:10]
Reactant: O=C(c1nn(-c2ccccc2)cc1NS(=O)(=O)c1ccccc1Br)N1CCOCC1
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: CN(c1cn(-c2ccccc2)nc1C(=O)N1CCOCC1)S(=O)(=O)c1ccccc1Br
Reaction time: 12 h
Yield: 97 %

Procedure:
To a solution of 2-bromo-N-[3-(morpholin-4-ylcarbonyl)-1-phenyl-1H-pyrazol-4-yl]benzenesulfonamide (30 mg; 0.06 mmol; 1.00 eq.) in THF (6 mL) is added sodium hydride (3 mg; 0.07 mmol; 1.20 eq.) and the reaction is stirred for 10 min before the addition of iodomethane (4 μL; 0.07 mmol; 1.10 eq.). After 12 h, DCM is added to the reaction mixture, ished with water (×2) and dried the organic phase over MgSO4 give 30 mg (97%) of the title compound as a white solid. 1H NMR (DMSO) δ 8.64 (s, 1H), 7.93-7.86 (m, 2H), 7.80-7.73 (m, 2H), 7.62-7.47 (m, 4H), 7.41-7.32 (m, 1H), 3.65-3.51 (m, 6H), 3.48-3.42 (m, 2H), 3.35 (s, 3H). HPLC (max plot) 89.7%; Rt 3.98 min. MS (ESI+): 507.2.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.Br[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[OH:21].[C:22]([O:30][CH:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([OH:39])[C:33]([CH3:41])([CH3:40])[CH2:32]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCCC>ClC1C=CC=CC=1>[C:22]([O-:30])(=[O:29])[CH3:23].[C:22]([O:30][CH:31]1[CH2:32][C:33]([CH3:40])([CH3:41])[N:34]([O:39][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[OH:21])[C:35]([CH3:38])([CH3:37])[CH2:36]1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: OC1CCCCC1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Clc1ccccc1
Solvent: CCCCCCC
Product: CC(=O)[O-]
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1O

Procedure:
Tributyltin hydride is added dropwise to a solution of 2-bromocyclohexanol and excess 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine in chlorobenzene. The mixture is heated to facilitate reaction. The crude reaction mixture is passed through silica gel with heptane and then heptanelethyl acetate to afford the title compound as a mixture os cis/trans isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][NH2:8].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)(Cl)Cl>[C:19]([NH:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: COc1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cccc(CCNC(C)=O)c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3-methoxyphenethylamine (56.6 g, 0.37 m) and triethylamine (38.0 g, 0.38 m) in CHCl3 (900 ml) was added acetyl chloride (33.0 g, 0.42 m) dropwise over a period of 30 minutes at 20°-25° C., and then the reaction was stirred overnight. The mixture was extracted with 500 ml ice water, then extracted further with 2×500 ml cold water. The chloroform layer was dried over MgSO4 and concentrated to N-acetyl-3-methoxyphenethylamine as an oil (90 g).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=1)[CH2:4][CH:5]([OH:7])[CH3:6].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]([CH:3]([N:2]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:4][CH:5]([OH:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH3:18]
Reactant: CCOc1cc(C(N)CC(C)O)ccc1OC
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 64.8 %

Procedure:
A mixture of 4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol hydrochloride (0.5 g, 1.81 mmol), 3-acetamidophthalic anhydride (0.37 g, 1.81 mmol) and triethylamine (0.18 g, 1.81 mmol) in dimethylformamide (10 mL) was heated at 80-90° C. for 7 hours. The mixture was concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate, washed with water, brine, dried, filtered and concentrated to an oil. This oil was purified by chromatography (silica gel, methylene chloride/ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (0.5 g, 65%); mp 132-134° C.; 1H NMR (CDCl3) δ 9.54 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.4 Hz, 1H), 7.46 d, J=7.3 Hz, 1H), 7.12-7.08 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 5.46 (t, J=7.8 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.80 (m, 1H), 2.59-2.42 (m, 2H), 2.25 (s, 3H), 1.65 (s, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3) δ 170.36, 169.20, 167.96, 149.04, 148.26, 137.29, 135.70, 131.50, 131.35, 124.60, 120.61, 117.85, 113.10, 111.25, 66.00, 64.39, 55.89, 52.43, 40.19, 24.92, 24.33, 14.73; Anal. Calcd. For C23H26N2O6: C, 64.78; H, 6.15; N, 6.57. Found: C, 64.86; H, 6.10; N, 6.46.