Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16]C2CCCCO2)[CH2:14][C@@H:13]([O:23]C2CCCCO2)[C@H:12]1[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[S:8].[NH3:42]>>[C:36]([CH2:35][CH2:34][CH2:33]/[CH:32]=[CH:31]\[CH2:30][C@H:12]1[C@@H:13]([OH:23])[CH2:14][C@@H:15]([OH:16])[C@@H:11]1[CH2:10][O:9][C:7](=[S:8])[NH:6][CH2:5][C:4]1[CH:39]=[CH:40][CH:41]=[C:2]([Cl:1])[CH:3]=1)(=[O:37])[NH2:42]
Reactant: N
Reactant: O=C(O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Product: NC(=O)CCC/C=C\C[C@@H]1[C@@H](COC(=S)NCc2cccc(Cl)c2)[C@H](O)C[C@@H]1O

Procedure:
According to the procedures described above in Examples 17 and 18 acid 7 was converted with use of ammonia to 10 mg of the above titled compound.
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH2:12][OH:13])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[C:1]1([C@@H:7]([NH2:14])[CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H](CCO)c1ccccc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H](CCO)c1ccccc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (S)-2-phenyl-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (S)-1-phenyl-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[CH:17]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[CH:19]1([CH2:18][CH:17]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=2)=[O:32])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(O)cn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of N-(5-benzyloxy-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (145.3 mg, 0.3 mmol) in methanol (5.1 mL) was treated with 10% palladium on activated carbon. The reaction mixture was stirred under hydrogen gas at 25° C. for 16 h. The catalyst was then filtered off through a pad of celite (ethyl acetate). The filtrate was concentrated in vacuo to give 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-(5-hydroxy-pyridin-2-yl)-propionamide (92.2 mg, 78.5%) as a tan solid: mp 79-81° C.; EI-HRMS m/e calcd for C19H20Cl2N2O2 (M+) 378.0896, found 378.0890.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[C:7]([N:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[C:12]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH3:35])[C:26]=2[CH3:36])[C:21]2[C:16](=[CH:17][C:18]([N+:22]([O-])=O)=[CH:19][CH:20]=2)[C:14](=[O:15])[O:13]1>Cl>[CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[C:7]([N:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:34][CH3:35])[C:26]=2[CH3:36])[C:21]2[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=2)[C:14](=[O:15])[O:13]1
Reactant: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc([N+](=O)[O-])ccc32)c2ccccc21
Agent: Cl
Product: CCn1c(C)c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N)ccc32)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.5 %

Procedure:
A solution of 25.0 g (0.054 mole) of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-nitrophthalide, prepared as described in part B above, in 285 ml of concentrated hydrochloric acid was heated to 60° C. at which temperature 31.25 g (0.142 mole) of stannous chloride dihydrate was added at such a rate as to maintain the temperature of 60° C. After the addition was complete, the solution was heated to 70° C. and held there for a period of one hour and then allowed to cool to 25° C. The green-colored solid which separated was collected by filtration and was slurried in five percent aqueous sodium hydroxide solution. The resulting suspension was extracted with 500 ml of toluene at room temperature and the toluene extract was filtered, decolorized, and dried over sodium sulfate. On standing, a cream solid separated from the toluene solution. The solid was filtered off and dried to obtain 2.9 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-6-aminophthalide (Formula III: Ro =R1 =R3 =Y1 =H; R2 =NH2 ; R=R5 =CH3 ; R4 =N(CH3)2 ; R6 =CH2CH3) having a melting point of 206°-209° C. Infrared analysis showed a maximum at 1727 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was concordant with the assigned structure. A toluene solution of the above compound developed an intense grape-black color when spotted on a paper coated with phenolic resin.
Reaction SMILES: [CH2:1]([N:5]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([O:32]C)=[O:31])[CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH2:1]([N:5]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:21][CH:22]=3)=[CH:16][C:11]=2[CH:10]=[C:9]([C:30]([OH:32])=[O:31])[CH2:8][CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCCN3CC(C)C)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To a solution of methyl 1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylate (1.20 g) in a mixture of ethanol-THF (10-5 ml) was added an aqueous 1N sodium hydroxide solution (5.2 ml) at room temperature. The mixture was stirred at 60° C. for 16 hours and cooled to 0° C. 1N Hydrochloric acid (6 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropylether to give 1-isobutyl-8-[4-(2-propoxyethoxy)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxylic acid (0.96 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([F:29])([F:28])[F:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15](O)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]([F:27])([F:29])[F:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:15]([NH:30][C:31]3[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])=[CH:33][CH:32]=3)=[O:16])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccncc2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1

Procedure:
626 mg (purity 50%, 0.74 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-4-yl)propanoic acid (racemate) and 1.2 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 155 mg (purity 94%, 33% of theory)
Reaction SMILES: [CH:1]([C:18]1[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[C:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=1[OH:32])([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[C:5]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=1[OH:17])[CH3:2].CN1CCCC1=O.[P:40](Cl)(Cl)[Cl:41]>C1(C)C=CC=CC=1>[Cl:41][P:40]1[O:17][C:4]2[C:5]([C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:6][C:7]([C:9]([CH3:12])([CH3:10])[CH3:11])=[CH:8][C:3]=2[CH:1]([CH3:2])[C:18]2[CH:23]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:21]=[C:20]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]=2[O:32]1
Reactant: ClP(Cl)Cl
Reactant: CC(c1cc(C(C)(C)C)cc(C(C)(C)C)c1O)c1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC1c2cc(C(C)(C)C)cc(C(C)(C)C)c2OP(Cl)Oc2c1cc(C(C)(C)C)cc2C(C)(C)C
Temperature: 25 °C
Yield: 34.8 %

Procedure:
To a solution of 50.9 g. (0.12 mol) of 2,2'-ethylidenebis(4,6-di-tert-butylphenol) and 1.73 mL (0.018 mol) of 1-methyl-2-pyrrolidinone in 275 mL of toluene at ambient temperature is added dropwise 15.7 mL (0.18 mol) of phosphorus trichloride. After the addition is complete, the reaction mixture is heated at reflux for 18 hours. After cooling to room temperature, the toluene is removed in vacuo and the residue is then recrystallized twice from 250 mL of acetonitrile. The acetonitrile is decanted from the product which is dried under vacuum to give 21.0 g (34.8% yield) of the title compound as an off-white solid melting at 194°-198° C.
Reaction SMILES: [F:1][C:2]1[CH:53]=[CH:52][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:40]=[CH:39][C:38]([CH2:41][N:42]4[CH2:47][CH2:46][CH:45]([C:48]([OH:51])([CH3:50])[CH3:49])[CH2:44][CH2:43]4)=[CH:37][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([N:22]3[CH:27]4[CH2:28][CH2:29][CH:23]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26]4)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[ClH:54].O1CCOCC1>C(Cl)Cl>[ClH:54].[ClH:54].[CH:23]12[N:22]([C:20]([C@@H:17]3[CH2:18][CH2:19][C@H:14]([N:13]4[C:12]5[CH:37]=[C:38]([CH2:41][N:42]6[CH2:43][CH2:44][CH:45]([C:48]([OH:51])([CH3:50])[CH3:49])[CH2:46][CH2:47]6)[CH:39]=[CH:40][C:11]=5[NH:10]/[C:9]/4=[N:8]\[C:6](=[O:7])[C:5]4[CH:52]=[CH:53][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:15][CH2:16]3)=[O:21])[CH:27]([CH2:28][CH2:29]1)[CH2:26][NH:25][CH2:24]2
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2C(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(C(C)(C)O)CC4)cc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)N5C6CCC5CNC6)CC4)c3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 8-(cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (70 mg, 0.096 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (0.120 mL, 0.479 mmol). The suspension was stirred overnight at RT. After 16 hours, the reaction was concentrated to provide (E)-N-(1-(cis-4-(3,8-diazabicyclo[3.2.1]octane-8-carbonyl)cyclohexyl)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide dihydrochloride as a white powder (68 mg, 101% yield). MS, m/z (C36H47FN6O3.2HCl): calcd, 630.4. found, 631.2 [M+H].
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:6]1([N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:18])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5].[CH3:26]I>CN(C)C=O>[CH2:19]([N:17]([CH3:18])[C:6]1([C:4]([NH:3][CH3:26])=[O:5])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:7]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1ccccc1)C1(C(N)=O)CN(C(=O)OC(C)(C)C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C1(N(C)Cc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (351 mg, 8.78 mmol) was added to a solution of tert-butyl 3-(aminocarbonyl)-3-[benzyl(methyl)amino]azetidine-1-carboxylate (described in Example 74) (1.4 g, 4.39 mmol) in dimethylformamide (14 ml) at 0° C.). After 1 hour at room temperature the reaction mixture was cooled to 0° C. and methyl iodide (0.44 ml, 7.02 mmol) added dropwise. The reaction mixture was allowed to stir at room temperature overnight, evaporated and the residues purified by preparative HPLC (standard basic conditions) to give tert-butyl 3-[benzyl(methyl)amino]-3-[(methylamino)carbonyl]azetidine-1-carboxylate as a solid, (460 mg, 31%). 1H NMR Spectrum: (CDCl3) 1.45 (s, 9H), 2.23 (s, 3H), 2.87 (d, 3H), 3.56 (s, 2H), 4.05 (d, 2H), 4.20 (brs, 2H), 6.80 (brs, 1H), 7.28 (m, 3H), 7.35 (m, 2H); Mass Spectrum: (M+H)+ 334.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:14]=3[O:13][C:12]=2[C:24]=1[CH2:25][O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32].[CH:33](N1CCCCC1)=[O:34].Cl>O1CCCC1.C(OCC)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:15]2[N:16]([CH3:17])[C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[C:24]([CH2:25][O:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[C:12]=3[O:13][C:14]=2[C:21]=1[CH2:33][OH:34]
Reactant: O=CN1CCCCC1
Reactant: COCCOCOCc1c(OC)ccc2c1Oc1cc(OC)ccc1N2C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOCOCc1c(OC)ccc2c1Oc1c(ccc(OC)c1CO)N2C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 88.1 %

Procedure:
8.9 ml of n-butyllithium solution were added under argon at -78° to a solution of 4.10 g (10.92 mmol) of 3,7-dimethoxy-4-[[(2-methoxyethoxy)methoxy]methyl]-10-methyl-10H-dibenzo-[b,e][1,4]oxazine in 10 ml of tetrahydrofuran and 40 ml of diethyl ether. The reaction mixture was brought slowly to 0° and stirred for 1.5 hours, whereupon the suspension was treated with 1.82 ml (1.5 eq.) of N-formylpiperidine, stirred at 0° for 30 minutes and poured into 100 g of ice, 100 ml of 0.1N hydrochloric acid solution and 150 ml of diethyl ether. The aqueous phase was extracted three times with chloroform and the combined organic phases were dried over MgSO4 and evaporated. The reddish residue was dissolved in 50 ml of tetrahydrofuran and treated at 0° under argon with 5 ml of lithium borohydride solution (2M in tetrahydrofuran). The reaction mixture was stirred at 0° for 30 minutes and then poured into 50 g of ice, 50 ml of saturated ammonium chloride solution and diethyl ether. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried over MgSO4 and evaporated. The residue was chromatographed on 200 g of silica gel with ethyl acetate/hexane (2:1), whereupon, after drying in a high vacuum, 3.90 g (88.1%) of 3,7-dimethoxy-6-[[(2-methoxyethoxy)-methoxy]methyl]-10-methyl-10H-dibenzo[b,e][1,4]oxazine-4-methanol were obtained as a colourless solid of m.p. 68°-70°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]([OH:21])=[O:20])=[CH:8][CH:9]=1
Reactant: O=C(O)c1cc2ccccc2n1-c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Product: Nc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
A large excess of Raney® nickel was added in portions to a stirred solution of 1-(4-nitrophenyl)-1H-indole-2-carboxylic acid (1.40 g, 5.0 mmol), hydrazine (1.0 mL, 32 mmol) in 20 mL of ethanol. After stirring at room temperature for 2 h the catalyst was then removed by filtering through a short pad of Celite®521. The filtrate was concentrated to give 1-(4-aminophenyl)-1H-indole-2-carboxylic acid (1.0 g, 80%) as a beige solid: MS (ESI) m/z 253 (MH+); MS (ESI) m/z 251 ([M−H]−).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:33][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.8 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-methoxyphenol (6.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.2 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (4.6 mg, 37.9% yield) as a thick oil. 1H NMR (400 MHz, CDCl3) δ 7.38–7.14 (m, 8H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.72–6.46 (m, 4H), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.64 (s, 3H), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (m, 2H), 2.37–1.72 (m, 8H), 1.25 (d, 6H, J=7.4 Hz); ESMS m/e: 487.4 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1([CH3:34])[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:14]([CH2:23][CH2:24][C:25]([N:27]2[C@H:31]([CH3:32])[CH2:30][O:29][C:28]2=[O:33])=[O:26])[CH2:13][O:12]1.[C:35]([O:39][C:40](=[O:43])[CH:41]=[CH2:42])([CH3:38])([CH3:37])[CH3:36]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:35]([O:39][C:40](=[O:43])[CH2:41][CH2:42][C@@H:24]([C:25]([N:27]1[C@H:31]([CH3:32])[CH2:30][O:29][C:28]1=[O:33])=[O:26])[CH2:23][C@H:14]1[CH2:13][O:12][C:11]([CH3:10])([CH3:34])[N:15]1[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])([CH3:38])([CH3:37])[CH3:36]
Reactant: C[C@@H]1COC(=O)N1C(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COC(=O)N1C(=O)[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
At 0° C., 1.0M TiCl4 in CH2Cl2 solution (8.55 mL, 0.7 eq) was added to CH2Cl2 (100 mL) followed by the addition of 1.0M TiCl(Oi-Pr)3 in hexanes solution (4.28 mL, 0.35 eq) and stirred 5 min DIPEA (2.87 mL, 1.35 eq) was added and stirred 15 min. A solution of (S)-tert-butyl 2,2-dimethyl-4-(3-((R)-4-methyl-2-oxooxazolidin-3-yl)-3-oxopropyl)oxazolidine-3-carboxylate (5.28 g, 12.22 mmol) in CH2Cl2 (50 mL) was added. The reaction mixture was stirred 1 hr at 0° C. To the solution, t-butylacrylate (2.22 mL, 1.25 eq) was added and the mixture was left stirred over 48 hr with concomitant warming to rt. The mixture was concentrated, partitioned between EtOAc (300 mL) and 1% HCl solution (100 mL). The organic layer was washed with sat. NaHCO3 solution (60 mL), brine (60 mL), dried over Na2SO4. After filtration and concentration, the residue was purified by ISCO (120 g column, 0˜35% EtOAc in Hexanes gradient) to afford 4.12 g (60%) (S)-tert-butyl 4-((R)-5-tert-butoxy-2-((R)-4-methyl-2-oxooxazolidine-3-carbonyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate as a yellowish solid. MS ESI+ve m/z 583 (M+Na).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=[O:3].[OH-].[Na+].[Cl:14][O-].[Na+].Cl>O>[Cl:14][C:8]1[C:9]([OH:10])=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][C:7]=1[OH:11]
Reactant: [O-]Cl
Reactant: CC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(O)c(Cl)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 65 %

Procedure:
A solution of 2,4,-dihydroxyacetophenone (6 g, 39.4 mmol), aqueous 1M sodium hydroxide (41.4 mL, 41.4 mmol) and water (200 mL) is stirred at room temperature. An aqueous 1.6M solution of sodium hypochlorite (32 mL) is added over a 1 hr period. The resulting dark brown solution is stirred 18 hr at room temperature. The reaction mixture is adjusted to a pH of 2-3 with concentrated aqueous hydrochloric acid. The resulting suspension is filtered and washed with water (4×100 mL). The filtered solid was dried under vacuum at 45° C. for 2.5 days to give the title compound (4.8 g, 65%) as a brown solid. LCMS 1 187 m+.
Reaction SMILES: C(OC([N:6]1[C:14]2[C:9](=[C:10]([Br:15])[CH:11]=[CH:12][CH:13]=2)[C:8]([O:16][CH3:17])=[N:7]1)=O)C.O.[Li+].[OH-]>C1COCC1>[Br:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[C:8]([O:16][CH3:17])=[N:7][NH:6]2
Reactant: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1n[nH]c2cccc(Br)c12
Reaction time: 15 h

Procedure:
To a stirring solution of 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV (1.27 g, 4.14 mmol) in THF (28 ml) and H2O (9 ml) was added LiOH (397 mg, 16.6 mmol). The reaction mixture was stirred at reflux for 2 hours then at room temperature for 15 hours. The mixture was concentrated. The residue was diluted with EtOAc (50 ml), washed with HCl (1M) and brine, dried over MgSO4, filtered and concentrated affording 4-Bromo-3-methoxy-1H-indazole CLXXXVI as an off-white solid (98% yield), which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][O:14][CH3:15])[C:8](=O)[CH2:7][CH2:6]2.CC1C=CC(N=[CH:25][C:26]2[C:27]([NH2:35])=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=2)=CC=1>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][C:9]2[CH2:8][C:7]3[C:6]([C:5]=2[CH:4]=1)=[N:35][C:27]1[CH:28]=[C:29]2[O:33][CH2:32][O:31][C:30]2=[CH:34][C:26]=1[CH:25]=3
Reactant: COCOc1cc2c(cc1OC)CCC2=O
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Product: COCOc1cc2c(cc1OC)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 25.3 %

Procedure:
Using the procedure of Example 1, 5-methoxy-6-methoxymethoxyindan-1-one (1000 mg, 4.5 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (1144 mg, 4.5 mmol) to yields 7-Methoxy-8-methoxymethoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (400 mg, 25% of theory).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([OH:13])[CH2:11][Cl:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Si:1]([O:8][CH2:9][CH:10]([O:13][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:14]1)[CH2:11][Cl:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1=COCCC1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](O)CCl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC(CCl)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
(R)-(−)-1-(tert-Butyldimethylsilanyloxy)-3-chloropropan-2-ol (11.19 g) prepared in reference example 31 was dissolved in dichloromethane (20 ml), then 3,4-dihydro-2H-pyran (5.87 ml) and pyridinium p-toluenesulfonate (catalytic amount) were added, then the reaction mixture was stirred at a room temperature overnight. The reaction mixture was concentrated under a reduced pressure, the residue was purified by use of a silica gel column chromatography (eluent: n-hexane/ethyl acetate=20/1), there was obtained 1-(t-butyldimethylsilanyloxy)-3-chloro-2-(tetrahydropyran-2-yloxy)propane (14.14 g, yield: 92.0%) as colorless liquid product.