Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:14]([CH3:32])=[C:13]([CH3:33])[N:12]=1>COCCOCCOC>[CH3:33][C:13]1[C:14]([CH3:32])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCOCCCc2nccs2)c1C
Temperature: 110 °C
Yield: 73.1 %

Procedure:
The method described in Example 80, Part E was used with the following exceptions. A solution of phenol (2.11 g, 22.4 mmol) in diglyme (5 mL) was added to the sodium hydride dispersion (0.87 g, 22 mmol) in diglyme (10 mL). A solution of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}amine (4.6 g, 15 mmol) in diglyme (25 mL) was added, and the addition flask was rinsed with additional diglyme (2×5 mL), which was added to the reaction flask. The resulting amber solution was heated at 110° C. for 3.25 hours and then allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with saturated aqueous ammonium chloride (1×50 mL), 1 N potassium hydroxide (2×50 mL), and brine (2×50 mL), and then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The oil was dried for three days under high vacuum at room temperature to provide 4.7 g of (2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}amine as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5](OC)[C:4]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)[CH3:2].[CH3:22][Mg]Br>O1CCCC1.C(OCC)C>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([CH3:22])[C:4]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)[CH3:2]
Reactant: CCc1cc(C(F)(F)F)cc(OC)c1C1=NC(C)(C)CO1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cc(C(F)(F)F)cc(C)c1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 50.4 %

Procedure:
To a 0° C. solution of 100 mg (0.332 mmol) 2-(2-ethyl-6-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (obtained by reaction of 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole with ethylmagnesium bromide) in 0.6 ml tetrahydrofuran, was added drop-wise 0.332 ml (0.996 mmol) of a 3M methylmagnesium bromide solution in diethyl ether maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature and stirred for 3.5 hours and then heated in a 70° C. oil bath for 4 days. The mixture was cooled in an ice bath and quenched dropwise with 3 ml saturated ammonium chloride solution. Ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude orange oil (286 mg) was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate (0 to 10%) to provide 50 mg (yield: 50.4%) of the title compound as a light yellow oil. MS (m/e): 286.2 (M+H+).
Reaction SMILES: CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:12][N:13]([C:15](=[N:43][S:44]([CH3:47])(=[O:46])=[O:45])[C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][C:25]3[C:28]([C:39]([NH2:41])=O)=[N:29][N:30]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:24]=3[C:23]2=[O:42])=[CH:18][CH:17]=1)[CH3:14].N1C=CC=CC=1>C(#N)C>[C:39]([C:28]1[C:25]2[CH2:26][CH2:27][N:22]([C:19]3[CH:20]=[CH:21][C:16]([C:15]([N:13]([CH3:14])[CH3:12])=[N:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:17][CH:18]=3)[C:23](=[O:42])[C:24]=2[N:30]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[N:29]=1)#[N:41]
Reactant: COc1ccc(-n2nc(C(N)=O)c3c2C(=O)N(c2ccc(C(=NS(C)(=O)=O)N(C)C)cc2)CC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccc(-n2nc(C#N)c3c2C(=O)N(c2ccc(C(=NS(C)(=O)=O)N(C)C)cc2)CC3)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
N,N-Dimethylformamide (0.1 mL) was added to acetonitrile (10 mL) and cooled to 0° C. Oxalyl chloride (0.113 mL, 1.29 mmol) was added to the reaction. Once gas evolution stopped, 6-[4-(dimethylamino-methanesulfonylimino-methyl)-phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid amide (0.020 g, 0.039 mmol) was dissolved in acetonitrile (2 mL) and added to the reaction and stirred at 0° C. for 20 min. Pyridine (1 mL) was then added to the reaction, and it was warmed to rt and stirred overnight. The reaction was quenched with 1N hydrogen chloride (50 mL), extracted with ether 3×50 mL), washed with brine (1×50 mL), dried with MgSO4, and concentrated. Purification by reverse phase HPLC and freeze-dried to afford the title compound (0.014 g, 72%): 1H NMR (CHCl3) δ 7.45 (d, j=8.8 Hz, 2H), 7.40 (d, j=1.1 Hz, 4H), 6.95 (d, j=8.7 Hz, 2H), 4.21 (t, j=6.6 Hz, 2H), 3.83 (s, 3H), 3.19 (s, 3H), 3.17 (t, j=6.1 Hz, 2H), 2.94 (s, 3H), 2.81 (s, 3H) ppm; Mass Spec 493.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:26])(=[O:25])[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)[C:11]([CH3:27])=[C:10]([C:28](Cl)=[O:29])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(Cl)Cl>[CH3:35][O:34][N:33]([CH3:32])[C:28]([C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19](=[O:25])(=[O:26])[N:20]=[CH:21][N:22]([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[C:11]=1[CH3:27])=[O:29]
Reactant: Cc1c(C(=O)Cl)cc(-c2ccc(Cl)cc2)n1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a cold (0° C.) mixture of Example 30A (1.9 g, 4.64 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.5 g, 5.11 mmol) in DCM (50 mL) was added TEA (1.62 mL, 11.6 mmol). The mixture was stirred at room temperature for five hours after which the solvents were removed under reduced pressure and the residue purified by chromatography using a mixture of DCM:methanol (95:5) to obtain the titled compound. 1H NMR (CDCl3) δ ppm 2.20 (3H), 2.47 (6H), 2.74 (3H), 3.39 (3H), 6.20 (1H), 7.33-7.42 (4H), 7.50-7.90 (5H); MS (ESI) m/z 489 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][N:11]1C(=O)C2C(=CC=CC=2)C1=O.NN>CO.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH2:10][NH2:11]
Reactant: O=C1c2ccccc2C(=O)N1CC1Cc2ccccc2O1
Agent: NN
Solvent: ClCCl
Solvent: CO
Product: NCC1Cc2ccccc2O1
Reaction time: 20 h

Procedure:
To a solution of 2-(2,3-dihydro-benzofuran-2-ylmethyl)-isoindole-1,3-dione (0.97 g, 3.47 mmol) in MeOH (15 mL) and CH2Cl2 (5 mL) is added hydrazine (0.55 mL, 17.4 mmol). After 20 h at rt, the mixture is filtered off and the filtrate is concentrated. The residue is diluted with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The extracts are dried (MgSO4), filtered, and concentrated to afford C-(2,3-dihydro-benzofuran-2-yl)-methylamine, which is used for a next step without further purification. LCMS: RT=1.25 minutes; MS: 150 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:24]CCCCCC>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:14]([CH3:16])[CH3:15])[C:17]([O:19][CH3:24])=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCCCCCC
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc(OC)cc1)C(C)C
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of N-[4-methoxybenzenesulfonyl]-(D)-valine (8369 g, 29.13 mol) in methanol (30 L) at 5° C. is added thionyl chloride (2176 mL, 29.7 mol) over 2.5 hours. After stirring for 3 hours at 5° C., the reaction is stirred for 36 hours at room temperature. Most of the solvent is evaporated, and the crude product is dissolved in toluene (80 L). The toluene layer is then washed with water (20 L), saturated sodium bicarbonate (20 L), water again (20 L), 2N hydrochloric acid (20 L), brine (20 L), dried (Na2SO4), and the solvent is evaporated. The solid obtained is dissolved in ethyl acetate (8 L) and heptane (16 L) is added to induce crystallization. The precipitated product is collected by filtration to provide methyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-3-methylbutanoate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]2([C:27]#[N:28])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:18]4[CH:23]=[CH:22][C:21]([C:24]5([C:27]#[N:28])[CH2:25][CH2:26]5)=[CH:20][CH:19]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: N#CC1(c2ccc(Cl)cc2)CC1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C#N)CC5)cc4)nc23)cn1

Procedure:
Reaction of 8-(1-methylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine with 1-(4-chlorophenyl)-1-cyclopropanecarbonitrile following general procedure 2 gives the title compound as a solid.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.[CH2:11]([O:18][CH2:19][C:20]1[C:21]([O:30][CH3:31])=[N:22][CH:23]=[CH:24][C:25]=1[C:26](=[O:29])[CH2:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1.[Zn]>[CH2:11]([O:18][CH2:19][C:20]1[C:21]([O:30][CH3:31])=[N:22][CH:23]=[CH:24][C:25]=1[C:26]([OH:29])([CH2:27][CH3:28])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCC(=O)c1ccnc(OC)c1COCc1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(CC(=O)OC(C)(C)C)c1ccnc(OC)c1COCc1ccccc1
Yield: 87.2 %

Procedure:
tert-butyl bromoacetate (13 ml, 80 mmol) is added dropwise to a zinc suspension (5.3 g, 80 mmol activated with 6N HCl over 10 seconds, then washed successively with water until a neutral pH is achieved, with acetone and with diethyl ether) in anhydrous tetrahydrofuran (60 ml) under reflux. The reaction medium is maintained under reflux for another 10 minutes after the addition is terminated. Then, a solution of 1-{3-[(benzyloxy)methyl]-2-methoxy-4-pyridinyl}-1-propanone (5.8 g, 20 mmol) in anhydrous tetrahydrofuran (20 ml) is added and the reaction mixture is agitated under reflux for another hour. The reaction is stopped at 0° C. with saturated aqueous ammonium chloride (100 ml) and the reaction mixture is extracted with diethyl ether. The combined extracts are dried over sodium sulphate and evaporated, which produces a yellow oil which is purified by column chromatography (SiO2, TBMO/HX: 5/95 to 10/90) in order to obtain the tert-butyl ester (J) (7 g, 95%) in the form of a limpid liquid.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:21])[CH2:7][C:6]2[C:8]([CH3:20])=[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.Br[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([Cl:30])[CH:24]=1>>[Cl:30][C:25]1[CH:24]=[C:23]([N:17]2[CH2:16][CH2:15][N:14]([C:9]3[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]4[O:4][C:3]([CH3:21])([CH3:2])[CH2:7][C:6]=4[C:8]=3[CH3:20])[CH2:19][CH2:18]2)[CH:28]=[CH:27][C:26]=1[CH3:29]
Reactant: Cc1ccc(Br)cc1Cl
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Agent: Cl
Product: Cc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1Cl
Yield: 53.4 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine hydrochloric acid salt (311 mg, 1.00 mmol) synthesized in Reference example 147 and 4-bromo-2-chloro-1-methylbenzene (308 mg, 1.50 mmol), the reaction was carried out in the same manner as Example 23 to obtain the title compound 213 mg (yield 58%).
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[F:29][C:30]([F:39])([F:38])[C:31]1[N:36]=[N:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:35]3[N:36]=[C:31]([C:30]([F:38])([F:29])[F:39])[CH:32]=[CH:33][C:34]3=[N:37][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]3)=[CH:7][CH:6]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: Nc1ccc(C(F)(F)F)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(F)(F)F)nn4c3-c3ccccc3)cc2)CCC1
Yield: 34 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (1.85 g, ˜80% purity, 3.45 mmol, 1.0 eq), 6-(trifluoromethyl)pyridazin-3-amine (CAS-Nr. 935777-24-5, 0.674 g, 4.14 mmol, 1.2 eq), N,N-diisopropylethylamine (0.60 mL, 6.89 mmol, 1.0 eq) and activated 3 Å molecular sieves in isopropanol (10.5 mL) was heated for 7 hours under reflux. On cooling, the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 100 g SNAP cartridge: hexane→hexane/ethyl acetate 2/1) to give 680 mg (34% yield) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:31][CH:32]([F:34])[F:33])(=O)=O)=CC=1>CN(C=O)C>[F:33][CH:32]([F:34])[CH2:31][O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCC(F)F
Yield: 84.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (4.6 g, 17.6 mmol), sodium hydride (55% content, 1 g, 22.9 mmol), 2,2-difluoroethyl p-toluenesulfonate (5 g, 21.6 mmol) and DMF (50 mL). The residue was purified by column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.85 g of the title compound as a colorless oily substance (85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:13])[O:8]C(C)(C)C)[C@H:3]1[C:14]([O:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1)[CH3:18])=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[OH:13])[C@H:3]1[C:14]([O:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:20]=1)[CH3:18])=[O:15]
Reactant: CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)OC(C)(C)C)C1(C)C)c1cccc(Oc2ccccc2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C)c1cccc(Oc2ccccc2)n1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
A mixture of 5.649 g of the product of Step A, 0.5 g of p-toluene sulfonic acid and 70 ml of toluene was refluxed until gas evolution ceased and the mixture was cooled to 0° C. and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain 4.741 g of (RS) 1-(6-phenoxy-2-pyridyl)-ethyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C(NC1C=C(OC(=O)C)C=CC=1)=O.[CH3:25][C:26](=[CH2:30])[CH2:27][CH2:28]O.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1C=CC=CC=1.O>[CH3:30][C:26](=[CH2:25])[CH2:27][CH2:28][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CCO
Reactant: CC(=O)Nc1cccc(O)c1
Agent: CC(=O)Oc1cccc(NC=O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=C(C)CCOc1cccc(NC(C)=O)c1
Temperature: 25 °C
Yield: 52 %

Procedure:
A suspension of the mixture of N-(3-hydroxy-phenyl)-acetamide and acetic acid 3-formylamino-phenyl ester (18.12 g, 0.12 mol), 3-methyl-but-3-en-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph3P (31.44 g, 0.12 mol) in benzene (250 mL) was heated at reflux overnight and then cooled to room temperature. The reaction mixture was poured into water and the organic layer was separated. The aqueous phase was extracted with EtOAc (300×3 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (11 g, 52%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14]([CH:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([C:31]([O:33]C)=[O:32])=[CH:30][C:17]1=2)=[O:15])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:31]([C:29]1[CH:28]=[CH:27][C:18]2[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH:16]([C:14]([NH:13][C:5]3[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=3[CH:10]([CH3:11])[CH3:12])=[O:15])[C:17]=2[CH:30]=1)([OH:33])=[O:32]
Reactant: COC(=O)c1ccc2c(c1)C(C(=O)Nc1c(C(C)C)cccc1C(C)C)c1ccccc1CO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1c2ccccc2COc2ccc(C(=O)O)cc21
Temperature: 25 °C
Yield: 92.5 %

Procedure:
After 0.58 g of 6,11-dihydro-N-(2,6-diisopropylphenyl)-2-methoxycarbonyldibenz[b,e]oxepin-11-carboxamide (Compound 24) obtained in Example 24 was dissolved in 24 ml of methanol, 6 ml of 5N sodium hydroxide was added to the solution. The mixture was heated under reflux for 5 minutes. After completion of the reaction, the mixture was cooled to room temperature and 4N hydrochloric acid was added thereto to adjust pH to 3. The mixture was extracted with ethyl acetate. After washing with saturated sodium hydroxide aqueous solution, the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to dryness to obtain 0.52 g of Compound 25.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc(Oc2cccc(CN3CCNCC3)c2)cc1

Procedure:
Synthesized according to General Procedure A: 3-phenoxybenzyl chloride (4{11}, 5 g, 22.9 mmol, 1 equiv.), piperazine (11.8 g, 137.2 mmol, 6 equiv.), THF (6.14 mL). Purification with flash column chromatography on silica gel (gradient, 4:1 to 1:4 EtOAc:MeOH) afforded 5{11} (5.72 g, 93%) as a light yellow oil. 1H-NMR (500 MHz, CDCl3): δ 7.35-7.32 (m, 2H) 7.28 (d, 1H, J=8.5 Hz), 7.12-7.08 (m, 2H), 7.05 (br s, 1H), 7.02 (d, 2H, J=8.0 Hz), 6.90 (dd, 1H, J=2.0, 8.0 Hz), 3.48 (s, 2H), 2.88 (t, 4H, J=5.0 Hz), 2.42 (br s, 4H), 1.66 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 157.2, 156.9, 140.2, 129.5, 129.2, 123.8, 122.9, 119.5, 118.5, 117.3, 63.1, 54.3, 45.9.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:4].[CH:31]([N-]C(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]([CH3:31])([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[CH:14][CH:15]=1)[C:6]([OH:8])=[O:7])=[O:4]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Yield: 112.9 %

Procedure:
To a solution of 2-methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (4.10 g, 10.0 mmol) obtained in Example 1 in tetrahydrofuran (50 ml) was dropwise added lithium diisopropylamide (1.5 M cyclohexane solution, 15.0 ml, 22.5 mmol) at −78° C. under argon atmosphere. The mixture was stirred at said temperature and methyl iodide (2.5 ml, 40 mmol) was dropwise added. The mixture was stirred at said temperature for 2 hr and 10% aqeuous ammonium chloride (20 ml) was added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The obtained organic layers were combined, washed with saturated brine (10 ml), dried over magnesium sulfate and concentrated under reduced pressure to give the crude title compound (4.78 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2)=[O:5])[CH3:2].OS(O)(=O)=O.[N+:25]([O-])([OH:27])=[O:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[CH:12][C:13]=2[N+:25]([O-:27])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn2c3c(ccc([N+](=O)[O-])c3c1=O)CCC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
1-Oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (1.0 g) was placed in round bottom flask and to that, mixture of H2SO4/HNO3 (1:1) was added and stirred for 3 hours at 0° C. The reaction mixture was poured on ice and precipitate was filtered off affording 900 mg of title product (LC/MS: 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=O)=[C:5]2[CH2:4][O:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O1CCCC1>O1CCCC1>[CH3:1][C:2]1([CH3:25])[C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:5]2[CH2:4][O:3]1
Reactant: CC1(C)OCc2c1nc1ccccc1c2NCCCN1CCCC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OCc2c1nc1ccccc1c2NCCCN1CCCC1

Procedure:
A solution of 1,3-dihydro-3,3-dimethyl-9-[[3-(2-oxo-1-pyrrolidinyl)propyl]amino]-furo[3,4-b]quinoline (9.5 g, described in Example 36) in tetrahydrofuran (150 ml) is slowly added to a mixture of lithium aluminum hydride (9.5 g) in tetrahydrofuran (600 ml). The mixture is heated at reflux for 3 hours and cooled. A solution of water-tetrahydrofuran (1:1) is added dropwise and the mixture is filtered. The filtrate is evaporated and a mixture of water-chloroform is added to the residue. The organic phase is separated, dried and evaporated. The residue is subjected to chromatography on a column of alumina (activity II) using acetone-benzene (3:7) as eluant. Evaporation of the eluates and crystallization of the residual oil gives the title compound, mp 70°-75° C. Treatment of the title compound with a solution of hydrogen chloride in ether gives the hydrochloride salt of the title compound, mp 170°-175° C.