Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-])=O)[C:5]([F:8])([F:7])[F:6]>CO.[Ni]>[CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])[C:5]([F:6])([F:7])[F:8]
Reactant: CC(C)C=C(c1ccccc1[N+](=O)[O-])C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: CC(C)CC(c1ccccc1N)C(F)(F)F
Reaction time: 10 h

Procedure:
A solution of 2.98 g (12.9 mmol) 1-(3-methyl-1-trifluoromethyl-but-1-enyl)-2-nitrobenzene in 30 ml methanol is hydrogenated over Raney-Nickel (ethanol) at 100° C. and 150 bar for 10 hours. Then the catalyst is filtered off and the solvent removed in a water-jet vacuum. The obtained crude product is purified by column chromatography over silica gel (eluant:hexane/methylene chloride=1:2). Yield: 1.9 g 2-(3-methyl-1-trifluoromethylbutyl)phenylamine in the form of a brown oil (1H-NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:23])=[CH:15][C:16]([O:21][CH3:22])=[C:17]([CH:20]=1)[CH:18]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:17]3[CH:20]=[C:13]([Cl:12])[C:14]([F:23])=[CH:15][C:16]=3[O:21][CH3:22])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COc1cc(F)c(Cl)cc1C=O
Solvent: CO
Solvent: C1CCNC1
Product: COc1cc(F)c(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (3.4 g, 20.3 mmol) and 5-chloro-4-fluoro-2-methoxy-benzaldehyde (3.2 g, 17 mmol) in methanol (50 mL) was added pyrrolidine (1.2 g, 17 mmol) dropwise. Then the mixture was heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered to give the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH3:14])([CH3:3])[CH2:5][CH2:6]2)=[CH:11][C:10]=1[OH:13]
Reactant: BrBr
Reactant: CC1(C)CCc2ccc(O)cc21
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCc2cc(Br)c(O)cc21
Reaction time: 8 h
Yield: 72 %

Procedure:
128 g of bromine in 100 ml of carbon tetrachloride were added dropwise over the course of 4.5 hours to a solution of 162 g of 3,3-dimethyl-5-hydroxy-indane in 400 ml of carbon tetrachloride at -9° to -2° C. The reaction solution was left to stand overnight at room temperature. It was then washed until neutral, and dried. Fractional distillation gave 139 g of 6-bromo-3,3-dimethyl-5-hydroxy-indane; boiling point: 141.5° C/10 mm Hg. ##STR32##
Reaction SMILES: O[CH:2]1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:5]([CH2:17][C:18]#[CH:19])[C:4]([CH3:21])([CH3:20])[CH2:3]1.C(O)=[O:23]>>[CH3:20][C:4]1([CH3:21])[N:5]2[N:6]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH:2]([CH2:19][C:18](=[O:23])[CH2:17]2)[CH2:3]1
Reactant: C#CCN1N(C(=O)OCc2ccccc2)C(O)CC1(C)C
Reactant: O=CO
Product: CC1(C)CC2CC(=O)CN1N2C(=O)OCc1ccccc1
Yield: 18 %

Procedure:
A stirred solution of 105 (2.5 g, 8.6 mmol) in formic acid (10 mL) was heated at 100° C. for 5 h. After complete consumption of 105 (as monitored by TLC), formic acid was evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with saturated with NaHCO3 solution (2×50 mL), water (50 mL) and brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified through preparative HPLC to afford 106 (0.52 g, 18%). 1H NMR (CDCl3) δ 7.30-7.40 (m, 5H), 5.25 (s, 2H), 3.62 (m, 1H), 2.76 (m, 1H), 2.42 (m, 1H), 2.20 (m, 1H), 2.09 (s, 1H), 1.65 (m, 1H), 1.22 (s, 3H), 1.13 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@H:19]([N:26]([C:34](=[O:36])[CH3:35])[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:18][C@@H:17]2[CH3:37])=[O:15])=[CH:10][CH:9]=1.[C:39](=[N:42]O)([NH2:41])[CH3:40].[H-].[Na+]>C1COCC1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([N:26]([C@H:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]([C:14](=[O:15])[C:11]3[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][CH2:4][C:3]4[O:2][N:42]=[C:39]([CH3:40])[N:41]=4)=[CH:13][CH:12]=3)[C@@H:17]([CH3:37])[CH2:18]2)[C:34](=[O:36])[CH3:35])=[CH:32][CH:31]=1
Reactant: COC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCc3nc(C)no3)cc2)c2ccccc21

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-(2-methyl-1-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-propoxy]-benzoyl}-1,2,3,4-tetrahydro-quinolin-4-yl)-acetamide was prepared from (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid methyl ester. Acetamide oxime (0.043 g, 0.58 mmol) was suspended in THF under N2 and NaH (60% dispersion in oil) (0.025 g, 1.0 mmol) was added followed by 4A° molecular sieves and heated to 60° C. for 1 h. (2S,4R)-4-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid methyl ester was added and heated to reflux for 4.5 h. The reaction was filtered and concentrated down and partitioned between CH2Cl2 and water. The aqueous layer was extracted 3×CH2Cl2 and dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (100% EtOAc) to afford (2S,4R)-N-(4-Chloro-phenyl)-N-(2-methyl-1-{4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-propoxy]-benzoyl}-1,2,3,4-tetrahydro-quinolin-4-yl)-acetamide in 44% yield.
Reaction SMILES: [CH3:1][N:2]1[C@H:14]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=32)[CH2:4][CH2:3]1.[I:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CC(O)=O>[I-:15].[CH2:16]([N+:11]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][C@@H:5]3[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:14]3[C:13]=2[CH:12]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCI
Reactant: CN1CC[C@H]2CCc3ccncc3[C@H]21
Solvent: CC(=O)O
Product: CCCCCCCCCC[n+]1ccc2c(c1)[C@@H]1[C@H](CC2)CCN1C
Product: [I-]
Yield: 66.2 %

Procedure:
To a stirred solution of cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinoline (80 mg, 0.43 mmol) in AcOH (2 ml) was added 1-iododecane (342 mg, 1.28 mmol). The mixture was heated at reflux under nitrogen for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 130 mg (67%) of cis-8-decyl-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-8-ium iodide (ACD) as a brown oil. 1H NMR (300 MHz, CDCl3) δ9.16 (1H, s, C9-H), 9.14 (1H, d, J5.4 Hz, C7-H), 7.82 (1H, d, J6.0 Hz, C6-H), 4.85 (2H, m. pyCH2), 3.43 (1H, d, J8.4 Hz, C9b-H), 2.30 (3H, s, NCH3), 1.50-3.10 (9H, m, CH2+CH), 1.96 (2H, m, pyCH2CH2), 1.00-1.40 (14H, m, 7×CH2), 0.78 (3H, t, J6.9 Hz, CH2CH3); 13C NMR (75 MHz, CDCl3) δ161.5, 143.4, 142.7, 138.9, 127.5, 63.3, 61.2, 55.8, 41.0, 35.7, 32.1, 31.9, 30.1, 29.5, 29.4, 29.3, 29.2, 28.2, 27.3, 26.1, 22.7, 14.2.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH:9]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[N:3]1([CH2:32][CH2:31][CH2:30][CH2:29][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=3)=[CH:16][CH:15]=2)[CH:7]=[N:6][CH:5]=[N:4]1
Reactant: CCCCC(Br)CCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCn3cncn3)cc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
To a suspension of sodium hydride (60% suspension in mineral oil) (0.296 g) in N,N-dimethylformamide (14 ml) was added 1,2,4-triazole (0.511 g) and 4-[4-(4-bromooctyloxy)phenyl]benzoic acid (1 g), and was stirred for 5 hours at 120° C. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to pH 2.5 with conc. hydrochloric acid. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-[8-(1,2,4-Triazol-1-yl)octyloxy]phenyl]benzoic acid (0.81 g).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[NH:9])[CH3:3].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[O:20].C(OCC)(=O)C>C1C=CC=CC=1>[CH3:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[C:12]=1[NH:18][C:19]([N:9]=[C:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH2:2][CH3:3])=[O:20]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CCN1CCCC1=N
Agent: Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCN1CCCC1=NC(=O)Nc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The hydrochloride of 1-ethyl-2-iminopyrrolidine (7.43 g.; 0.05 mole) is converted to free base (5.6 g.; 0.05 mole) in benzene in the usual manner. Then 7.35 g. (0.05 mole) of 2,6-dimethylphenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred at room temperature for 13/4 hours and then the solvent is evaporated to dryness in vacuo to give an oily residue. Trituration with ethyl acetate and cooling produces a solid product, 1-(2,6-dimethylphenyl)-3-(1-ethyl-2-pyrrolidylidene)urea, m.p. = 120°-122° C. Recrystallization from acetone gives the pure product, m.p. - 121°-123° C.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7](C(O)=O)[C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[N-]=[N+]=[N-].[Na+].[CH2:27]([OH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C[N:36]([CH:38]=[O:39])C>C1(C)C=CC=CC=1.O>[CH2:27]([O:34][C:38](=[O:39])[NH:36][C:7]1[C:6](=[O:18])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)C=O
Reactant: OCc1ccccc1
Reactant: CCCCn1c2c(cc(C(=O)O)c1=O)CCCC2
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCn1c2c(cc(NC(=O)OCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
1-Butyl-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (4-002-01) (100 mg, 0.38 mmol) was dissolved in toluene (5 mL), and to the reaction mixture were added thionyl chloride (57 μL, 0.76 mmol) and catalytic amount of DMF, and the reaction mixture was reacted at 75° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in acetone (5 mL), and then to the reaction mixture was added an aqueous solution of sodium azide (29 mg, 0.42 mmol) (0.5 mL), and the reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added water (5 mL), the reaction mixture was extracted with ethyl acetate (10 mL), washed with brine (5 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was dissolved in toluene (5 mL), and the reaction mixture was reacted at 120° C. for 30 min, and then benzyl alcohol (46 μL, 0.44 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 120° C. for 2 h. The reaction mixture was purified by silica gel column chromatography (toluene/ethyl acetate), to give (1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)carbamic acid benzyl ester (6-007) (90 mg, 63%) as a white foamy substance.
Reaction SMILES: Br[C:2]1[C:3]([N:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)=[C:4]([C@H:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:29][O:30][C:31]1[CH:47]=[CH:46][C:34]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]([O:16][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:40]2[CH:39]=[CH:38][C:37]([O:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:47][CH:46]=3)=[CH:42][CH:41]=2)[C:3]=1[N:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccc(COc2ccc(B(O)O)cc2)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(Br)c1N1CCC(C)(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(OCc3ccc(OC)cc3)cc2)c1N1CCC(C)(C)CC1
Reaction time: 2 h
Yield: 64 %

Procedure:
A mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.0454 g, 0.100 mmol), (4-((4-methoxybenzyl)oxy)phenyl)boronic acid (0.039 g, 0.150 mmol) and 2M Na2CO3 (0.125 ml, 0.249 mmol) in DMF 92 mL) was degassed for 10 min. Then, Pd(Ph3P)4 (0.012 g, 9.97 μmol) was added, degassed for 5 min and placed in a oil bath pre-heated to 110 C. After 2 h, cooled and purified by pre-HPLC to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-((4-methoxybenzyl)oxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.0376 g, 0.064 mmol, 64.1% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 7.40-7.44 (m, 2H), 7.15-7.18 (m, 1H), 7.04-7.09 (m, 3H), 6.94-6.98 (m, 2H), 6.05 (br. s., 1H), 5.05-5.11 (m, 2H), 4.27 (qd, J=7.1, 10.8 Hz, 1H), 4.18 (qd, J=7.1, 10.7 Hz, 1H), 3.86 (s, 3H), 3.19 (br. s., 1H), 2.87 (br. s., 1H), 2.63 (br. s., 3H), 2.24 (br. s., 4H), 2.05 (br.s., 1H), 1.26 (t, J=7.1 Hz, 3H), 1.20 (s, 9H), 0.90 (m, 3H), 0.66 (br. s., 3H). 4H of piperidine were not resolved. LCMS (M+H)=589.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16](C)[C:17](C(C)(C)C)=O)[N:9]=[CH:8][N:7]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:6]2=[O:32].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH3:17])[N:9]=[CH:8][N:7]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[C:6]2=[O:32]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)C(=O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNCCOc1cc2ncn(COC(=O)C(C)(C)C)c(=O)c2cc1OC
Yield: 73.4 %

Procedure:
A solution of 6-methoxy-7-(2-(N-methyl-N-(t-butylcarbonyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.39 g, 3 mmol) in methylene chloride (4 ml) and TFA (4 ml) was stirred at ambient temperature for 1 hour. Toluene was added, and the volatiles were removed by evaporation. The residue was triturated with ether and the resulting solid was collected by filtration. The solid was dissolved in water, sodium hydrogen carbonate was added and the aqueous mixture was extracted with methylene chloride. The organic extract was dried (MgSO4) and the solvent removed by evaporation. The residue was triturated with ether and the solid was collected by filtration to give 6-methoxy-7-(2-(methylamino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (800 mg, 73%). 1H NMR Spectrum: (DMSOd6; CF3COOD) 1.13(s, 9H); 2.72(s, 3H); 3.45(br s, 2H); 3.95(br s, 3H); 4.5(t, 2H); 5.94(s, 2H); 7.31(s, 1H); 7.6(s, 1H); 8.47(s, 1H) MS-ESI: 364 [MH]+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[CH:9]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(Oc2cc(Oc3cccc([N+](=O)[O-])c3)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc(Oc2cc(Oc3cccc(N)c3)cc(C(F)(F)F)c2)c1
Temperature: 90 °C
Yield: 87 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 55 g (0.131 mol) of 1,3-bis(3-nitrophenoxy)-5-trifluoromethylbenzene, 150 g of methyl cellosolve and 5 g of 5% Pd/c having a moisture content of 50% were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered off. The filtrate was heated to 90° C., mixed with 140 g of water and cooled to room temperature. The precipitated crystals were filtered and dried under reduced pressure to obtain 1,3-bis(3-aminophenoxy)-5-trifluoromethyl benzene as colorless solid. The product was 41 g (87% yield) and had a melting point of 98.0°~98.6° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=1[F:27].[CH2:28]1[O:31][C@@H:29]1[CH3:30]>C1COCC1>[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[C:16]([CH2:28][C@H:29]([OH:31])[CH3:30])[C:15]=1[F:27]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Reactant: C[C@@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@@H](O)Cc1c(C(=O)NC(C)(C)C)ccc(Br)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (11.7 mL, 82.0 mmol) in THF (200 mL) was treated with n-butyllithium (33 mL, 82 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (9.0 g, 33 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, (R)-(+)-propylene oxide (6.9 mL, 98 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude material was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound. LC-MS: m/z 332.08 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[BrH:11].[CH2:12]([N:15]([CH2:28][CH2:29][CH3:30])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([OH:27])[C:22]=2[NH2:26])[CH2:17]1)[CH2:13][CH3:14]>C(OCC)C>[BrH:11].[CH2:28]([N:15]([CH2:12][CH2:13][CH3:14])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([OH:27])[C:22]=2[NH:26][CH:1]=[O:3])[CH2:17]1)[CH2:29][CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN(CCC)C1CCc2c(ccc(O)c2N)C1
Agent: Br
Solvent: CCOCC
Solvent: O=CO
Product: CCCN(CCC)C1CCc2c(ccc(O)c2NC=O)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.42 ml of acetic anhydride is added all at once to 2 ml of 98% formic acid, kept at 0° C., and the mixture is left at 0° C. for 15 minutes. Then, still using an ice-bath, 1.34 g of 2-dipropylamino-5-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide are introduced therein with a spatula and the whole is stirred for one hour at 0° C. After 50 ml of diethyl ether have been added and the solid has been filtered off, the latter is recrystallised from a 50/50 methanol/ethyl acetate mixture. This gives 1 g of the final product melting at 213° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].O>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
3-Hydroxy-9β-oestra-1,3,5(10)-trien-17-one (370 mg., 1.4 mmole) was treated with acetic anhydride (3 ml.) in pyridine (3 ml.) at steam-bath temperature for 45 min. The cooled solution was poured into water (50 ml.), and extracted with ether (50 ml.). The ether extract was washed with 2N-sulphuric acid (25 ml.), then water (2 × 25 ml.) and the solvent evaporated in vacuo to give the title compound as a chromatographically pure oil (390 mg., 90%), υmax. 1758, 1735 and 1200 cm. -1.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1([F:23])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1.Br[CH:25]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=2)[C:26]1=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[F:23][C:9]1([F:8])[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([CH:25]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([F:37])[CH:31]=3)[C:26]2=[O:38])[CH2:10]1
Reactant: Cc1ccc(N2CCC(Br)C2=O)cc1F
Reactant: COc1ccc(C2CCNCC2(F)F)cc1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCN(C3CCN(c4ccc(C)c(F)c4)C3=O)CC2(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
To a solution of 3,3-difluoro-4-(4-methoxyphenyl)piperidine trifluoroacetate (67 mg, 0.2 mmol) in DMF (0.8 mL) was added 3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (from Example 49, step C, 96 mg, 0.35 mmol) and DIPEA (0.1 mL, 0.6 mmol). The mixture was stirred at rt for 18 h, then raised to 80° C. for 2 h. The mixture was cooled, the solvent was removed under vacuum and the residue was purified via silica gel chromatography, eluting with a gradient from 0 to 100% ethyl acetate in hexanes to yield 62 mg of 3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (along with 20 mg of the sideproduct, 1-(3-fluoro-4-methylphenyl)-3-hydroxypyrrolidin-2-one). LCMS (method U) RT 3.755 min, m/z 419.3 (M+H+); 1H NMR (500 MHz, chloroform-d) δ 7.51 (d, J=11.9, 2H), m 7.26-7.26 (3H), m 7.20 (1H), 6.90 (d, J=8.7) 3.82 (s, 3H), 3.65-3.78 (m, 3H), 3.2-3.45 (m, 3H), 2.87-3.00 (m, 1H), 2.72-2.85 (m, 0.4H), 2.65 (t, 0.5H), 2.37-2.48 (m, 1H), 2.27 (s, 3H), 2.1-2.25 (m, 2H), 1.87-1.95 (m, 1H). Chiral HPLC (method A-2) revealed that the chirality present in the starting material for step A had been lost.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:26]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:27])[N:12]=2)=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=4)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO>CC(O)=O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:26]=[C:15]3[C:16]4[C:21]([CH2:22][CH2:23][N:14]3[C:13](=[O:27])[N:12]=2)=[CH:20][C:19]([O:24][CH3:25])=[CH:18][CH:17]=4)[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc([N+](=O)[O-])c2)nc1=O
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2cccc(N)c2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
To a solution of 2-(3-nitro-phenylamino)-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (5) (525.4 mg, 1.4 mmol) in AcOH (40 mL), Zn powder (ca. 300 mg) was added and stirred at room temperature for 3 hrs, then at 40° C. overnight. After cooling, MeOH was added to the mixture and insoluble materials were removed by filtration. The MeOH solution was purified on BondElut® SCX (Varian Incorporated) then passed through BondElut® NH2 (Variant Incorporated). Result solid was washed with MeOH to give the title compound (215.1 mg, 46%). MS (ESI) (M+H)+ 335.