Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-:1][C:2]#N.[K+].[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23]2[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=2[NH2:30])[CH2:18][CH2:17]1.Cl>O>[O:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH:6]1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=3[NH:30][C:2]2=[O:1])[CH2:18][CH2:17]1
Reactant: Nc1ccc(Cl)cc1NC1CCN(CC2COc3ccccc3O2)CC1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2n1C1CCN(CC2COc3ccccc3O2)CC1

Procedure:
A solution of 4.8 g of potassium cyanate in 10 ml of water was added to 14.5 g of 1-[(benzo-1,4-dioxan-2-yl)-methyl]-4-(5-chloro-2-aminoanilino)-piperidine in 5 ml of 10% strength hydrochloric acid and 40 ml of water, whilst cooling and stirring. When the addition had ended, the mixture was stirred at room temperature for 1 hour and then under reflux for 24 hours. After the mixture had been cooled, it was extracted with chloroform. The extract was washed with 5% strength hydrochloric acid, dried and filtered and the filtrate was concentrated.
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11]CC)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])C.[C:17]1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])[C:3]#[CH:17]
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), propandiol-1,2 (2.9 ml) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-propargyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 155° to 160° C. at 1 mm of Hg pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[C:20](O)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH2:39]([NH2:43])[CH2:40][CH2:41][CH3:42]>O1CCCC1.C(Cl)Cl>[CH2:39]([NH:43][C:20]([C@@H:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:21])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
7.699 g (25.9 mmol) of N-benzyloxycarbonyl-2(S)-indolinecarboxylic acid prepared as in Example 16 a) are dissolved in tetrahydrofuran (150 ml), under nitrogen. 2.986 g (25.9 mmol) of N-ethylmorpholine are added, at 0° C., followed by 3.54 g (25.9 mmol) of isobutyl chloroformate. After 45 minutes, 1.903 g (25.9 mmol) of n-butylamine are added and the suspension is stirred overnight. Methylene chloride (300 ml) is added and the organic phase is washed with 10% citric acid (3×100 ml) and then NaHCO3 (3×100 ml). After drying and evaporation, a white solid is obtained which is recrystallized from methanol.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.C1C(=O)N([Br:20])C(=O)C1>C(#N)C.CCOC(C)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][C:7]=1[Br:20]
Reactant: CCOC(=O)c1cnc(N)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1cnc(N)c(Br)n1
Yield: 78 %

Procedure:
To a solution of ethyl 5-aminopyrazine-2-carboxylate (880 mg, 5.26 mmol) in acetonitrile (20 mL) at RT was added NBS (984 mg, 5.53 mmol), the resultant solution was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc, washed with sat NaHCO3, brine and water, dried, filtered, and concentrated to afford the crude product, which was purified by ISCO 24 g silica gel column, 0 to 50% EtOAc in Heptane, 30 min). 1.01 g, 78% yield. LC-MS (m/z): 247.9 (MH+), 0.51 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(OC[C@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 183 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2R)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=155-157° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (dd, J=6.4, 7.6 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.68-7.64 (m, 1H), 7.51-7.47 (m, 1H), 7.25-7.22 (m, 2H), 6.86-6.84 (m, 2H), 4.14-4.11 (m, 1H), 3.98-3.96 (m, 2H), 2.94 (brs, 3H), 2.80-2.77 (m, 2H), 2.70-2.62 (m, 2H), 2.56-2.50 (m, 1H), 2.17 (d, J=13.6 Hz, 2H), 1.96-1.84 (m, 2H); LCMS: 486 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=33.67 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:19])=[N:8][N:9]([C:11]2[C:16]([CH:17]=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[B-].[Na+]>CO.C(OCC)(=O)C>[OH:18][CH2:17][C:16]1[C:11]([N:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]([CH3:19])=[N:8]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1cn(-c2ncccc2C=O)nc1C
Agent: [B-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)c1cn(-c2ncccc2CO)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of 1-(3-formyl-pyridin-2-yl)-3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 3.9 mmol) in methanol (25 mL), sodium borohydrate (220.2 mg, 5.8 mmol) is added. The mixture is stirred at room temperature for 2 hr. The solvent is eliminated and the crude is dissolved in ethyl acetate and washed with saturated aqueous solution of ammonium chloride. The organic layer is separated, dried over sodium sulfate, filtered and the solvent evaporated under reduced pressure to give 1 g of ethyl 1-[3-(hydroxymethyl)-2-pyridyl]-3-methyl-pyrazole-4-carboxylate. MS (m/z): 262 (M+1)
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O1CCCC1.O.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>[CH3:10][C:5]1[CH:4]=[CH:3][C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(I)ccc1C
Reactant: CCB(CC)c1cccnc1
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: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(-c2cccnc2)ccc1C
Temperature: 25 °C
Yield: 100 %

Procedure:
5-iodo-2-methyl anisole (9.60 g, 38.70 mmol) and diethyl-(3-pyridyl)borane (5.70 g, 38.70 mmol) were dissolved in 60 mL tetrahydrofuran in a 250 mL round bottom flask equipped with a magnetic stirrer. Sodium carbonate (8.20 g, 77.40 mmol) and 30 mL water were added followed by tetrakis(triphenylphosphine)palladium(0) (0.90 g, 0.77 mmol) and 15 mL ethanol. The mixture was heated at reflux for 24 h under nitrogen then cooled to ambient temperature. The mixture was diluted with 200 mL water and extracted with diethyl ether (2×200 mL). The organic phases were combined and extracted with 1N HCl (3×150 mL). The acidic extractions were combined and made basic with 5N aqueous sodium hydroxide. This basic layer was extracted with diethyl ether (3×150 mL) and the extracts were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 7.71 g (99%) of 2-methyl-5-(3-pyridyl)-anisole as a brown oil.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Nc1ncc(Br)nc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(Br)nc1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 2.5 g of 3,5-dibromo-pyrazin-2-ylamine in 60 ml 1,2-dimethoxy-ethane is added 1.19 g tetrakis(triphenylphosphine) palladium at room temperature and stirred for ½ hour. To the resulting orange solution is added a solution of 2.65 g sodium carbonate in 30.0 mL water and 1.56 g of p-chlorophenylboronic acid and the mixture is stirred for 18 hours at 100° C. The starting material is completely consumed as evidenced by tlc. The reaction mixture was partitioned between water and ethyl acetate; the phases are separated and the organic phase is dried over sodium sulfate evaporated and purified by chromatography on silica gel with heptane:ethyl acetate=1:1. to yield 2.37 g of the title compound as light yellow crystals, MS (ISP) 284.0, 286.0 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]1=[O:14])=[O:5])C.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O>[CH2:15]([O:13][C:9]1[C:8](=[O:14])[N:7]([CH2:6][C:4]([OH:3])=[O:5])[CH:12]=[CH:11][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cn1cccc(O)c1=O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cn1cccc(OCc2ccccc2)c1=O
Yield: 41 %

Procedure:
1-Ethoxycarbonylmethyl-3-hydroxypyrid-2-one (10 g) is dissolved in methanol/water (9:1 v/v) (400 ml). To this solution is added benzyl chloride (3 molar excess) and NaOH until the pH is above 12. The mixture is then refluxed for six hours to give a clear orange solution. The methanol is removed by rotary evaporation and the aqueous solution is extracted with dichloromethane to remove excess benzyl chloride. The aqueous phase is diluted slightly by adding extra water and then acidified to pH 2 using concentrated hydrochloric acid which results in the precipitation of a beige solid. The mixture is cooled and the precipitate filtered off and washed with diethyl ether. The crude product is recrystallised from ethanol to give 3-benzyloxy-1-carboxymethylpyrid2-one (5.4 g, 41%), m.p. 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:34]=[C:33]([CH2:35]OS(C)(=O)=O)[O:32][N:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:33]2[O:32][N:31]=[C:30]([CH3:29])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(COS(C)(=O)=O)on1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)on1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 3-methyl-isoxazol-5-ylmethyl ester (described in Heterocycles, 23(3), 571-83; 1985) gave the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1C(=O)c1ccccc1
Yield: 86 %

Procedure:
2-Benzoylbenzoic acid was reacted with (S)-2-amino-3-phenyl-1-propanol by the method of procedure 3c. 2.6 g (86%) of the product were obtained.
Reaction SMILES: C(O[C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:28][CH3:29])=[C:13]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:14]=2)[CH:9]=1)=[O:7])(C)(C)C.[CH:30]([NH2:32])=O>C(Cl)Cl.CO>[CH3:29][O:28][C:12]1[C:13]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:14][C:15]2[CH:16]=[C:17]3[C:8]([C:6](=[O:7])[NH:32][CH:30]=[N:18]3)=[CH:9][C:10]=2[CH:11]=1
Reactant: NC=O
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCCN1CCOCC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc2cc3c(=O)[nH]cnc3cc2cc1OCCN1CCOCC1
Temperature: 178 °C

Procedure:
A mixture of 3.5 g (8.6 mmol) of 3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic acid tert-butyl ester and 60 ml of formamide is heated at 178° C. for 2 hours, then cooled. To this is added 4:1 methylene chloride/methanol. The resulting solution is washed several times with brine, dried over anhydrous sodium sulfate and evaporated to yield an oil. The oil is purified by silica gel chromatography, utilizing a gradient of 99:1 to 88:12 methylene chloride/methanol to give sticky solid, which is triturated with ethyl acetate to yield 1.5 g of 7-methoxy-8-(2-morpholin-4-yl-ethoxy)-3H-benzo[g]quinazolin-4-one as a tan solid, mp 230-232° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:36]=[CH:35][C:12]([O:13][CH2:14][C:15]3([CH3:34])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[C:18]([CH3:33])[C:19]([CH3:32])=[C:20]([O:27][CH2:28][C:29]([OH:31])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:11][CH:10]=2)[S:3]1.O1CCO[CH2:39][CH2:38]1.Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3([CH3:34])[CH2:24][C:23](=[O:25])[C:22]4[C:17](=[C:18]([CH3:33])[C:19]([CH3:32])=[C:20]([O:27][CH2:28][C:29]([O:31][CH2:38][CH3:39])=[O:30])[C:21]=4[CH3:26])[O:16]3)=[CH:35][CH:36]=2)[S:3]1
Reactant: C1COCCO1
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)COc1c(C)c(C)c2c(c1C)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of α-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-4-oxo-chroman-6-yloxy}acetic acid (obtained as described in Example 59), 0.5 ml of a 4N dioxane solution of hydrogen chloride and 5 ml of ethanol was allowed to stand overnight at room temperature. The reaction mixture was then poured into water and the solution was neutralized with sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was subjected to preparative silica gel thin layer chromatography (developing solvent, benzene:ethyl acetate=7:3 by volume) to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][O:4][CH2:5][CH2:6][CH2:7][OH:8].C1(CCCCOCCC=O)C=CC=CC=1>>[F:1][C:2]([F:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][O:4][CH2:5][CH2:6][CH:7]=[O:8]
Reactant: OCCCOCC(F)(F)c1ccccc1
Agent: O=CCCOCCCCc1ccccc1
Product: O=CCCOCC(F)(F)c1ccccc1
Yield: 60.3 %

Procedure:
Obtained from Intermediate 81 (3.0 g, 14.4 mmol) by the procedure described in Intermediate 13. Purification by column chromatography with silica gel eluting with methylene chloride gave the title compound (1.86 g, 60%) as oil.
Reaction SMILES: [OH-:1].[Li+].[C:3]([O:7][C:8]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[C:13]([CH3:22])([CH3:21])[CH2:12][C:11]1=[O:23])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1>[C:3]([O:7][C:8]([NH:10][C:19]1[CH:18]=[CH:17][C:16]([F:20])=[CH:15][C:14]=1[C:13]([CH3:22])([CH3:21])[CH2:12][C:11]([OH:23])=[O:1])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC(C)(C)c2cc(F)ccc21
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)cc1C(C)(C)CC(=O)O
Reaction time: 24 h

Procedure:
375 ml (0.75 mol) of an aqueous 2 M lithium hydroxide solution is added to a solution of 44 g (0.15 mol) of 1-tert-butoxycarbonyl-3,4-dihydro-4,4-dimethyl-6-fluoro-2-quinolone in 1 l of THF. After 24 hours at room temperature, the batch is concentrated by evaporation, brought to pH 4 with 10% citric acid and extracted with ether. The combined organic extracts are washed with saturated NaCl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 34.0 g of 3-(2-tert-butoxycarbonylamino-5-fluorophenyl)-3-methylbutyric acid [1H-NMR (CDCl3) δ (ppm)=1.62 (br.s, 15 H), 2.77 (s, 2H), 6.41 (br, 1H), 6.93 (td, 1H), 7.07 (dd, 1H), 7.20 (br, 1H)], which dissolves in 1 l of THF and is mixed at 0° C. with 17 ml (121 mmol) of triethylamine and 11.5 ml (121 mmol) of ethyl chloroformate. After 10 minutes at 0° C., 20.7 g (546 mmol) of sodium borohydride is added to it, and 1 l of MeOH is slowly added in drops to it. The batch is stirred for another 30 minutes at 0° C., concentrated by evaporation and diluted with ethyl acetate. It is washed with saturated NaCl, dried on Na2SO4 and purified by column chromatography on silica gel with hexane-ethyl acetate. Yield: 6.7 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12]([NH:14][NH:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:11][C:10](=[O:26])[CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35](=O)[CH3:36].[I-].[Na+]>COCCOC.C(O)C>[CH3:36][C:35]1[C:11]2[C:10](=[O:26])[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:13][C:12]=2[N:14]=[N:15][CH:34]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3ccccc3Cl)C2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cnnc2c1C(=O)CC(c1ccccc1Cl)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
A mixture of 5-(2-chlorophenyl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.17 g), anhydrous potassium carbonate (1.1 g), chloroacetone (0.335 g), sodium iodide (0.4 g), ethanol (7.5 ml) and 1,2-dimethoxyethane (7.5 ml) was stirred at 80° C. for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography to give 4-methyl-7-(2-chlorophenyl)-5,6,7,8-tetrahydrocinnolin-5-one (0.34 g) as pale yellow crystals.
Reaction SMILES: C[CH2:2][O:3]C(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@@H:52]([O:54][CH3:55])[CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@@H:52]([O:54][CH3:55])[CH3:53])=[C:44]([CH:2]=[O:3])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Reactant: CO[C@@H](C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Product: CO[C@@H](C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 15, intermediate c) from (4R,9aR)-7-bromo-6-(1-(S)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 51, intermediate).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O.O>[C:1]([NH:4][C@@H:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:18]3[C:23]([CH:24]=[C:25]4[C:30]=2[CH:29]=[CH:28][CH:27]=[CH:26]4)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1)NC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1)C(=O)O
Reaction time: 16 h
Yield: 900 %

Procedure:
To a solution of 96 (80 mg, 0.02 mmol) in THF/water, 2:1 (3 mL) was added lithium hydroxide monohydrate (17 mg, 0.40 mmol) and the resulting suspension was allowed to stir for 16 h. The reaction mixture was diluted with water (30 mL) and the THF was removed by evaporation. The aqueous layer was washed with DCM (40 mL) to remove unreacted starting material. The aqueous phase was acidified with 10% HCl and the resulting precipitate was extracted with DCM (3×40 mL). The combined organics were dried and evaporated to yield the title compound (69 mg, 0.18 mmol, 90%) as a white solid. Mp 76° C. [α]D20 +29.7 (c. 0.1, EtOH). 1H NMR (CDCl3, 300 MHz): δ 8.47 (s, 1H, ArH10″); 8.02 (d, J=8.4 Hz, 2H, ArH3″ and ArH6″); 7.59 (d, J=8.7 Hz, 2H, ArH8″ and ArH1″); 7.45 (m, 2H, ArH4″ and ArH5″); 7.35 (m, 6H, ArH2″ and ArH7″, 4×ArH′); 6.27 (d, J=6.6 Hz, 1H, NH); 5.00 (m, 1H, H2); 3.39 (dd, J=4.8, 12.9 Hz, 1H, H3a); 3.26 (dd, J=6.3, 14.4 Hz, 1H, H3b); 2.07 (s, 3H, COCH3). Mass Spectrum (ES, +ve) m/z 383 (70%) [MH+]. HRMS calcd for C25H22NO3 384.1600, found 384.1610.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=O)[C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+].[CH3:14][C:15]([NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1)([CH3:17])[CH3:16]>C(O)C.O>[CH3:17][C:15]([NH:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH:29]=[CH:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[CH:24][CH:23]=1)([CH3:14])[CH3:16]
Reactant: CC(=O)c1ccc(OCCNC(C)(C)C)cc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)NCCOc1ccc(C(=O)C=Cc2cccc3[nH]ccc23)cc1
Reaction time: 24 h
Yield: 79.8 %

Procedure:
A mixture of 2.55 g of indole-4-carboxaldehyde and 4 ml of 50% sodium hydroxide solution was added with stirring under an inert atmosphere to a solution of 3.5 g of the product of Step B in 40 ml of ethanol and after stirring for 24 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and the wash water was reextracted with an 8-2 chloroform-methanol mixture. The extract was washed with water and aqueous sodium chloride solution and the combined organic phases were dried over a deshydrant and were evaporated to dryness. The residue was chromatographed over silica gel and eluted with a 9-1 ethyl acetate-triethylamine mixture to obtain 4.3 g of 1-[4-{-2-(1,1-dimethylamino)-ethoxy}-phenyl]-3-[1H-indol-4-yl]-2-propen-1-one (E) melting at ≃162° C.