Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]2[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:22]=2)=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[F:3][C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:30])[CH2:16][C:17]2[NH:18][C:19](=[O:29])[CH:20]=[C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:22]=2)=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
0.4 ml of 2M sodium hydroxide is added to a solution of 310 mg of methyl 2-fluoro-5-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate prepared in Example 57, in 7 ml of methanol. After stirring overnight at ambient temperature, a further 0.4 ml of 2M sodium hydroxide is added and the resulting mixture is brought to reflux for 3 hours. After cooling, the reaction mixture is concentrated under reduced pressure. The evaporation residue is taken up with water. The aqueous phase is extracted with ethyl acetate and then acidified with a 1N aqueous solution of hydrochloric acid (pH=5). The insoluble material is filtered off. The filtrate is concentrated under reduced pressure and then taken up with water and a few drops of a 1N aqueous solution of hydrochloric acid. The precipitate formed is filtered off, rinsed with petroleum ether and concentrated to dryness under reduced pressure. 52 mg of 2-fluoro-5-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoic acid are obtained in the form of a pale pink solid, the characteristics of which are the following:
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]([NH2:7])=[NH:6].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:21])=[O:20])[CH:17]=2)[C:12]([Cl:28])=[CH:11][N:10]=1.O>CS(C)=O>[Cl:28][C:12]1[C:13]2[C:18](=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:21])=[CH:15][CH:14]=2)[C:9]([NH:6][C:5]([NH2:7])=[NH:4])=[N:10][CH:11]=1
Reactant: N=C(N)N
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)c3ccccc3)cc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
NaH (18 mg, 80% dispersion by wt in mineral oil, 0.60 mmol) was added in one portion to a solution of guanidine hydrochloride (90 mg, 0.94 mmol) in DMSO (2 mL) and the mixture was heated at 50° C. under N2 for 30 min. 1,4-Dichloro-7-(phenylsulfonyl)isoquinoline (80 mg, 0.236 mmol) was added and the mixture heated at 50-60 C. for 0.5 h. The cooled mixture was poured into water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was dissolved in EtOAc and a solution of HCl in Et2O (1 M) was added which gave a precipitate. The solvents were evaporated in vacuo and the residue triturated with EtOAc to give 4-chloro-1-guanidino-7-(phenylsulphonyl)isoquinoline (65 mg, 0.18 mmol) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-:31].[Na+]>CC(C)=O>[N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][CH:15]([I:31])[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC(I)CC1

Procedure:
A mixture of 1-(p-nitrobenzyloxycarbonyl)-4-(p-toluenesulfonyloxy)piperidine (14.78 g) in acetone (222 ml) and sodium iodide (12.71 g) was refluxed for 23 hours. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was diluted with ethyl acetate and the extract was washed successively with aqueous 10% sodium sulfite and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated to give 1-(p-nitrobenzyloxycarbonyl)-4-iodopiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[CH:15]=[N:14][C:13]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[N:12][C:11]=2[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12
Reactant: Cc1ccc(N)cc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1

Procedure:
A mixture of Example 1E (132.0 mg, 0.367 mmol) and p-toluidine (86 mg, 0.807 mmol) was heated in a capped vial at 90° C. for 1 hour. After cooling, the residue was treated with saturated aqueous NaHCO3 and brine and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/ethyl acetate (8:2 to 7:3) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 7.08 (d, J=1.8 Hz, 1H), 7.26-7.23 (m, 2H), 7.49-7.47 (m, 3H), 7.57-7.55 (m, 2H), 7.66-7.61 (m, 1H), 7.72-7.67 (m, 1H), 7.88-7.72 (m, 1H), 9.24 (s, 1H). MS (ESI+) m/z 403.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][CH:21]1[NH:26][CH:25]([CH3:27])[CH2:24][N:23]([C:28]([C:30]2[NH:34][C:33]([CH:35]=O)=[C:32]([CH3:37])[CH:31]=2)=[O:29])[CH2:22]1>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:33]4[NH:34][C:30]([C:28]([N:23]5[CH2:22][CH:21]([CH3:20])[NH:26][CH:25]([CH3:27])[CH2:24]5)=[O:29])=[CH:31][C:32]=4[CH3:37])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC(C)NC(C)C2)[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(3,5-dimethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 93.1 mg (73%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.39 (br s, 1H, NH), 11.75 (br s, 1H, NH), 9.23 (br s, 1H), 8.32 (s, 1H), 7.73 (dd, J=2.6 & 6.7 Hz, 1H), 7.41 (m, 1H), 7.33-7.38 (m, 2H), 6.57 (d, J=2 Hz, 1H), 4.22 (m, 2H, CH2), 2.68 (m, 2H, CH2), 2.52 (m, 2H, 2×CH), 2.22 (s, 3H, CH3), 0.99 (d, J=6 Hz, 6H, 2×CH3), 0.98 (s, 3H, CH3). MS 510 [M++1].
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[C:8]([F:22])[CH:7]=1>C(O)=O.O>[F:22][C:8]1[CH:7]=[C:6]([CH:2]=[O:1])[CH:21]=[CH:20][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2F)cn1
Solvent: O=CO
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.4 %

Procedure:
Take up 5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyridine-2-carboxamide (0.316 g, 1.04 mmol) in 88% formic acid (5.2 mL). Stir at room temperature for 1.25 hours before diluting with water. Extract with dichloroethane (2×50 mL). Wash the organic layer with brine (1×25 mL), dry over Na2SO4, filter and concentrate to give the title compound (0.269 g, 99.6%): TOF MS ES+ 261.1 (M+H)+, HRMS calcd for C13H10N2O3F 261.0675 (M+H)+, found 261.0682, time 0.37 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR 9.0 min, 100% purity.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C@@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][C@H:28]([C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: Cc1ncc([C@H](C)N)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@@H](C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (60 mg, 0.21 mmol) and (S)-1-(2-methylpyrimidin-5-yl)ethanamine (29 mg, 0.21 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (74 μL, 0.42 mmol) was subjected to microwave irradiation at 180° C. for 1 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-60% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[C:17](C1C=C(C#CC=C2CCN(C(OC(C)(C)C)=O)CC2)C=NC=1)#[N:18]>>[NH:14]1[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]2[CH:5]=[CH:6][C:7]([C:2]#[N:3])=[N:18][CH:17]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#Cc2cncc(C#N)c2)CC1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Product: N#Cc1ccc(C#CC=C2CCNCC2)cn1

Procedure:
The title compounds were prepared following the procedure described for the compound of Example 3 but starting respectively from the compounds of Example 45 and 46 instead of the compound of Example 2. The crudes were used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]1[N:14]([CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:13](=[O:24])[NH:12][C:11]1=[O:25])([OH:3])=[O:2].C(CCCCCCC1N(CCC(O)CCCCC)C(=O)NC1=O)(O)=O>>[C:1]([CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH:10]1[N:14]([CH2:15][CH2:16][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:13](=[O:24])[NH:12][C:11]1=[O:25])([OH:3])=[O:2]
Reactant: CCCCCC(O)CCN1C(=O)NC(=O)C1CC=CCCCC(=O)O
Agent: CCCCCC(O)CCN1C(=O)NC(=O)C1CCCCCCC(=O)O
Product: CCCCCC(O)CCN1C(=O)NC(=O)C1CC#CCCCC(=O)O

Procedure:
This compound was then catalytically hydrogenated to the corresponding 5-(6-carboxyhex-2-enyl)-1-(3-hydroxyoctyl) hydantoin and subsequently to the corresponding saturated compound which was found to be identical with the title compound of Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]1[O:13][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 33 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
(2S,3S)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (3.57 g) and potassium carbonate (3.29 g) were added to an ethanol:water (97:3) mixed solution (35.7 ml). The mixture was stirred at 27° C. for 22 hours and further at 33° C. for 4 hours. A 11.3% citric acid aqueous solution (40.3 g) was added thereto, and the cooling was then conducted to −10° C. Crystals were collected by filtration, washed with water (35.7 ml), and dried under reduced pressure to obtain desired (2S,3S)-3-tert-butoxycarbonylamino-1,2-epoxy-4-phenylbutane (2.88 g) in a yield of 95%.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[N:5]([CH3:15])[C:4]1=[O:16])[CH3:2].[C:19](O)(=[O:21])[CH3:20]>[Ni]>[CH2:1]([C:3]1([CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:19](=[O:21])[CH3:20])[CH:10]=2)[N:5]([CH3:15])[C:4]1=[O:16])[CH3:2]
Reactant: CCC1(CC)C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Reactant: CC(=O)O
Agent: [Ni]
Product: CCC1(CC)C(=O)N(C)c2ccc(NC(C)=O)cc21

Procedure:
3,3-Diethyl-1-methyl-5-nitro-1,3-dihydro-indol-2-one (9.3 g) is dissolved in acetic acid (100 ml) and subjected to a catalytic hydrogenation with Raney-nickel (1 g) at 3 bar. After completion of the hydrogenation the mixture is filtered and evaporated. The residue is treated with acetic anhydride (10 ml) for 3 h at RT. The mixture is concentrated in vacuo and purified by flash chromatography on silica gel eluting with light petroleum/EtOAc. After re-crystallization from diisopropyl ether the compound (7.1 g) is obtained as a white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH:20]([CH3:21])[CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C1NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)C1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of potassium t-butoxide (3.53 g, 29 mmol) in THF was added to a solution of 2-phenylmethyl-4-isopropyl-1, 2,5-thiadiazolidin-3-one 1,1-dioxide (7.7 g, 29 retool) in THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (20.38 g, 0.143 mol) and the resulting mixture was allowed to stir at room temperature for 2.5 hours. The resulting mixture was quenched with brine, extracted with ether, and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 7.1 g (88%) of 2-phenylmethyl-4-isopropyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =isopropyl; R3 =CH3) as a solid, m.p. 52.5°-54° C.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.[N+:14]([C:17]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])([O-:16])=[O:15].[Cl-].[NH4+]>CCCCCC.O1CCCC1.C(OCC)C>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[CH:19]([C:18]1[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:17]=1[N+:14]([O-:16])=[O:15])[OH:20]
Reactant: COc1cccc(C=O)c1[N+](=O)[O-]
Reactant: Fc1cccc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(C(O)c2c(F)cccc2F)c1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 1 h

Procedure:
77.5 ml of a 1.6M solution of n-butyllithium (1.5 eq.) in hexane are added dropwise in order to maintain a temperature of less than or equal to −70° C. to a solution of 12.3 ml of 1,3-difluorobenzene (1.5 eq.) in 150 ml of tetrahydrofuran over 1 hour. After an additional 1 hour at −70° C., a solution of 15 g of 2-nitro-3-methoxybenzaldehyde in tetrahydrofuran is added over 1 hour still at −70° C. The reaction medium is stirred for 4 hours at −70° C. and then brought to a temperature of −5° C. over 1 hour. The reaction medium is then diluted by adding diethyl ether and then slowly hydrolyzed with a saturated aqueous solution of ammonium chloride. After decantation, the organic phase is washed with water and then dried over anhydrous sodium sulfate. The residue is chromatographed on silica gel, eluting with a dichloromethane/cyclohexane mixture (1/1) (v/v) in order to obtain 13.4 g of the expected product.
Reaction SMILES: [C:1](Br)(=[O:3])[CH3:2].[C:5]([O:22][CH2:23][CH:24]([CH2:45][O:46][Si](C(C)(C)C)(C)C)[O:25][C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CCCCCCC>[C:5]([O:22][CH2:23][CH:24]([CH2:45][O:46][C:1](=[O:3])[CH3:2])[O:25][C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)Br
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC(COC(=O)CCCCCCCCCCCCCCC)CO[Si](C)(C)C(C)(C)C
Solvent: CCCCCCC
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OC(COC(C)=O)COC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
Acetylbromide (123 g) was added into heptane solution of 1-palmitoyl-2-linoleoyl-3-t-butyl-dimethylsilyl-glycerol, which was obtained in Example 4, and the reaction mixture was stirred for 12 hours at room temperature. Heptane (400 ml) was added into the reaction mixture, and the cooling purified water (400 ml) was dropwisely added thereto for extracting the organic layer. The separated organic layer was washed with a solution of saturated sodium bicarbonate (100 ml) and purified water (400 ml), and then the washed organic layer was dehydrated with anhydrous MgSO4, and filtered. 1-palmitoyl-2-linoleoyl-3-acetyl-glycerol (178 g) was obtained with a silica gel (Si-60, 230-400 mesh) column chromatography(heptane:ethyl acetate=36:1 by volume) (theoretical amounts: 63.5 g, yield: 28.0%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C[S-].[Na+]>>[N:16]1([CH2:15][C:9]2([C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: COc1ccc(C2(CN3CCOCC3)CCOCC2)cc1
Agent: C[S-]
Agent: [Na+]
Product: Oc1ccc(C2(CN3CCOCC3)CCOCC2)cc1
Yield: 75 %

Procedure:
The title compound (1.70 g, 75%) was prepared using 4-{[4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-yl]methyl}-morpholine and sodium thiomethoxide similarly to the procedure used for intermediate 72. HRMS ESI+ m/z 278.1740 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25](=O)[C:26](OC)=[O:27].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[C:19]2[C:25]1[C:26](=[O:27])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: COC(=O)C(=O)c1c[nH]c2ccc(F)cc12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5ccc(F)cc45)C(=O)NC3=O)c21
Temperature: 65 °C
Reaction time: 20 h
Yield: 42.2 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (350 mg, 1.86 mmol) and methyl 2-(5-fluoro-1H-indol-3-yl)oxoacetate (427 mg, 1.93 mmol) in DMF (25 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (6.5 mL, 6.5 mmol) at room temperature under N2. The reaction was heated to 65° C. and stirred for 20 h at this temperature. The reaction mixture was then cooled to room temperature and quenched with 1.0 N hydrochloric acid, extracted with EtOAc (50 mL), washed with H2O (2×30 mL), saturated NaCl (2×30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (282 mg, 42%) as a maroon solid, mp 230° C. dec. 1H NMR (DMSO-d6) δ 11.95 (bs, 1H), 11.18 (bs, 1H), 7.98 (s, 1H), 7.64 (m, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 6.99 (m, 1H), 6.92 (m, 1H), 6.83 (m, 1H), 6.48 (m, 1H), 5.91 (m, 1H), 3.67 (s, 3H). MS (APCI): m/z=360 [C21H14FN3O2+H]+
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:11](=O)[NH:12][C:13]([Cl:15])=[CH:14][C:8]3[C:9]=2[CH:4]([CH2:5][CH2:6][CH:7]=3)[CH2:3]1.B(F)(F)F.CO>C1COCC1>[CH3:1][CH:2]1[C:10]2[CH2:11][NH:12][C:13]([Cl:15])=[CH:14][C:8]3[C:9]=2[CH:4]([CH2:5][CH2:6][CH:7]=3)[CH2:3]1
Reactant: CC1CC2CCC=C3C=C(Cl)NC(=O)C1=C32
Agent: FB(F)F
Solvent: CO
Solvent: C1CCOC1
Product: CC1CC2CCC=C3C=C(Cl)NCC1=C32
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 600 mg (2.5 mmol) of 2-methyl-3-oxo-5-chloro-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine, a compound of Formula 16 prepared, for example, as described in Preparation 16, dissolved in 25 ml of THF was combined with 8 ml of a 1M solution of BF3.THF in tetrahydrofuran. The reaction mixture was stored at ambient temperature for 16 hours. A few ml of methanol was added dropwise and the solvents were removed under vacuum. The residue was treated with 25 ml of 5% HCl and digested on a steam bath for 3 hours. After cooling to ambient temperature, the aqueous solution was washed once with ether, made alkaline with NaOH, and extracted with ether. The ether extract was concentrated to give 2-methyl-5-chloro-1,3,4,8,9,9a-hexahydro-2H-indeno[1,7-cd]azepine, a compound of Formula I, as the free base; (HBr salt, ethanol, mp 279°-281° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH2:24][O:25][CH3:26])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:5])[CH3:2]
Reactant: COCCN
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(NCCOC)c2cnc(-c3ccccc3)nc2n(CCOC)c1=O

Procedure:
To 2.4 g. (0.006 mole) of 5-chloro-7,8-dihydro-8-(2-methoxyethyl)-7-oxo-2-phenyl-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in 100 ml. of ethanol was added 0.45 g. (0.006 mole) of 2-methoxyethylamine and 0.65 g. (0.006 mole) of Na2CO3. This mixture was refluxed 3 hours, then filtered and the filtrate chilled. A solid formed and was filtered off and rinsed with petroleum ether--m.p. 160°-163° C. No further purification was necessary.
Reaction SMILES: [F:1][C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH:14]=[C:15]3[S:21]([CH3:23])=O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=1.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:29][CH2:23][S:21][C:15]1[C@:16]2([CH2:18][C@H:19]([OH:20])[C@@:2]3([F:1])[C@@H:11]([CH2:10][CH2:9][C:8]4[C@:3]3([CH3:25])[CH:4]=[CH:5][C:6](=[O:24])[CH:7]=4)[C@@H:12]2[CH2:13][CH:14]=1)[CH3:17])(=[O:28])[CH3:27]
Reactant: CS(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 110 °C

Procedure:
A mixture of 1.5 g of 9-fluoro-11β-hydroxy-17-(methylsulfinyl)androsta-1,4,16-trien-3-one, 70 ml of acetic anhydride and 2 g of fused sodium acetate is heated at 110° C under nitrogen for 2 hours. The acetic anhydride is partially removed by distillation under vacuum and the resulting slurry is diluted with 1:1 chloroform-water. The organic layer is separated, washed with diluted sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is dissolved in 4:1 chloroform-hexane and chromatographed on a 40 g-silica gel column. Elution with 1:4 hexane-chloroform gives 940 mg of slightly impure material. Two crystallizations from acetone-hexane give 350 mg of the title compound, melting point 193°-194° C.