Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[F:2][C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].[CH3:9][C:10]([CH3:55])([CH3:54])[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[C:32](=[O:33])[N:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)[N:30]=[CH:29][C:28]=3[N:41]3[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:12]>ClCCl>[F:2][C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].[C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[C:32](=[O:33])[N:31]([C:34]4[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=4)[N:30]=[CH:29][C:28]=3[N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)(=[O:12])[C:10]([CH3:55])([CH3:54])[CH3:9]
Reactant: Cc1ccc(-n2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccc(-c4ccc(OC(=O)C(C)(C)C)cc4)cc3)c2=O)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2ncc(N3CCNCC3)c(Oc3ccc(-c4ccc(OC(=O)C(C)(C)C)cc4)cc3)c2=O)cc1
Reaction time: 0.75 h

Procedure:
0.2 ml of water and 2.2 ml of trifluoroacetic acid are added dropwise to a solution of 568 mg (0.889 mmol) of the compound from Example 2 in 4.5 ml of dichloromethane at room temperature. After 45 min, the reaction mixture is concentrated and thoroughly dried under high vacuum.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[S:22][CH:23]=[CH:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([OH:30])=O)=[C:16]2[CH2:15]1.N>CN(C)C=O>[CH3:13][N:14]1[C:20](=[O:21])[C:19]2[S:22][CH:23]=[CH:24][C:18]=2[N:17]2[CH:25]=[N:26][C:27]([C:28]([NH2:3])=[O:30])=[C:16]2[CH2:15]1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccsc2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2ccsc2C1=O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
5.66 g (34.9 mmol) of 1,1'-carbonyldiimidazole were added portionwise to a suspension of 8.8 g (33.4 mmol) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-carboxylic acid (EP 150 040 A2) in 80 ml of dimethylformamide. The resulting pale brown solution was heated to 50° for 45 minutes. Subsequently, the solution was cooled to room temperature and 8.1 ml of aqueous ammonia solution were added dropwise thereto. After a further 30 minutes the reaction mixture was poured into 100 ml of ice-water and the resulting precipitate was filtered off and rinsed with water, ethanol and subsequently with ether. After drying at 70°/10 Torr there were obtained 7.6 g (86%) of 5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-3-carboxamide as colourless crystals of m.p. 294°-296°.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].[OH-].[K+]>C(O)C.O>[CH2:18]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCCCCCCCCBr
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCCCCCCOc1ccc(O)cc1
Yield: 36.4 %

Procedure:
Hydroquinone (37.65 g, 342 mmol) and dec-9-enyl bromide (25 g, 114 mmol) were dissolved in ethanol (150 ml) with warming under a nitrogen atmosphere. The solution was heated under reflux and a solution of potassium hydroxide (6.83 g, 121 mmol) in water (20 ml) was added dropwise over 1 h. The resulting suspension was heated under reflux (3 H) then poured on to water (500 ml) and extracted with ether (3×100 ml). The combined extracts were dried (MgSO4), evaporated in vacuo and the residue extracted with heptane (300 ml). On cooling, it afforded a first crop of the phenol (10.31 g). The remaining material was chromatographed (flash grade silica gel, petroleum ether 40-60° C./diethyl ether 3/2). 2 was isolated as white plates (Rf=0.57). Combined yield=15.61 g (55%). Mp=54° C.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18](F)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([N:8]1[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][C:18]([O:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)=[N:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccc(F)nc2OCCN1Cc1ccccc1
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(Oc3ccc(Cl)cc3)nc2OCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A mixture of the compound obtained in Example 28, step 1 (0.50 g), 4-chlorophenol (0.22 mL), potassium carbonate (0.76 g) and DMF (10 mL) was stirred at 100° C. for 16 hr. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give 4-benzyl-8-(4-chlorophenoxy)-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5(2H)-one (0.59 g, 84%) as a white powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].CS(C)=O.Cl.[CH:26]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2>CCOC(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:32]2[CH:26]3[CH2:31][CH2:30][CH:29]2[CH2:28][CH2:27]3)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: C1CC2CCC1N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Temperature: 55 °C
Reaction time: 3 h

Procedure:
4-fluoro-1-nitro-2-(trifluoromethyl)benzene (7) (901 g, 4.309 mol) was introduced into a 30 L jacketed vessel along with Na2CO3 (959.1 g, 9.049 mol) and DMSO (5 L, 5.5 vol) under nitrogen atmosphere and stirring. 7-azabicyclo[2.2.1]heptane hydrochloride (8-HCl) (633.4 g, 4.740 mol) was then added to the vessel in portions. The temperature was gradually raised to 55° C. When the reaction was substantially complete, the mixture was diluted with 10 vol EtOAc and washed with water (5.5 vol) three times or until DMSO in the aqueous layer disappeared (HPLC). The organic layer was concentrated to 4 vol and then the solvent was swapped with cyclohexane until all the EtOAc was removed, and the total volume in the flask was about 4 vol containing cyclohexane. The reaction mixture was heated to 60° C. on a rotary evaporator for 30 min. Then the solution was cooled to room temperature with stirring or rotation for 3 h. When all the solid crystallized, the solution was concentrated to dryness to provide 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (9).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)=O.[OH:22][CH:23]([CH2:28][NH2:29])[CH2:24][C:25]([OH:27])=[O:26].N12CCN(CC1)CC2>O>[N:1]1([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:29][CH2:28][CH:23]([OH:22])[CH2:24][C:25]([OH:27])=[O:26])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc(N2CCCCCC2)cc1
Reactant: NCC(O)CC(=O)O
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CC(O)CNS(=O)(=O)c1ccc(N2CCCCCC2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 150.4 %

Procedure:
4.1 g of (4-hexahydro-azepin-1-yl-benzenesulphonyl) chloride then 12 cm3 of acetone are added to a solution of 1.4 g of 3-hydroxy-4-amino butanoic acid and 3.36 g of 1,4-diazabicyclo [2.2.2]octane (DABCO) in 18 cm3 of water. Agitation is carried out for 6 hours at ambient temperature, the acetone is evaporated off, the residue is cooled down to 0° C. and 7.5 cm3 of 2N hydrochloric acid is added. Extraction is carried out with chloroform, the extracts are dried and evaporated to dryness. 6.3 g of desired product is obtained, used as it is for the following stage.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:42])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][C@H:30]3[C@H:37]4[C@H:33]([O:34]C(C)(C)[O:36]4)[C:32](=[O:40])[O:31]3)[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:41])[CH:17]=1.O>C1COCC1>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:42])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][C@H:30]3[C@H:37]([OH:36])[C@H:33]([OH:34])[C:32](=[O:40])[O:31]3)[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:41])[CH:17]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC[C@@H]1OC(=O)[C@H]2OC(C)(C)O[C@@H]12
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC[C@@H]1OC(=O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a mixture of 4-(3,5-dichloropyridin-4-ylamino)-8-(((3aS,4S,6aS)-2,2-dimethyl-6-oxotetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)-7-methoxy-2H-chromen-2-one (60 mg, 0.12 mmol, Example 50), water (0.1 mL), and THF (3 mL). The mixture was stirred at rt for 2 d. Then, more trifluoroacetic acid (3 mL) was added over time until the reaction was complete by LCMS. The mixture was concentrated to give 4-(3,5-dichloropyridin-4-ylamino)-8-(((2S,3R,4S)-3,4-dihydroxy-5-oxotetrahydrofuran-2-yl)methoxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 7.97 (d, 1H), 7.21 (d, 1H), 5.74 (s, 1H), 4.63 (s, 1H), 4.61 (d, 1H), 4.49 (m, 1H), 4.42 (d, 1H), 4.23 (d, 1H), 3.91 (s, 3H); MS (ESI): 482.8.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:4]([CH2:3][N:2]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN=Cc1ccccc1

Procedure:
To ethyl glycinate hydrochloride (36.4 g) suspended in 500 ml methylene chloride were added magnesium sulfate (22 g) and triethylamine (72 ml, 52.4 g). Benzaldehyde (27.6 g) was added dropwise at 15°-20° C. with stirring. The mixture was stirred at room temperature for two hours, filtered and stripped. To the residue was added 300 ml diethylether and 150 ml brine. After separation the organic layer was collected, and the aqueous layer was extracted with 100 ml ether. The organic phases were combined, dried (MgSO4), filtered and stripped to yield the title product as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1.[Si:21]([O:28][CH2:29][CH2:30][C@H:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:38][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:29][O:28][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22])=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1
Reactant: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 69 %

Procedure:
A solution of 209 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 181 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropylamine in 5 ml of methylene chloride was stirred at room temperature for 1 hour and the conversion was checked by LCMS. Since no conversion had taken place yet, the solvent was concentrated by rotary evaporation and the residue was stirred at room temperature for 19 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (237 mg) with a molecular weight of 595.7 g/mol (C27H39BrN2O4SSi); MS (ESI): m/e=596 (M+h+).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:33]=1[CH:34]=O.COC(=O)C.[Cl:47]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:47].[F:31][C:32]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:33]=1[CH2:34][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][C@@H:11]([CH3:24])[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](CNCC(c1ccccc1)c1ccccc1)COc1cccc(CC(=O)O)c1
Reactant: COc1ccc(C=O)c(F)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)=O
Product: COc1ccc(CN(CC(c2ccccc2)c2ccccc2)C[C@@H](C)COc2cccc(CC(=O)O)c2)c(F)c1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]2-methyl-propoxy}-phenyl)acetic acid and 2-fluoro-4-methoxybenzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 98 mg (98%). MS (ESI) 542.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[N:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=[O:25])[O:17][N:16]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:22]2[C:23]([CH2:24][OH:25])=[CH:26][CH:27]=[CH:28][N:29]=2)[O:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2C=O)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2ncccc2CO)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of 2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]nicotinaldehyde (1.64 g), tetrahydrofuran (20 ml) and ethanol (20 mL) was added sodium borohydride (80 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-isopropyl ether to give colorless needle crystals (1.50 g, 91%) of [2-[[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-5-isoxazolyl]methoxy]-3-pyridyl]methanol. melting point: 136-137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1COCC1.CO.[ClH:29]>O1CCOCC1>[ClH:29].[ClH:29].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N2CCC(N)CC2)nc1
Reaction time: 17 h
Yield: 86.8 %

Procedure:
A solution of tert-butyl [1-(5-methylpyridin-2-yl)piperidin-4-yl)carbamate (0.23 g, 0.79 mmol) in HCl in Dioxane (4M, 2 ml), THF (1 ml) and MeOH (1 ml) was stirred at room temperature. After 17 h, the reaction mixture was filtered, and the residue washed with EtOAc and dried to give the title compound (181 mg, 86.8%) as a solid. 1H NMR (500 MHz, D2O): 7.80 (d, 1H), 7.60 (s, 1H), 7.15 (d, 1H), 4.10-4.03 (m, 2), 3.53-3.44 (m, 1H), 3.21 (t, 2H), 2.16-2.10 (m, 5H), 1.65 (dq, 2H); 13C NMR (D2O): 150.8, 146.8, 133.9, 123.9, 112.9, 47.7, 44.7, 28.8; Mass Spectrum: M+H 192
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](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.CO.[NH2:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[OH-].[Na+]>[Pd].C(O)=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[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:24][C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: Nc1ncccn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=CO
Product: O=c1c2cc(F)ccc2nc(CNc2ncccn2)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.200 g, 0.66 mmol), methanol (20 mL), and 2-aminopyrimidine (0.059 g, 0.62 mmol) was refluxed 29 hours. The mixture was cooled to room temperature and 10% palladium on carbon (0.236 g) and formic acid (1.1 mL) were added. The mixture was allowed to stir at ambient temperature overnight. The reaction was treated with 6 N sodium hydroxide to adjust the pH to 10. The mixture was filtered through celite and the pad was washed with ethyl acetate. The filtrate was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20 g) with elution proceeding as follows: 10% ethyl acetate/hexane (500 mL), nil; 20% ethyl acetate/hexane (250 mL), unweighed impurity, 20% ethyl acetate/hexane (100 mL), mixed fraction, unweighed; 20% ethyl acetate/hexane (150 mL) and 30% ethyl acetate/hexane (150 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol (a side product). Elution was continued: 30% ethyl acetate/hexane 410 mL), nil; 40% ethyl acetate/hexane (450 mL), nil; 40% ethyl acetate/hexane (50 mL) and 50% ethyl acetate/hexane (450 mL), 0.028 g (8%) of 3-(2-Chloro-phenyl)-6-fluoro-2-(pyrimidin-2-ylaminomethyl)-3H-quinazolin-4-one as a white solid which had: mp 182-185° C.; 1H NMR δ 8.29 (d, J=5 Hz, 2H), 7.92 (dd, J=3, 8 Hz, 1H), 7.82 (dd, J=5, 9 Hz, 1H), 7.66-7.64 (m, 1H), 7.55-7.49 (m, 3H), 7.40-7.38 (m, 1H), 6.63 (t, J=5 Hz, 1H), 4.28 (dd, J=4.5, 18 Hz, 1H), 4.11 (dd, J=4, 18 Hz, 1H). Analysis calculated for C19H11ClFN5O.0.75 H2O: C, 58.05; H, 3.20; N, 17.81. Found: C, 58.06; H, 3.25; N, 17.33. APCI MS m/z=382 P+1).
Reaction SMILES: O.[C:2]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[CH:3]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O>[C:10]1([NH:9][C:2](=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a 300 ml flask equipped with a water separator connected to reflux condenser, stirrer and a thermometer, 15.44 g of maleic anhydride (hereinafter abbreviated as MAN), 70 ml of xylene (hereinafter abbreviated as Xy) and 10 ml of dimethylformamide (hereinafter abbreviated as DMF) were charged. A mixture of 13.97 g of aniline (hereinafter abbreviated as AN) and 20 ml of xylene was added with stirring at 80° C. at a constant rate over 15 minutes and further aged for 15 minutes to obtain N-phenylmaleamic acid as a white slurry. To the slurry, 0.530 g (2.5% by mole per mole of MAN) of stannous oxide (hereinafter abbreviated as SnO) was added and the mixture was heated to reflux with stirring. Water generated by the reaction was removed by azeotropic distillation and the reaction was carried out at about 140° C. for 3.5 hours. The white slurry of PMA gradually dissolved as the dehydration reaction progressed and an orange yellow solution was obtained from which the catalyst component precipitated.
Reaction SMILES: [C:1]([O:6][C:7]1[CH2:20][C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:18](/[CH:29]=[CH:30]/[C@@H:31]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](O)=[O:16])(=[O:5])[CH2:2][CH2:3][CH3:4].ClC(OCC(C)C)=O.[OH-].[NH4+:54].Cl>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl>[C:1]([O:6][C:7]1[CH2:20][C@@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:18](/[CH:29]=[CH:30]/[C@@H:31]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8]=1[S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH2:54])=[O:16])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: [NH4+]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)O)=C(OC(=O)CCC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCC[C@@H](/C=C/[C@@H]1C(SCCCCCC(N)=O)=C(OC(=O)CCC)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A methylene chloride (3 ml) solution of (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienoic acid (201 mg) was cooled to -40° C., then isobutyl chloroformate (47 μl) and triethylamine (63 μl) were added to the solution which was then stirred as is at -40° C. for 30 minutes. Further 1 ml of 30% ammonium hydroxide solution was added and the mixture was stirred overnight while raising the temperature to room temperature. The reaction solution was diluted by ethyl acetate then was neutralized by dilute hydrochloric acid. The desired substance was extracted from the mixture by ethyl acetate and extract was successively washed by saturated sodium hydrogen carbonate and saturated sodium chloride solution. This solution was concentrated under reduced pressure, then was purified by silica gel column chromatography (45% ethyl acetate/hexane) to obtain (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienamide (169 mg, 84%).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].Cl.C(OC(C)C)(=[O:21])C>C(O)(C)C>[CH3:11][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:1])[C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].[C:5]1([C:3](=[O:21])[CH:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:1])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(c1ccccn1)C(N)c1ccccc1
Reactant: CC(=O)OC(C)C
Agent: Cl
Solvent: CC(C)O
Product: CC(C(=O)c1ccccc1)c1ccccn1
Product: CC(C)(c1ccccn1)[C@H](N)c1ccccc1

Procedure:
(R)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine is prepared starting from racemic 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. This oil is dissolved in isopropyl acetate and a solution of 5-6 N HCl in isopropyl alcohol is added. The mixture is concentrated, and triturated in ether to yield 3 as a white solid. M.p.=188° C. 1HNMR (300 MHz, CD3OD): δ 1.59 (s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H). MS: m/z 227.