Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][C:12](=O)[CH2:11][O:10]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[N:8]=[CH:7][C:6]([CH:9]2[O:10][CH2:11][CH2:12][NH:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C1COC(c2ccc(C(F)(F)F)nc2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2CNCCO2)cn1
Temperature: 0 °C
Reaction time: 12 h
Yield: 44.4 %

Procedure:
In a 500 mL round-bottomed flask, 6-(6-(trifluoromethyl)pyridin-3-yl)morpholin-3-one (0.65 g, 2.64 mmol) was combined with THF (35 ml) to give a light yellow solution. The reaction mixture was cooled to 0° C. LiAlH4 (3.3 ml of a 2M solution in THF, 6.6 mmol) was added by dropwise addition. The reaction mixture was allowed to warm to room temperature and then stirred for 12 h. The reaction mixture was cooled to 0° C. and quenched carefully by sequential addition of H2O (0.27 mL), 2M NaOH (0.54 mL) and then H2O (0.54 mL). The mixture was stirred for 10 min., filtered through Celite and the Celite washed 1 time with THF and several times with ethyl acetate. The combined filtrate and washes were concentrated. The crude residue was purified by flash chromatography (silica gel, 40 g, 0.5% to 5% MeOH in dichloromethane) to afford 2-(6-(trifluoromethyl)pyridin-3-yl)morpholine (272 mg) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.92 (br. s., 1H) 2.76 (dd, J=12.38, 10.36 Hz, 1H) 2.88-3.07 (m, 2H) 3.13 (dd, J=12.25, 2.65 Hz, 1H) 3.81 (td, J=11.37, 2.78 Hz, 1H) 4.01-4.15 (m, 1H) 4.63 (dd, J=10.36, 2.53 Hz, 1H) 7.69 (d, J=8.08 Hz, 1H) 7.84-7.96 (m, 1H) 8.63-8.77 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O>C(O)C.Cl.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)n2ccc3ccccc32)c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)n2ccc3ccccc32)c1
Temperature: 77.5 °C
Reaction time: 4 h

Procedure:
1-(3-Nitrobenzenesulfonyl)-1H-indole (obtained from step (ii)) (6.62 mmol, 2.0 grams) was taken in ethanol (10 mL) in a 50 mL three-necked round-bottomed flask. Iron powder, (33.11 mmol, 1.85 grams) was added to it at 25° C. followed by addition of water (2 mL) and 1-2 drops of hydrochloric acid. The reaction mixture was then stirred for a period of 4 hours at 75-80° C. After completion of the reaction, the reaction mixture was filtered through buchner funnel and solid mass on the filter was washed twice with hot ethanol (20 mL). Combined ethanol layer was concentrated under vacuum and the residual mass was poured onto ice-cold water (30 mL) and basified with 40% sodium hydroxide solution. Aqueous layer was extracted with dichloromethane (50 mL×3). The combined dichloromethane extracts were washed with water, brine and dried over anhydrous magnesium sulfate. The volatile substances were then removed tinder reduced pressure to obtain 2.4 grams thick syrupy mass which was purified by column chromatography using neutral silicagel (100-200 mesh), eluent being ethyl acetate and n-hexane (2:3).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2/[C:3]/1=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1.O[N:20]1[C:24]2C=CC=[CH:28][C:23]=2N=N1.C(N)CC.Cl.CON(OC)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH:20][CH2:24][CH2:23][CH3:28])=[O:12])=[CH:9][C:4]=2/[C:3]/1=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1Nc2sc(C(=O)O)cc2/C1=C/c1ccc[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(OC)OC
Agent: Cl
Solvent: CCCN
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)c1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Yield: 38.7 %

Procedure:
A solution of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxylic acid (30 mg, 0.12 mmol), 1-hydroxy-benzotriazole (18 mg, 0.13 mmol), propylamine (11 μl, 0.13 mmol), 1-(3-dimethoxyaminopropyl)-3-ethylcarbodiimide hydrochloride (25 mg, 0.13 mmol) and diisopropylethylamine (23 μl, 0.13 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 3 hours then diluted with ethyl acetate and washed with 2M hydrochloric acid, saturated sodium bicarbonate and water. The resulting solution was dried over magnesium sulfate and evaporated to dryness. The residue was triturated with water/isopropyl alcohol to give 14 mg of (Z)-5,6-dihydro-5-oxo-N-propyl-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as an orange solid. MS(ES): m/e 302 [M+H].
Reaction SMILES: [OH-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[N:17]([CH:26]3[CH2:28][CH2:27]3)[N:18]=[CH:19][C:20]=2[C:21]([O:23]CC)=[O:22])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>CCO>[C:3]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]2[N:17]([CH:26]3[CH2:28][CH2:27]3)[N:18]=[CH:19][C:20]=2[C:21]([OH:23])=[O:22])[CH2:14][CH2:15]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCOC(=O)c1cnn(C2CC2)c1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c(C(=O)O)cnn2C2CC2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A solution of 1.71 mL (3.42 mmol) of 2M NaOH was added to 0.540 g (1.49 mmol) N-Boc-4-(2-cyclopropyl-4-ethoxycarbonyl-2H-pyrazol-3-yl)-piperidine in 15 mL of EtOH. After stirring at 60° C. for 18 h, the solution was concentrated and dissolved in 100 mL of EtOAc (100 mL) and 10 mL of 5% HCl (10 mL). The extract was washed with 50 mL of brine (50 mL), dried over MgSO4, filtered, concentrated, and chromatographed (0–100% EtOAc in hexanes) to give 330 mg of N-Boc-4-(4-carboxy-2-cyclopropyl-2H-pyrazol-3-yl)-piperidine as a white powder.
Reaction SMILES: [CH2:1]([P:3]([OH:12])([CH2:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:4])[CH3:2].[O-]CCCC.[O-]CCCC.[O-]CCCC.[O-]CCCC.[Ti+4:33]>C1(C)C=CC=CC=1>[Ti:33].[CH2:1]([P:3]([OH:12])([CH2:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8])=[O:4])[CH3:2]
Reactant: [Ti+4]
Agent: CCCC[O-]
Agent: CCP(=O)(O)CC(C)C(=O)OC
Solvent: Cc1ccccc1
Product: [Ti]

Procedure:
177 g (1 mol) of methyl 3-(ethylhydroxyphosphinyl)-2-methylpropionate (produced as in Example 6) and 140 g of titanium tetrabutoxide are refluxed in 500 ml of toluene for 40 hours. The resulting butanol is distilled off from time to time with proportions of toluene. The solution formed is subsequently freed of solvent to leave 196 g of methyl 3-(ethylhydroxyphosphinyl)-2-methylpropionate titanium salt.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:15]([C:17]1[C:22]2[NH:23][C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)=[N:25][C:21]=2[CH:20]=[CH:19][C:18]=1[OH:35])=[O:16].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(=O)(O)[O-].[Na+].O1CCCC1>[OH:35][C:18]1[CH:19]=[CH:20][C:21]2[N:25]=[C:24]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:31])=[CH:28][CH:27]=3)[NH:23][C:22]=2[C:17]=1[CH:15]=[O:16]
Reactant: CN1CCNCC1
Reactant: O=Cc1c(O)ccc2nc(-c3ccc(C(=O)O)cc3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(-c3nc4ccc(O)c(C=O)c4[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
To dry tetrahydrofuran (5 mL), 1-methylpiperazine (69 μL, 63 mg, 0.62 mmol), triethylamine (196 μL, 142 mg, 1.40 mmol), 4-(7-Formyl-6-hydroxy-1H-benzoimidazol-2-yl)-benzoic acid (80 mg, 0.28 mmol), 1-hydroxybenzotriazole (84 mg, 0.62 mmol) and 1-ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride (120 mg, 0.62) were added in the above order. The mixture was stirred at room temperature overnight. The resulted brown solution was suspended in saturated sodium bicarbonate (60 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried (Na2SO4), evaporated and purified by column chromatography (Kieselgel 60), eluting with chloroform-methanol 9:1. The title compound (35 mg, 0.096 mmol, 34%) was isolated as a white powder.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.[CH3:14][N:15]1[C:19](=O)[CH2:18][CH2:17][CH2:16]1.[NH4+].[Cl-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>CCOCC>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:16]2[CH2:17][CH2:18][CH2:19][N:15]2[CH3:14])=[CH:9][N:8]=1
Reactant: CN1CCCC1=O
Reactant: Brc1ccc(Br)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN1CCCC1c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of BuLi (16.9 mmol) in hexanes (1.6 M, 10.6 ml) was added to a stirred solution of 2,5-dibromopyridine (40 g, 16.9 mmol) in Et2O (300 ml) at −78° C. under N2. The resulting suspension was then stirred at −78° C. for 1 h. N-Methyl pyrrolidinone (1.62 ml, 16.9 mmol) was added and the reaction allowed to warm slowly to room temperature and then stirred at RT for a further 1 h. NH4Cl solution (50 ml) was added and the organics were extracted with Et2O (3×100 ml). The combined organics were washed with brine (50 ml) and then concentrated under reduced pressure. The crude residue was taken up in 1,2-dichloroethane (50 ml), sodium triacetoxyborohydride (3.94 g, 16.9 mmol) was added portionwise and then the reaction mixture was stirred at room temperature overnight. 2 N NaOH solution (50 ml) was added and the organics were extracted with CH2Cl2 (3×100 ml), dried (MgSO4), and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography on silica using 3% MeOH/CH2Cl2 containing 1% NH3 to yield the desired pyridine (480 mg, 10%). m/z (ES+) 241, 243 (1:1, M+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:26])[N:14]([CH3:25])[N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]=1S(C)=O)[CH3:2].CN1CCCC1=[O:33].[OH-].[Na+].Cl>O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:26])[N:14]([CH3:25])[N:15]=[C:16]([C:21]([F:24])([F:23])[F:22])[C:17]=1[OH:33])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C(F)(F)F)nn(C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C(F)(F)F)nn(C)c1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
To a 30 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-39) (0.375 g), N-methylpyrrolidone (3.49 g), water (1.75 g), and sodium hydroxide (0.34 g) were added at room temperature. The resulting mixture was stirred at 50° C. for 4 hours. Then, the resulting mixture was cooled to room temperature, added 12N hydrochloric acid (1.5 ml) and water (15 ml), and extracted with ethyl acetate (30 ml). The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=7:1 to hexane: ethyl acetate=5:1 to hexane: ethyl acetate=3:1) to give 0.147 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxyl-2-methyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((1-16)-(1)-39).
Reaction SMILES: CC(C)([O-])C.[K+].CS([O:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([O:27][Si](C(C)(C)C)(C)C)[C@H:25]([O:35][Si](C(C)(C)C)(C)C)[C@@H:24]([CH2:43][O:44][CH3:45])[O:23]2)=[C:15]([NH:46][CH2:47][CH:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[N:14]=1)(=O)=O.[CH3:61][N:62]([CH2:64][CH2:65]O)[CH3:63]>CN(C)C=O>[CH3:61][N:62]([CH3:63])[CH2:64][CH2:65][O:11][CH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@H:22]2[C@H:26]([OH:27])[C@H:25]([OH:35])[C@@H:24]([CH2:43][O:44][CH3:45])[O:23]2)=[C:15]([NH:46][CH2:47][CH:48]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[N:14]=1
Reactant: CN(C)CCO
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COS(C)(=O)=O)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(COCCN(C)C)nc32)[C@H](O)[C@@H]1O
Yield: 23.5 %

Procedure:
Potassium tert butoxide (112 mg, 1 mmol) was added to a stirred solution of {9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}methyl methanesulfonate (200 mg, 0.25 mmol) (preparation 16) and 2-(N,N-dimethylamino)ethanol (0.16 ml, 1.5 mmol) in N,N-dimethylformamide (3 ml). The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (30 ml) after 30 min. The aqueous phase was extracted with dichloromethane (60 ml). The organic phase was separated, dried with anhydrous magnesium sulfate and the solvent removed under reduced pressure to give a residue that was azeotroped with toluene to remove traces of N,N-dimethylformamide. This was then purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (94:5:1) increasing in polarity to (84:14:2) to give the title compound (33 mg) as a foam. MS: 563 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:17][CH2:16][CH2:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:27])=[O:26]
Reactant: OCCCc1c(Cl)cccc1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 3-(3-chloro[1,1'biphenyl]-2-yl)-1-propanol (30.0 g, 0.12 mole) and pyridine (11.9 g, 0.15 mole) in methylene chloride (300 ml) was cooled to 0°. Methanesulfonyl chloride (13.9 g, 0.12 mole) was added dropwise to the mixture. After complete addition the mixture was allowed to warm to room temperature and stir for approximately 18 hours. The reaction mixture was diluted with ice water (50 grams) and washed successively with dilute hydrochloric acid (200 ml), saturated aqueous sodium chloride (700 ml) and dilute aqueous sodium hydroxide (200 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to yield (3-chloro[1,1'-biphenyl]-2-yl)propanyl methylsulfonate as a brown oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:5]1=[O:25])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]([CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:5]1=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N=[N+]=[N-])CCCC1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CN1C(=O)C(N)CCCC1c1ccccc1
Yield: 100.3 %

Procedure:
A solution of 8.95 g of this azide in 75 ml ethanol is hydrogenated over 2 g 10% Pd-C at 45° C. for 5 hr. The solution is then filtered and concentrated to afford 8.3 g 3-amino-1-t-butoxycarbonylmethyl-7-phenylperhydroazepin-2-one. NMR (CDCl3, TMS): δ1.4 (s, 9H); δ1.7-2.5 (M+s, 8H); δ3.4 (d, 1H, J=17 hz); δ3.95 (d, 1H, J=17 hz); δ4.0 (broad m, 1H); δ4.95 (broad d, 1H); δ7.3 (s, 5H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:3][CH:2]=1
Reactant: CC(C)CC(=O)Cl
Reactant: COc1ccccc1
Product: COc1ccc(C(=O)CC(C)C)cc1
Yield: 96 %

Procedure:
In the first and second steps, after anisole (2) is reacted with isovaleryl chloride to afford 1-(4-methoxy-phenyl)-3-methyl-butan-1-one (3), the compound (3) is reacted with bromine, sulfuryl chloride, N-bromosuccinimide or copper bromide, to prepare 2-bromo-1-(4-methoxy-phenyl)-3-methyl-butan-1-one (4). At this time, the reaction temperature is preferably maintained in the range from −10 to 40° C., and the reaction solvent is selected from polar solvents, including dichloromethane, acetonitrile, ethylacetate, lower alcohols such as methanol, ethanol or isopropanol, ethers such as tetrahydrofuran or 1,4-dioxane, dimethylformamide, or dimethylsulfoxide, and mixtures thereof. Among the materials reacting with the compound (3) in the second step, bromine is preferably used because it is inexpensive and increases the yield (yield: 96% or more).
Reaction SMILES: Br[C:2]1(Br)[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.CS(C)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C)C1C=CC=CC=1>O>[NH:22]([C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: CC1CCC(Br)(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)c1ccccc1
Product: CC1CC=C(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Reaction time: 72 h
Yield: 55.8 %

Procedure:
1.83 g. (0.005 moles) of 9,9-dibromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are dissolved in 5 ml. of dimethyl sulfoxide. To the solution 0.5 ml. (0.0055 moles) of aniline and 1.3 ml. (0.01 moles) of N,N-dimethylaniline are added. The reaction mixture is allowed to stand for three days, whereupon it is poured onto 20 ml. of water. The crystals are filtered off, washed with a small amount of water, dried and recrystallized from acetonitrile. 0.83 g. (55.8%) of 9-anilino-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid are obtained, melting at 169° to 170° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:28])[C@@H:18]4[O:27][C@@H:19]42)=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7].CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=CC=4)CC2)C)OC1>>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15]([CH2:16][C@@H:17]([OH:28])[CH2:18][C@@H:19]2[OH:27])=[CH:14][CH:13]=3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C1OCCO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 78.3 %

Procedure:
The procedure of Example 24 was repeated except that 3.4 mg (0.00887 mmole) of 20-(1,3-dioxolan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol was used in lieu of 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol to give 2.7 mg of 20-(1,3-dioxolan-2-yl)pregna-5,7-diene-1α,3β-diol (yield: 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[Mg].[CH3:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)C>[OH:19][C:18]1([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=2)[N:14]([CH3:13])[C:15](=[O:20])[CH2:16][CH2:17]1
Reactant: CN1C(=O)CCC1=O
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CN1C(=O)CCC1(O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
To a Grignard prepared from 37 g. (0.16 mole) of 3-bromobenzotrifluoride and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone; m.p. 137°- 139°C.
Reaction SMILES: CO.[OH-].[Na+].C([O:8][C:9]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[N:28](C(OC(C)(C)C)=O)[CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.O.O1CCOCC1>[OH:8][C:9]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:39][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[NH:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(=O)Oc1ccc(N2CCCCC2)cc1C(=O)Nc1cc(-c2cccn2C(=O)OC(C)(C)C)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2ccc[nH]2)ccc1C(=O)O)c1cc(N2CCCCC2)ccc1O
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Methanol (2.0 mL) and a 4 mol/L aqueous solution of sodium hydroxide (0.19 mL) were added to a dioxane (2.0 mL) solution of the obtained tert-butyl 2-(2-acetoxy-5-(piperidin-1-yl)benzamido)-4-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)benzoate, followed by stirring at 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and then a 4 mol/L aqueous solution of sodium hydroxide (0.077 mL) was added thereto, followed by stirring at 60° C. for 2 hours. The reaction mixture was cooled to room temperature and then adjusted to a pH of 7.8 with a 10% aqueous solution of citric acid, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-91% chloroform/methanol] to obtain 8 mg of 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(1H-pyrrol-2-yl)benzoic acid as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:6]=[CH:5][C:4]=1[N+:18]([O-])=O.[H][H]>CO.[Pd]>[NH2:18][C:4]1[CH:5]=[CH:6][C:7]([CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(OC)n1)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(Cc1ccc(N)c(OC)n1)OCC
Yield: 93.2 %

Procedure:
A mixture of diethyl [(6-methoxy-5-nitropyridin-2-yl)methyl]phosphonate (Compound 286C, 750 mg, 2.465 mmol) and Pd/C (0.247 mmol) in 3 mL methanol was stirred under 1 atmosphere of hydrogen at room temperature overnight. The crude mixture was filtered through celite and the product (630 mg, 93% yield) was used directly in next step. 1H NMR (DMSO-d6) δ=6.82 (d, J=7.6 Hz, 1 H), 6.66 (dd, J=7.7, 2.8 Hz, 1 H), 4.81 (s, 2 H), 3.97 (quin, J=7.3 Hz, 4 H), 3.84 (s, 3 H), 3.13 (d, J=21.2 Hz, 2 H), 1.18 (t, J=7.1 Hz, 6 H). MS (ES+): m/z 275.19 (100) [MH+]; HPLC: tR=0.81 min (UPLC, Analytical).