Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13].[CH3:29]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:29][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]2[C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[N:24][C:23]=3[CH:17]2[CH2:16]1)(=[O:14])=[O:13]
Reactant: CB1OB(C)OB(C)O1
Reactant: O=C1c2cccnc2C2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3Br)CCN12
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: [K+]
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN2C(=O)c3cccnc3C2C1
Temperature: 90 °C
Yield: 55.9 %

Procedure:
A mixture of 9-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-a]pyrazin-5(7H)-one (265 mg; may be prepared as described in Intermediate 24), trimethylboroxin (182 mg), potassium carbonate (200 mg) and Pd(PPh3)4 (109 mg) was heated to 90° C. under argon for 6 hours. The reaction mixture was partitioned between EtOAc and saturated sodium bicarbonate solution, and then the aqueous was re-extracted with EtOAc. The combined organic phases were washed with brine, dried through a hydrophobic frit and evaporated to a brown oil (335 mg). The residue was purified by chromatography eluting with 0-90% ethyl acetate in iso-hexane over 12 column volumes. The desired fractions were combined and evaporated to give the title compound as a pale yellow crystalline solid (128 mg).
Reaction SMILES: [BH4-].[Na+].C(O)C.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](OCC)=[O:16])=[C:9]([N+:25]([O-])=O)[CH:8]=1>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15](=[O:16])[NH:25]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(=Cc1ccc(Cl)cc1[N+](=O)[O-])C(=O)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1Cc2ccc(Cl)cc2NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
Sodium borohydride (2.082 g) was added to an ethanol (200 ml) solution of diethyl 2-[(4-chloro-2-nitrophenyl)methylidene]malonate(34.92 g). The reaction mixture was stirred at 0° C. for one hour, to which was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. Iron (26.70 g) was added to an aqueous acetic acid (300 ml) solution of the residue, which was heated under reflux. The reaction mixture was left standing for cooling, and ethyl acetate (300 ml) was added to the reaction mixture. The precipitated insoluble substances were removed by filtration and the filtrate was concentrated. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried and concentrated. The obtained crude crystals were washed with IPE to give the entitled compound (14.50 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:15]1([CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:5]2[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(O)CCNC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (50 L). To the resulting mixture was slowly added a solution of diphenylbromomethane (1.78 g, 7.2 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=30:1 (volumetric ratio)) to produce 1-(diphenylmethyl)-3-methylpyrrolidin-3-ol (1 g) in a yield of 52.0%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([F:23])[F:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([F:23])[F:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)F)C2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc(Br)cc1N(CC(F)F)C1CCOCC1
Temperature: 50 °C
Reaction time: 7 h
Yield: 92.7 %

Procedure:
To a stirred solution of methyl 5-bromo-3-[(2,2-difluoroethyl)(oxan-4-yl)amino]-2-methylbenzoate (571 mg, 1.5 mmol) in a mixture of THF (14.6 ml) and MeOH (2.2 ml), was added 4M NaOH (14.6 ml). The reaction mixture was stirred at 50° C. for 7 hours. The heat was switched off and the reaction mixture was stirred at room temperature for 16.5 hours. THF was removed in-vacuo and the aqueous residue was acidified to pH 4 by the addition of 6M HCl (aq) (10 ml) with ice cooling. The resulting solid was collected by filtration and washed with water (20 ml), dried in-vacuo at 30-40° C. for 3 hours to give the title compound (526 mg, 96%) as a light beige solid. LC-MS 100%, 1.98 min (3.5 minute LC-MS method), m/z=377.9, 378.9, 379.9, 380.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.91 (d, J=1.58 Hz, 1H) 7.49 (d, J=1.58 Hz, 1H) 5.43-5.75 (m, 1H) 4.01 (dd, J=11.43, 3.55 Hz, 2H) 3.42 (td, J=13.95, 3.78 Hz, 2H) 3.32 (t, J=11.35 Hz, 2H) 2.98 (tt, J=11.37, 3.53 Hz, 1H) 2.52 (s, 3H) 1.77 (d, J=10.88 Hz, 2H) 1.56-1.69 (m, 2H). OH not visible.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7](I)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1c(I)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1ccncc1
Product: O=C(c1c(-c2ccncc2)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-cyclopropyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 63) was reacted with pyridine-4-yl-boronic acid to give the title compound as light brown oil. MS: 510.3 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[N+:8]([C:11]1[CH:12]=[C:13]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]([CH3:7])([C:3]([NH:20][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:19])=[O:18])=[O:4])[CH3:6]
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.2 %

Procedure:
To a mixture of trimethylacetic acid (5.55 g, 54 mmol), 3-nitrobenzenesulphonamide (11 g, 54 mmol) and 4-dimethylaminopyridine (6.65 g, 54 mmol) in anhydrous dichloromethane (400 ml), under an atmosphere of nitrogen, was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (10.43 g, 54 mmol). The mixture was stirred at ambient temperature for 24 h. The mixture was extracted with 1M NaOH (50 ml) and the separated aqueous phase was mixed with dichloromethane (200 ml) and acidified with 5M HCl. The two layers were separated and the aqueous phase was further extracted with dichloromethane (2×100 ml). The combined organic phases were dried (Na2SO4) and evaporated to dryness. The resultant solid was recrystallised from methanol to afford the title compound (9 g, 58%) as a colourless solid. mp 178°-81° C. 1H NMR (360 MHz, D6-DMSO) δ 1.07 (9H, s), 7.95 (1H, t, J=8.0 Hz), 8.30-8.34 (1H, m), 8.52-8.56 (1H, m), 8.57-8.60 (1H, m), 12.02 (1H, brs).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:13][CH3:14])[CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.[N+]([O-])(O)=O.[Br:19]Br>O.[N+]([O-])([O-])=O.[Ag+]>[Br:19][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[CH2:3][CH:2]([CH3:1])[CH2:13][CH3:14])[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: CC[C@H](C)Cc1ccc(C(=O)O)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCC(C)Cc1ccc(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.1 %

Procedure:
A solution of silver nitrate (177 g, 1.1 mol) in water (500 ml) was dropwise added to a solution in water (500 ml), of a mixture of (S)-4-(2'-methylbutyl)benzoic acid (200 g, 1.0 mol), nitric acid (680 ml) and bromine (183 g, 1.1 mol), under ice-cooling, followed by agitating the mixture at room temperature for 5 hours, feeding it into ice water, filtering deposited crystals, adding a 10% sodium carbonate aqueous solution (2 l), sufficiently agitating the mixture, filtering off a remaining insoluble substance, acidifying the filtrate with sulfuric acid, filtering deposited crystals and recrystallizing from acetic acid (1 l) to obtain 3-bromo-4-(2'-methylbutyl)benzoic acid (106.0 g, m.p. 78.8°-79.7° C.).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].FC(F)(F)S(O[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.O>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]=2)=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C=O)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 88.2 %

Procedure:
To 400 mg (2.67 mmol) of 4-formyl-phenylboronic acid diluted in a dimethoxyethane/water mixture (40 ml/4 ml) are respectively added 1.33 g (5.78 mmol) of tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate, 154 mg (0.133 mmol) of palladium tetrakistriphenylphosphine and 1.74 g (5.34 mmol) of cesium carbonate. The solution is purged under argon then stirred at 80° C. for 18 h and filtered on Celite with ethyl acetate. The filtrate is washed with water, then with sodium chloride saturated solution, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 85:15 to 70:30) to yield 677 mg of tert-butyl 4-(4-formylphenyl)-5,6-dihydropyridine-1(2H)-carboxylate in the form of a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:9]([O-])(=[O:11])[CH3:10].[Na+]>C(OC(=O)C)(=O)C>[C:9]([O:8][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])(=[O:11])[CH3:10]
Reactant: CC(=O)[O-]
Reactant: CCCCCC(C)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCCCCC(C)OC(C)=O
Yield: 67 %

Procedure:
2-Heptanol (162 g, 1.4 mol, Aldrich) and sodium acetate (16 g, Aldrich) were heated to 100° C. and then acetic anhydride (190 ml, BDH GPR) was added over a 1 hour period at 100-130° C. The mixture was heated to reflux for 3 hours. The reaction mixture was then cooled, washed with water, washed with aqueous sodium bicarbonate to neutrality, dried over sodium sulfate, and then concentrated. Fractional distillation of the crude residue under vacuum provided 1-methylhexyl acetate (107-108°/95-100 mm Hg, 67% yield), the structure of which was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy, and infra red spectroscopy (not shown).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:20][O:19]3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([Mg]Cl)=[CH2:22]>C1COCC1.[Cu]I>[C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]([OH:19])[CH2:20][CH:21]=[CH2:22])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc([C@@H]3CO3)oc2-c2ccccc2)cc1
Reactant: C=C[Mg]Cl
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@H](O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-(4,5-diphenyloxazol-2-yl)oxirane (12 g) and CuI (0.19 g) in THF (240 ml) was dropwise added a solution of vinylmagnesium chloride in THF (1.0M solution, 101 ml) at −78° C. under N2. The mixture was stirred for 1 hour at room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (4S)-4-(4,5-diphenyloxazol-2-yl)-4-hydroxy-1-butene (9.2 g).
Reaction SMILES: CCCC1N(CC2C=CC(C3C(C4N([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)N=NN=4)=CC=CC=3)=CC=2)C(C(OCC2OC(=O)OC=2C)=O)=C(C(O)(C)C)N=1.[OH2:61]>>[C:28]1([C:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[OH:61])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O
Product: OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Reaction temperature at which deprotection of trityl Olmesartan medoxomil takes place is preferable at about 0° C. to 60° C. more preferably at 10° C. to 30° C. In another preferred embodiment the combination of trityl Olmesartan medoxomil, water-immiscible organic solvent and acid is maintained for about 1 to 6 hours and more preferably 2 to 4 hours. Triphenyl carbinol formed dissolves in solvent toluene and the deprotected Olmesartan medoxomil is in aqueous solution. Both the layers are separated. Aqueous layer is washed with toluene and the pH of the aqueous layer is adjusted to about 5 to 6 using a base. Suitable bases include but are not limited to, alkali and alkaline earth metal hydroxides, carbonates, and hydrogen carbonate salts. Specific exemplary bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and calcium carbonate. Potassium carbonate and sodium bicarbonate are preferred. After contacting the solution with the base, the solution is extracted with ethyl acetate twice. Combined ethyl acetate layers are washed with 5% sodium chloride solution. Olmesartan medoxomil is obtained by distillation of the solvent.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[CH:9]=[N:8][CH:7]=[C:6]([N:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:20])[CH:17]=4)[C:12]3=[O:21])[C:5]=2[CH2:4][CH2:3]1.CCN(CC)CC.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:21])[N:11]([C:6]1[C:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:29](=[O:31])[CH3:30])[C:10]=3[CH:9]=[N:8][CH:7]=1)[CH2:19]2
Reactant: NC1CCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a stirred solution of 2-(7-amino-6,7-dihydro-5H-[2]pyrindin-4-yl)-5-chloro-2,3-dihydro-isoindol-1-one (126 mg, 0.42 mmol) and Et3N (1.0 mL) in DCM (10 mL) was added acetyl chloride (0.032 mL, 0.44 mmol) at 0° C. and stirred at 0° C. for 1 hour. The resulting mixture was extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give a racemic mixture of title compound (121 mg, 85%) as light yellow solid. MS: 342.1 (M+H+). This racemic mixture was then separated by chiral HPLC to afford (−)-N-[(S or R)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide (33 mg, example 318), MS: 342.1 (M+H+) and (+)-N—[(R or S)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide (27 mg, example 319). MS: 342.1 (M+H)+.
Reaction SMILES: [N:1]([C:4]1([CH2:19][OH:20])[O:8][CH:7]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]([OH:17])[CH:5]1[OH:18])=[N+:2]=[N-:3].CO[C:23](OC)([CH3:25])[CH3:24].S(O)(C)(=O)=O.C(N(CC)CC)C>CC(C)=O>[N:1]([C:4]1([CH2:19][OH:20])[CH:5]2[O:18][C:23]([CH3:25])([CH3:24])[O:17][CH:6]2[CH:7]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[O:8]1)=[N+:2]=[N-:3]
Reactant: COC(C)(C)OC
Reactant: [N-]=[N+]=NC1(CO)OC(n2ccc(=O)[nH]c2=O)C(O)C1O
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OC2C(n3ccc(=O)[nH]c3=O)OC(CO)(N=[N+]=[N-])C2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Compound 48.2 (1.81 g, 6.35 mmol) was dissolved in 60 mL acetone, treated with 2,2-dimethoxypropane (60 mL) and MsOH (1.23 mL, 19.09 mmol). The mixture was stirred at rt for overnight. Triethylamine was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was partitioned between CHCl3 and water; the organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in EtOAc to give compound 48.3 (2.12 g, 100% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:8]=2[N:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[S:6]1(=[O:24])=[O:23].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.Cl>>[F:15][C:12]1[CH:13]=[CH:14][C:8]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[S:6](=[O:24])(=[O:23])[N:5]([CH2:4][CH2:3][CH2:2][NH:28][CH:25]3[CH2:27][CH2:26]3)[CH2:10][C:9]=2[CH:11]=1
Reactant: O=S1(=O)N(CCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Reactant: NC1CC1
Agent: Cl
Product: O=S1(=O)N(CCCNC2CC2)Cc2cc(F)ccc2N1c1ccccc1F
Yield: 96 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(3-bromopropyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to cyclopropylamine and then treated with HCl to provide N-{3-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]propyl}cyclopropanamine (0.102 g, 96%) as a white solid:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[CH3:17])[CH3:2].[CH2:19](OC(=O)COC1C=C(C)C=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:19])[C:10]([S:13]([Cl:16])(=[O:14])=[O:15])=[CH:9][C:8]=1[CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Reactant: CCOC(=O)COc1cc(C)ccc1C
Product: CCOC(=O)COc1cc(C)c(S(=O)(=O)Cl)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.2, using compound 21.1 as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.86 (1H, s); 6.61 (1H, s); 4.74 (2H, s); 4.30 (2H, q, J=7.1 Hz); 2.71 (3H, s); 2.31 (3H, s); 1.32 (3H, t, J=7.1 Hz).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[O:8]1CC[CH2:10][CH2:9]1>>[C:1]([CH:4]([C:9](=[O:8])[CH3:10])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)CC(C)=O
Reactant: C1CCOC1
Product: CC(=O)C(C(C)=O)C(C)=O

Procedure:
Gaseous acetyl fluoride is bubbled into a suspension of 30.0 g. (0.1 mole) of the thallous salt of acetylacetone in 150 ml. of dry tetrahydrofuran, under nitrogen, at a rate of 3.0 cc./minute for a total of 30 minutes. After filtration through Celite, the solution is concentrated and the residue distilled to give 13.5 g. (96%), b.p. 90°-95°/1.0 mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]([NH2:11])=[O:10].[CH2:12](OC(OCC)OCC)C>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:12]=[N:11][C:9]([OH:10])=[N:8]1
Reactant: CCOC(OCC)OCC
Reactant: NC(=O)NNc1ccccn1
Solvent: CCO
Product: Oc1ncn(-c2ccccn2)n1
Temperature: 15 °C

Procedure:
A mixture of 31.9 g (0.21 m) of 2-pyridinylhydrazinecarboxamide and 17.50 ml of triethylorthoformate was refluxed for 6 hours with the ethanol formed as a by-product being continuously removed by distillation thereby maintaining the reaction temperature at 130°-140° C. At the completion of the reaction, the reaction mixture was cooled to 15° C. and the solid 1-(2-pyridinyl)-1H-1,2,4-triazol-3-ol product was recovered by filtration. The product after washing with methylene chloride was recovered in a yield of 25.2 g (74 percent of theoretical). The product melted at 260°-262° C. and upon analysis was found to have carbon, hydrogen, and nitrogen contents of 52.26, 3.90 and 34.79 percent, respectively, as compared with the theoretical contents of 51.89, 3.73 and 34.55 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[C:36]([O:35][C:33]([N:27]1[CH2:32][CH2:31][N:30]([CH2:12][C:9]2[C:10](=[O:11])[N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[CH:8]=2)[CH2:29][CH2:28]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 98.9 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a pale brown oil (yield: 98.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][N:35]=2)[N:14]=1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc([N+](=O)[O-])cn3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Reaction of tert-butyl 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate and 2-(2-aminoethylamino)-5-nitropyridine gave tert-butyl 4-(2,4-dichlorophenyl)-2-({2-[(5-nitro(2-pyridyl))-amino]ethyl}amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.