Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)[N:31]=1>O1CCCC1>[N:31]1[CH:30]=[CH:35][CH:34]=[CH:33][C:32]=1[C:36]1[N:37]=[C:38]([C:10]2[S:9][CH:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: c1ccc(-c2cscc2-c2ccccc2)cc1
Reactant: Brc1cccc(-c2ccccn2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(-c2csc(-c3cccc(-c4ccccn4)n3)c2-c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
After placing 3.5 g of 3,4-diphenylthiophene and 60 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 11 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 4.1 g of a zinc chloride/tetramethylethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 3.8 g of 2-bromo-6-(2-pyridyl)pyridine and 0.52 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, the organic layer was extracted, and the concentrate obtained using an evaporator was purified by recrystallization to obtain 4.5 g of 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene. After placing 3.3 g of the 2-(6-(2-pyridyl)-2-pyridyl)-3,4-diphenylthiophene and 80 ml of tetrahydrofuran in a flask and cooling to −30° C. in an argon atmosphere, 6.2 ml of a 1.5 mol/l concentration n-butyllithium/n-hexane solution was added dropwise. The mixture was stirred at −30° C. for 2 hours, and then 2.4 g of a zinc chloride/tetramethyl-ethylenediamine complex was added before raising the temperature to room temperature. After stirring for 30 minutes, 2.2 g of 2-bromo-6-(2-pyridyl)pyridine and 0.30 g of a palladium chloride/bistriphenylphosphine complex were added and the mixture was stirred for 2 hours at reflux temperature. After completion of the reaction, the product was cooled to room temperature, purified water was added, and the organic layer was extracted. The organic layer was concentrated with an evaporator and purified by column chromatography and recrystallization to obtain 1.1 g of BPPDPT.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:15](OC(=O)C)(=[O:17])[CH3:16].S(=O)(=O)(O)O>>[C:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Agent: O=S(=O)(O)O
Product: CC(=O)n1c2ccccc2c2cc(Br)ccc21

Procedure:
20 g of 3-bromocarbazole was converted to its acetyl derivative by refluxing with acetic anhydride (3 vol) with traces of conc. sulfuric acid. Aqueous workup yielded an off-white solid, which was then washed with n-hexane and dried under vacuum to obtain 23 g 9-acetyl-3-bromocarbazole, quantitatively. And N-acetyl derivative of carbazole, benzocarbaole and dibenzocarbazoles were prepared following the same procedure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Yield: 89.4 %

Procedure:
A solution of (R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-phenylpentanoic acid (2.2 g, 7.5 mmol) and 5% rhodium on carbon (0.22 g) in methanol (220 ml) was stirred at 20-25° C., under hydrogen (10 atmospheres, 150 p.s.i.) for 24 hours and then filtered through celite. The filtrate was concentrated in vacuo to leave the title compound as an oil (2.0 g, 89% yield, 95% pure by NMR).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([O:1][C@@H:2]1[C@H:3]([O:4][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@@H:5]([O:6][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:7]([O:8][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@@H:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[O:10]1)=[O:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
D-glucose (25.0 g, 0.139 mol) was suspended in anhydrous dichloromethane (416 mL) under nitrogen and the resulting mixture was stirred for 5 minutes at room temperature, then cooled to 0° C. and stirred for 10 minutes. To the resulting mixture was then added TEA (154.7 mL), dropwise over about 10-15 min, with stirring; then DMAP (1.25 g, 0.0102 mol) in one portion. To the resulting mixture was added pivaloyl chloride (136 mL) diluted with dichloromethane (83 mL) at 0° C., over 30 min. The ice bath was removed and the resulting mixture stirred at room temperature for 20 hours. The resulting mixture was then poured into dichloromethane (500 mL) and hydrochloric acid (1.5M, 375 mL) and the resulting phases separated. The organic layer was washed with sodium bicarbonate solution (550 g in 500 mL DI water, 1N) and then evaporated to a small volume. To the resulting residue was added ethanol (95%, 240 mL) and the mixture heated to reflux temperature to yield a homogeneous mixture. The resulting mixture was cooled to 0° C., resulting in the formation of white crystals, which were filtered and dried in vacuo at room temperature, overnight, to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[CH2:21][CH2:22]2)[CH:34]=[C:33]([O:46][CH3:47])[C:32]=1[OH:48]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CN1CCN(C2CCN(c3c(C(=O)C4CC4)cnc4ccc(Br)cc34)CC2)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(N5CCN(C)CC5)CC4)c3c2)cc(Cl)c1O
Yield: 48 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (102 mg, 0.225 mmol was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (42 mg, 0.150 mmol) to afford the desired product (16.8 mg, 48%) as an orange-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (2, 1H), 8.30 (d, J=1.4 Hz, 1H), 8.08-8.00 (m, 2H), 7.33 (d, 0.1=2.1 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 4.00 (s, 3H), 3.57 (d, J=12.9 Hz, 2H), 3.34 (s, 3H), 3.24-3.16 (m, 2H), 2.79-2.52 (m, 7H), 2.36 (s, 3H), 2.11 (d, J=11.3 Hz, 2H), 1.96-1.83 (m, 2H), 1.34-1.28 (m, 2H), 126-1.19 (m, 2H); ESI MS m/z 535 [C30H35ClN4O3+H]+; HPLC>99% (AUC), tR=10.13 min.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N+:14]([C:17]1[CH:18]=[C:19]2[O:24][CH2:23][CH2:22][N:21]3C([O:27][C:28]([C:30]([CH:31]=1)=[C:20]23)=O)=O)([O-:16])=[O:15].Cl>CN(C)C(=O)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[N:21]2[CH2:22][CH2:23][O:24][C:19]3[C:20]2=[C:30]([CH:31]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=3)[C:28]=1[OH:27])=[O:4])[CH3:7]
Reactant: O=c1oc(=O)n2c3c(cc([N+](=O)[O-])cc13)OCC2
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cc([N+](=O)[O-])cc3c2n(c1=O)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of diethyl malonate (0.54 g) in N,N-dimethylacetamide (10 ml) was added sodium hydride (60%; 135 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 3,4-dihydro-7-nitro-2H-1,4-benzoxazine-4,5-dicarboxylic anhydride (0.73 g), and the mixture was stirred at 120° C. for 2 hours. The mixture was poured into diluted HCl, and the precipitates were collected and washed with water to afford yellow crystals of 2,3-dihydro-6-ethoxycarbonyl-7-hydroxy-9-nitro-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (0.85 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])=[O:3].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)C>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]=1[OH:18])[CH:1]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccccc1)c1ccc(OCc2ccccc2)cc1O
Reaction time: 0.17 h
Yield: 166.8 %

Procedure:
17.63 g (72.6 mmoles) of 2-hydroxy-4-benzyloxyacetophenone, 17.60 g (165.8 mmoles) of benzaldehyde and 35.20 g of 50% strength sodium hydroxide solution in 200 ml of ethanol were stirred for 3 days, during which crystals precipitated. The crystal sludge was acidified with 100 ml of 5N hydrochloric acid and was stirred for 10 minutes. The mixture was filtered with suction to give 40.0 g of moist crystals. The crude product was recrystallized from 800 ml of ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:6]([CH:7]=[N:8][C@H:9]([CH2:15][F:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:5]([OH:18])=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[CH2:7][NH:8][C@H:9]([CH2:15][F:16])[CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC[C@@H](CF)N=Cc1cc(Cl)ccc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)CC[C@@H](CF)NCc1cc(Cl)ccc1O
Temperature: 25 °C

Procedure:
0.42 g of 18 dissolved in a small amount of ethyl alcohol was added drop-by-drop to a mixture of 0.06 g of sodium borohydride, 3.6 ml of ethyl alcohol and 0.9 ml of water, at 10° C. The resulting solution was stirred and allowed to warm to room temperature overnight. The resulting mixture was quenched with water, and the resulting mixture was extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and the solvent was evaporated to give 19, as an oily solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][OH:32])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:34](O)(=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].Cl.CN(C)CCCN=C=NCC.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH2:25][CH2:26][C:27](=[O:33])[N:28]5[CH2:31][O:32][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2N1CO
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)OCN1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution (20 ml) of 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-1-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (640 mg, 2.066 mmol) synthesized in the same manner as in Example 1, stearic acid (587 mg, 2.062 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (395 mg, 2.062 mmol) in methylene chloride was added 4-dimethylaminopyridine (33.6 mg, 0.275 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. This was purified by moderate-pressure silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and further by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 0:1) and concentrated under reduced pressure to give the title compound (yield 649 mg, 64.5%) as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:19]=1[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](O)=[O:27])[CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:6][CH2:7][N:2]([C:26]([C:23]3[CH:22]=[C:21]([CH2:20][C:19]4[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:18]=4[F:17])[O:25][N:24]=3)=[O:27])[CH2:3][CH2:4]2)=[CH:9]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cc2cc(F)ccc2F)on1)N1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
The mixture of 3-(piperidin-4-yl)-1H-indole hydrochloride (0.060 g; 0.253 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid (0.061 g; 0.253 mmol), HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.096 g: 0.253 mmol) and N,N-diisopropylethylamine (0.110 mL; 0.634 mmol) in DMF (3 mL) was stirred for 72 hours at room temperature and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 0 to 10% of ethyl acetate in dichloromethane) to give 0.069 g (65%) of (4-(1H-indol-3-yl)piperidin-1-yl)(5-(2,5-difluorobenzyl)isoxazol-3-yl)methanone as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.[C:26]([C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1)#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([C:34]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]34[O:16][CH2:15][CH2:14][C@H:13]3[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:9]4)[CH:7]=2)=[O:35])=[N:32][CH:33]=1)#[N:27]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(C#N)cn4)ccc3F)OCC[C@H]2CS1
Yield: 41 %

Procedure:
A solution of (±)-tert-butyl (4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate from step G of Preparation 1 (9 mg), 5-cyanopicolinic acid (6 mg), HATU (14 mg), and DIEA (11 μL), in DMF (0.12 mL) was stirred at rt for 2 h, and the crude reaction mixture was subjected to preparative HPLC eluting with 0-100% B (A: 95% H2O/5% MeCN, 10 mM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 12 min period to give the title compound as a white foam (5 mg, 41%). 1H NMR (500 MHz, CDCl3) δ 9.90 (1H, s), 8.94 (1H, s), 8.45 (1H, d, J=8.0 Hz), 8.24 (1H, dd, J=2.0, 8.5 Hz), 8.03 (1H, m), 7.72 (1H, m), 4.10-4.25 (2H, m), 3.32 (1H, m), 3.02 (1H, m), 2.90 (1H, m), 2.42 (1H, m), and 2.23 (1H, m) and 1.51 (9H, s). MS (M+H)+: 498.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:6]3[N:7]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CCC(=O)Cl
Reactant: Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1nnc2c3c(c(N4CCOCC4)nn12)CCCC3
Yield: 76.3 %

Procedure:
To a solution of 5.80 gm (0.0211 mole) of the compound of Example 15 in 50 ml of CH2Cl2 was added 3.03 g (0.03 mole) of triethylamine, 384 mg (0.003 mole) of 4-dimethylaminopyridine and 2.78 g (0.03 mole) of propionyl chloride. The mixture was heated at reflux for 15 hours, cooled, and partitioned between CH2Cl2 and aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give a thick oil which crystallized on trituration with toluene-hexane. The resulting white solid was collected to give 5.32 gm of N-(7,8,9,10-tetrahydro-6-(4-morpholinyl)-1,2,4-triazolo [3,4-a]phthalazin3-yl)propanamide; mp 164-166° C. (ethanol-ether). Calculated: C, 58.16; H, 6.71, N, 25.44. Found: C, 58.17; H, 6.70; N, 25.67.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][CH2:6]O.S(Cl)([Cl:15])=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][CH2:6][Cl:15]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CCO)cc1O
Solvent: ClCCl
Product: COc1ccc(CCCl)cc1O
Yield: 33 %

Procedure:
A mixture of 3-hydroxy-4-methoxyphenethyl alcohol (2.25 g) and thionyl chloride (5 ml) in methylene chloride (120 ml) was heated under reflux for 16 hours and evaporated. The residue was azeotroped twice with hexane and purified by chromatography on silica (30 g) using methylene chloride plus 0-6% methanol as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless solid (0.82 g, 33%), m.p. 53°-54°, which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[N:5][N:4]=1)[CH3:2].[CH:16]([Cl:19])([Cl:18])[Cl:17].[OH-].[K+]>CN(C=O)C.CO>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:12]([C:11]1[CH:14]=[CH:15][C:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)=[CH:9][CH:10]=1)[OH:13]
Reactant: ClC(Cl)Cl
Reactant: CCc1nnc(-c2ccc(C=O)cc2)o1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1nnc(-c2ccc(C(O)C(Cl)(Cl)Cl)cc2)o1
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-(5-ethyl-1,3,4-oxadiazol-2-yl)benzaldehyde (1.6 g, 7.9 mmol) in anhydr DMF (7 mL) was added CHCl3 (2.13 g, 17.8 mmol). After cooling to −10° C., a solution of KOH (0.31 g, 5.5 mmol) in anhydr MeOH (1.5 mL) was added dropwise over 20 min. After stirring at −10° C. for 1 hr, the reaction mixture was quenched with 1 M HCl. The solid formed was collected on a Büchner, washed with H2O and dried under vacuum to give 2,2,2-trichloro-1-(4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)ethanol as a white solid (2.0 g, 80% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:31])[S:27][CH2:26][NH:25][C@@H:24]1[C:28]([NH2:30])=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[C@H:24]([C:28]([NH2:30])=[O:29])[C:23]([CH3:31])([CH3:22])[S:27][CH2:26]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)SCN[C@@H]1C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)SCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)[C@@H]1C(N)=O

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (R)-5,5-dimethylthiazolidine-4-carboxamide hydrochloride in the presence of TBTU and DIEA to obtain the title compound as light yellow solid; MS (EI): m/e=427.4 [MH+].
Reaction SMILES: O.[NH2:2][NH2:3].O=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH2:14][C:15]([OH:17])=O>C(O)C>[N:2]1[NH:3][C:15](=[O:17])[CH2:14][CH:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=12
Reactant: NN
Reactant: O=C(O)CC1Cc2ccccc2C1=O
Solvent: O
Solvent: CCO
Product: O=C1CC2Cc3ccccc3C2=NN1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of 0.53 g (0.011 mol) of hydrazine hydrate dissolved in 25 mL ethanol was added 1.2 g (0.0089 mol) of the product from step B. The reaction mixture was refluxed for 18 hours, cooled to room temperature, concentrated under vacuum, added 100 mL H2O and extracted with ethyl acetate (3×50 mL), washed with brine (1×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 1.0 g of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[N:11][C:10]=1[O:18][CH2:19][CH2:20][O:21][CH3:22].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:35][CH2:36][C:37]([CH:40]1[CH2:42][CH2:41]1)([OH:39])[CH3:38]>CN(C)C=O>[CH:40]1([C:37]([OH:39])([CH3:38])[CH2:36][NH:35][C:15]([C:13]2[CH:12]=[N:11][C:10]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:14]=2)=[O:17])[CH2:42][CH2:41]1
Reactant: CC(O)(CN)C1CC1
Reactant: COCCOc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COCCOc1ncc(C(=O)NCC(C)(O)C2CC2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
To a solution of 0.030 g (0.0009 mol) of 6-(2,4-dichloro-phenyl)-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid in 2.0 ml dimethylformamide was added at room temperature 0.029 g (0.0018 mol) of 1,1′-carbonyldiimidazole and the mixture was stirred at room temperature for 1 hour. To the resulting brown solution was added 0.020 g (0.0018 mol) 1-amino-2-cyclopropyl-propan-2-ol and the mixture was stirred for 3 hours. The reaction mixture was then partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic layer washed with 10% aqueous sodium bicarbonate and brine dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel using a gradient of heptane to ethyl acetate to yield 0.021 g of the title compound as colorless oil. MS (ISP) (M+H+)=440.4.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:19][CH2:18][S:17][CH:16]2[C:20]([OH:22])=O)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[NH2:23][C@H:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][C@H:24]([NH:23][C:20]([C@H:16]1[N:15]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([C:1]([CH2:4][CH3:5])([CH3:3])[CH3:2])=[CH:11][CH:10]=2)(=[O:13])=[O:14])[CH2:19][CH2:18][S:17]1)=[O:22])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: N[C@@H](CCO)c1ccccc1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)N2CCSC2C(=O)O)cc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)N2CCS[C@H]2C(=O)N[C@@H](CCO)c2ccccc2)cc1

Procedure:
Following the general strategies and protocols outlined in Example 1, starting from 3-[(4-tert-pentylphenyl)sulfonyl]-1,3-thiazolidine-2-carboxylic acid (Intermediate 8) and commercial (3S)-3-amino-3-phenyl-1-propanol, the title compound was obtained in 99% purity by HPLC.