Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC=CC=1CN1C=C(C2C3C(=NC=C(C4C=C(NS(C)(=O)=O)C=CC=4)C=3)NC=2)C=N1.Br[C:35]1[CH:36]=[C:37]2[C:43]([C:44]3[C:45]([CH3:58])=[N:46][N:47]([CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[CH:52]=4)[C:48]=3[CH3:49])=[CH:42][N:41]([S:59]([C:62]3[CH:68]=[CH:67][C:65]([CH3:66])=[CH:64][CH:63]=3)(=[O:61])=[O:60])[C:38]2=[N:39][CH:40]=1.[CH3:69][N:70]([CH3:95])[CH2:71][CH2:72][CH2:73][O:74][C:75]1[CH:80]=[CH:79][C:78](B2OC(C)(C)C(C)(C)O2)=[CH:77][C:76]=1[NH:90][S:91]([CH3:94])(=[O:93])=[O:92].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:95][N:70]([CH3:69])[CH2:71][CH2:72][CH2:73][O:74][C:75]1[CH:80]=[CH:79][C:78]([C:35]2[CH:36]=[C:37]3[C:43]([C:44]4[C:45]([CH3:58])=[N:46][N:47]([CH2:50][C:51]5[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[CH:52]=5)[C:48]=4[CH3:49])=[CH:42][N:41]([S:59]([C:62]4[CH:63]=[CH:64][C:65]([CH3:66])=[CH:67][CH:68]=4)(=[O:60])=[O:61])[C:38]3=[N:39][CH:40]=2)=[CH:77][C:76]=1[NH:90][S:91]([CH3:94])(=[O:93])=[O:92]
Reactant: CN(C)CCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(Br)cnc32)cc1
Agent: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5ccccc5F)c4)c3c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCN(C)C)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 13.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example 1, 5-bromo-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step-i of example-14) (250 mg, 0.4 mmol) was coupled with N-(2-(3-(dimethylamino)propoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (intermediate-30) (200 mg, 0.5 mmol) in sodium carbonate (154 mg, 1.4 mmol) PdCl2(dppf) (18 mg, 0.05 mmol), 1,2-dimethoxyethane/water (2/2 mL) to afford 40 mg (12% yield) of the titled compound after purification by preparative TLC (SiO2)-eluted by 30% ethyl acetate in hexane.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Reactant: C1COCCN1
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of ethyl 6-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (4.0 g, 11 mmol) in morpholine (7 mL) was heated at reflux for three days, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane; the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to provide 4.4 g of 2-(ethoxymethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1>[Br:20][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2ccccc12
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
1-Naphthalene methanol (2.0 g, 12.7 mmol) was dissolved in toluene (30 mL) and pyridine (1.02 mL, 12.7 mmol) was added. The solution was cooled to 0° C. PBr3 (1.19 mL, 12.7 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The mixture was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to give 1-(bromomethyl)naphthalene (1.5 g, 53%) as a colourless oil, This intermediate was used in the following reaction. Sodium ethoxide (169 mg, 2.49 mmol) was added to DMF (5 mL) at 0° C., and the suspension was stirred for 10 min. 7-hydroxy-4-methylcoumarin (438 mg, 2.49 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h, then allowed to reach room temperature. To this mixture 1-(bromomethyl)naphthalene (500 mg, 2.26 mmol) was added portionwise. Resulting reaction mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue was taken up in EtOAc, and washed with brine (2×50 mL), water (2×50 mL) and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and product was purified by flash chromatography, eluting with hexane:EtOAc (2:1) to give 43 (200 mg, 28%) as a white solid. Mpt=181-183° C. H1 NMR (500 MHz, acetone-d6): δ=8.10 (1H, d, ArH), 8.00-7.99 (2H, m, Ar), 7.97-7.71 (2H, m, ArH), 7.70-7.53 (3H, m, ArH), 7.24 (1H, s, ArH), 7.09 (1H, d, CH), 6.23 (1H, s, CH), 5.68 (2H, s, CH2), 2.40 (3H, s, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:19]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>O1CCOCC1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Reactant: CB(O)O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ccc(C)cn2)c1C
Temperature: 0 °C
Yield: 88.8 %

Procedure:
A suspension of 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (4 g) in Reference Example 24 (2), methylboronic acid (1.54 g), 1,1′-bis(di-tert-butylphosphino)ferrocene (306 mg), palladium acetate (145 mg) and tripotassium phosphate (11 g) in 1,4-dioxane (30 ml) was stirred under reflux. After completion of the reaction, the mixture was allowed to cool, ice water and a saturated aqueous solution of ammonium chloride were added thereto, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 5-methyl-1-(5-methylpyridin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (2.81 g) as a white solid. MS (ESI) m/z: 246 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[OH:41][CH2:40][C:39]([NH:38][S:35]([C:31]1[CH:30]=[C:29]([NH:28][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:21])[F:20])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:11])[F:10])=[C:2]([CH3:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])([CH3:43])[CH3:42]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Yellow solid. MS (ISP) 614.2 [(M−H−]; mp 230° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:8])[NH:6][CH:7]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5](=[O:8])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Br)c[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A round bottom flask was charged with methyl 5-bromo-2-oxo-1,2-dihydropyridine-3-carboxylate (0.500 g, 2.2 mmol), phenylboronic acid (0.66 g, 5.4 mmol), and copper(II) acetate (0.78 g, 4.3 mmol). Dichloromethane (25 mL) was added, followed by 4 A molecular sieves (500 mg, activated) and pyridine (0.70 mL, 8.6 mmol). The reaction mixture was stirred overnight at room temperature in the presence of air. The reaction mixture was diluted with dichloromethane and filtered through a small pad of Celite, washing well with dichloromethane. The filtrate was concentrated under vacuum. The remaining residue was purified by silica gel chromatography (1% methanol/dichloromethane) to give methyl 5-bromo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate as a yellow foam/oil (0.655 g, 1.9 mmol, 89% yield). MS (ESI pos. ion) m/z: 309 (MH+). Calc'd exact mass for C13H10BrNO3: 308.
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][C@@H:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([N:40]2[CH2:44][CH2:43][C@@H:42]([NH:45][C:46]([NH:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=4)=[O:47])[CH2:41]2)=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:13]([OH:56])[C@@H:12]1[OH:57])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][C@H:11]1[CH2:15][C@@H:14]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([N:40]2[CH2:44][CH2:43][C@@H:42]([NH:45][C:46]([NH:48][CH2:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=4)=[O:47])[CH2:41]2)=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:13]([OH:56])[C@@H:12]1[OH:57]
Reactant: O=C(NCc1ccccn1)N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)OCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Agent: [Pd]
Solvent: CCO
Product: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)NCc5ccccn5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ((1S,2R,3S,4R)-4-{6-(2,2-diphenyl-ethylamino)-2-[(R)-3-(3-pyridin-2-ylmethyl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-carbamic acid benzyl ester (0.13 g, 166 μmol) in ethanol (9 ml) under an inert atmosphere of Argon is treated with Palladium (10% on charcoal) (44 mg). The reaction mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight and then filtered through Celite™. The filtrate is concentrated in vacuo to afford the title compound. (MH+ 649.89)
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=2)=[O:24])[O:5][C@@H:4]([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:3]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)C[C@@H]2F)cc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2',3'-dideoxy-3'-fluorouridine (1 g, 4.34 mmoles) in dry pyridine (25 ml) at 0° C. was slowly added freshly distilled p-toluoyl chloride (0.63 ml, 4.78 mmoles). After the addition was complete, the mixture was stirred at 50° C. for 1.5 hrs., cooled and the solvent removed under reduced pressure. The residue was dissolved in chloroform (35 ml) and the solution extracted with 1M sulphuric acid (2×20 ml), water (2×30 ml) and dried (sodium sulphate). Evaporation of the solvent and purification of the residue by silica column chromatography eluting with 5% MeOH/CH2Cl2 afforded the title compound.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][O:20][C:21]([CH2:23]P(=O)(OCC(F)(F)F)OCC(F)(F)F)=[O:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:48][C:49]([Si:52]([CH3:92])([CH3:91])[O:53][CH:54]([CH:59]([CH3:90])[CH:60]=[C:61]([CH3:89])[CH2:62][CH:63]([CH3:88])[CH:64]([O:80][Si:81]([C:84]([CH3:87])([CH3:86])[CH3:85])([CH3:83])[CH3:82])[CH:65]([CH3:79])[CH:66]([OH:78])[CH:67]([CH3:77])[CH2:68][O:69][CH2:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[CH:55]([CH3:58])[CH:56]=O)([CH3:51])[CH3:50].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH3:19][O:20][C:21](=[O:22])/[CH:23]=[CH:56]\[C@H:55]([CH3:58])[C@H:54]([O:53][Si:52]([C:49]([CH3:51])([CH3:50])[CH3:48])([CH3:92])[CH3:91])[C@@H:59]([CH3:90])/[CH:60]=[C:61](/[CH3:89])\[CH2:62][C@H:63]([CH3:88])[C@@H:64]([O:80][Si:81]([C:84]([CH3:85])([CH3:86])[CH3:87])([CH3:83])[CH3:82])[C@H:65]([CH3:79])[C@@H:66]([OH:78])[C@@H:67]([CH3:77])[CH2:68][O:69][CH2:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1
Reactant: CC(=CC(C)C(O[Si](C)(C)C(C)(C)C)C(C)C=O)CC(C)C(O[Si](C)(C)C(C)(C)C)C(C)C(O)C(C)COCc1ccccc1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C\[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C(/C)C[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](C)[C@@H](O)[C@@H](C)COCc1ccccc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
18-Crown-6 (349 mg, 1.32 mmol, 2 eq) is added to a solution of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (355 mg, 1.78 mmol, 2.7 eq) in toluene (7 mL) at 23° C. and stirred for 5 min. The mixture is cooled to −20° C. KHMDS (1.78 mmol, 2.7 eq, 0.5 M in toluene) is added dropwise and stirred for 30 min. The mixture is warmed to 0° C. and stirred for 30 min. Then the mixture is cooled to −20° C., a solution of crude (2R,3R,4S,5Z,8S,9R, 10R, 11 S,12S)-3,9-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-11-hydroxy-2,4,6,8,10,12-hexamethyl-13-(phenylmethoxy)-5-tridecenal in toluene (3 mL) is added to the mixture and stirred for 5 min. The mixture is warmed to 0° C. and stirred for 4 h. Saturated NH4Cl (15 mL) is added, and the resultant mixture is washed with brine, dried and concentrated. The crude product is chromatographed (10% EtOAc in hexane) to give 266 mg (two-step: 52%) of the desired compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1>CO>[CH3:11][C@@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: C[C@@H]1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CO
Product: C[C@@H]1COCCN1c1ccc([N+](=O)[O-])cn1
Temperature: 150 °C
Yield: 77.6 %

Procedure:
A mixture of 1 g (6.18 mmol) of 2-chloro-5-nitropyridine and 1.31 g (12.36 mmol) of (R)-3-methylmorpholine is heated in a Biotage microwave machine for 1 hour at 150° C. The reaction medium is taken up in MeOH and then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to (95/5 v/v) to give 1.07 g of (R)-3-methyl-4-(5-nitro-pyridin-2-yl)-morpholine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]2[O:16][CH2:17][CH2:18][O:19][C:14]=2[CH:13]=1)=O)C>C1COCC1>[O:16]1[C:15]2[CH:20]=[CH:21][C:12]([CH2:10][OH:9])=[CH:13][C:14]=2[O:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ccc2c(c1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a suspension of LiAlH4 (2.8 g, 74 mmol) in THF (20 mL) was added dropwise a solution of 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid ethyl ester (15 g, 72 mmol) in THF (10 mL) at 0° C. under N2 atmosphere. The mixture was stirred at room temperature for 1 h and then quenched carefully by addition of water (2.8 mL) and NaOH (10%, 28 mL) with cooling. The precipitated solid was filtered off and the filtrate was evaporated to dryness to yield (2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanol (10.6 g) that was taken into the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 6.73-6.78 (m, 3H), 5.02 (t, J=5.7 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 4.17-4.20 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[C:15](OC)=O.FC(F)(F)S(OC1C=CC(C(=O)C)=CC=1C#[N:35])(=O)=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[C:15]#[N:35]
Reactant: COC(=O)c1cc(C(C)=O)ccc1-c1ccco1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Product: CC(=O)c1ccc(-c2ccco2)c(C#N)c1

Procedure:
The title compound was prepared according to the procedure for preparation of 4-(2-furyl)-3-(methoxycarbonyl)phenyl-1-ethanone using 2-Cyano-4-acetylphenyl trifluoromethanesulfonate instead of 2-Methoxycarbonyl-4-acetylphenyl trifluoromethanesulfonate.
Reaction SMILES: C(OC([O:11][C@@H:12]([C@@H:14]1[C@@H:17]([C@H:18]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[CH3:19])[N:16]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:15]1=[O:38])[CH3:13])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:11][C@@H:12]([C@@H:14]1[C@@H:17]([C@H:18]([C:20]([OH:22])=[O:21])[CH3:19])[N:16]([CH2:30][C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:15]1=[O:38])[CH3:13]
Reactant: C[C@@H](OC(=O)OCc1ccccc1)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](O)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=O)O

Procedure:
A solution of (3S,4S)-3-[(1R)-1-benzyloxycarbonyloxyethyl]-4-[(1R)-1-benzyloxycarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one (81.50 g) in ethanol (800 ml) was subjected to hydrogenation at room temperature in the presence of 10% palladium-carbon (8.15 g) under atmospheric pressure, followed by filtration to remove the catalyst. The filtrate and the washings were combined and evaporated to give (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)-1-carboxyethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:30][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: NC1CCCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NC3CCCC3)cc2n1
Yield: 73 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (96 mg, 0.3 mmol) was converted, using cyclopentylamine instead of aminomethylcyclopropane, to the title compound (84 mg, 73%) which was obtained as a light yellow foam. MS: m/e=387.3 [M+H]+.
Reaction SMILES: Cl.[CH2:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[CH2:4][N:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N([CH2:22][CH3:23])CC)C>C(Cl)(Cl)Cl>[CH2:7]1[CH:6]2[CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH:5]2[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:23]1[CH:22]=[CH:2][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (10 g, 0.04 mol; see Preparation A above) and triethylamine (14 mL, 0.1 mol) were mixed in CHCl3 (100 mL). N-benzyloxy-carbonyloxy succinimide (11 g, 0.044 mol), dissolved in CHCl3 (100 mL), was added at 0–5° C. The mixture was allowed to slowly reach room temperature and was stirred at rt for 5 h. The reaction mixture was washed with water, dried (Na2SO4) and evaporated, giving the sub-title compound in quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:15])([CH3:14])[C:11](Cl)=[O:12]>>[CH3:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: Nc1cc(Cl)ccn1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccn1

Procedure:
The synthetic strategy used in the preparation of compounds 4, 5, 6, 7, and 8 is illustrated in FIG. 2. Polychlorinated pyridines were synthesized from the 2-amino-4-chloro-pyridine (compound 3). For example, compound 3 was dissolved in concentrated hydrochloric acid (HCl), reacted at 0° C. with hydrogen peroxide (H2O2), and allowed to warm to room temperature yielding a mixture of 2-amnino-4,5-dichloro-pyridine (compound 4), 2-amino-3,4-dichloro-pyridine (compound 5), and 2-amino-3,4,5-trichloro-pyridine (compound 6). In another method, compound 3 was dissolved in concentrated hydrochloric acid (HCl) and heated at reflux temperature to yield 2-amino-4,5-dichloro-pyridine (compound 4) in 97% yield. In another method, compound 3 was dissolved in concentrated hydrochloric acid (HCl), reacted at 0° C. with hydrogen peroxide (H2O2), and allowed to warm to room temperature yielding 2-amino-3,4,5-dichloro-pyridine (compound 6) in 80% yield. In still another method, compound 3 was reacted with trimethylacetyl chloride ((CH3)3COCl) to yield 2-trimethylacetamido-4-chloro-pyridine (compound 7). Compound 7 was then reacted with N-chlorosuccinimide (NCS) to yield 2-trimethylacetamido-4,5-chloro-pyridine (compound 8). Compound 8 was then reacted with hydrochloric acid (HCl) to yield 2-amino-4,5-chloro-pyridine (compound 4).
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19]CC)=[O:18])[C:12]2=[C:11]([Br:22])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[C:11]([Br:22])[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCn2c(C(=O)c3ccccc3)cc(Br)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1)c1cc(Br)c2n1CCC2C(=O)O

Procedure:
A solution of 250 mg. of ethyl 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 8 ml. of methanol is treated under an atmosphere of nitrogen, with a solution of 200 mg. of sodium hydroxide in 1 ml. of water, maintaining the reaction mixture at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution which remains is diluted with 5 ml. of water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 5-benzoyl-7-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:24]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
A mixture of 4-{[4-(2-tert-Butylphenyl)piperazin-1-yl]carbonyl}phenol obtained in Example 20 (1.0 g), methyl bromoacetate (542 mg), potassium carbonate (1.38 g), and N,N-dimethylformamide (30 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (430 mg, 59%) as white crystals.