Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.[CH2:4]([O:6][C:7](=[N:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([O:19]CC1C=CC=CC=1)=[O:18])[CH3:8])[CH3:5].C1COCC1.CO.O>O>[CH2:4]([O:6][C:7](=[N:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([OH:19])=[O:18])[CH3:8])[CH3:5]
Reactant: CCOC(C)=NOc1ccccc1C(=O)OCc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(C)=NOc1ccccc1C(=O)O
Temperature: 25 °C
Yield: 80.3 %

Procedure:
LiOH.H2O (431 mg, 10.3 mmol) was added to a solution of ethyl-N-(2-benzyloxycarbonylphenoxy)acetimidate 18 (802 mg, 2.56 mmol) in a 9/3/3 mL mixture of THF/MeOH/H2O and the reaction was stirred at room temperature. After 6 h the reaction was diluted with H2O (100 mL), washed with CH2Cl2 (4×30 mL), acidified to pH˜5.0-5.5 with 0.5 N HCl, and extracted with EtOAc (4×30 mL). The combined organics were washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford 20 as a white solid (459 mg, 80%). 1H-NMR (500 MHz, d6-Acetone) δ 1.34 (t, J=6.9 Hz, 3H), 2.18 (s, 3H), 4.20 (q, J=6.9 Hz, 2H), 7.02 (ddd, J=0.9, 7.3, 7.8 Hz, 1H), 7.51 (ddd, J=1.8, 7.3, 8.7 Hz, 1H), 7.60 (dd, J=0.9, 8.7 Hz, 1H) 7.86 (dd, J=1.8, 7.8 Hz, 1H); 13C-NMR (125 MHz, d6-Acetone) δ 14.6, 14.7, 63.8, 115.2, 118.5, 121.3, 132.4, 134.5, 160.2, 166.8, 167.4; ESI-MS 224 m/z [MH]+, C11H14NO4 requires 224.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(chloromethyl)-4-methoxybenzene (0.46 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.83 g, 62%).
Reaction SMILES: [NH2:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14].[CH2:15]([O:22][CH2:23][C:24](Cl)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C.Cl>ClCCl.C1COCC1>[CH2:15]([O:22][CH2:23][C:24]([NH:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:14])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NN1Cc2cccc([N+](=O)[O-])c2C1=O
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1ccccc1)NN1Cc2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
870 mg (4.5 mmol) 2-amino-7-nitro-2,3-dihydro-isoindol-1-one (prepared analogously to method 2) are dissolved in 82 ml dichloromethane and 64 ml THF. The solution is combined with 2.8 ml (3.3 eq, 20 mmol) benzyloxyacetyl chloride, 4.8 ml (28.0 mmol) N-ethyldiisopropyl-amine and 10 mg N,N-dimethylaminopyridine and stirred for 3 h at 25° C. Then the reaction mixture is combined with 100 ml aqueous 0.1 N hydrochloric acid and extracted three times with 50 ml of ethyl acetate. The organic phase is dried with magnesium sulphate, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of dichloromethane:methanol (95:5).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1>ClCCl>[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:28]3[CH:29]=[C:30]4[O:35][CH2:34][O:33][C:31]4=[CH:32][C:27]=3[CH2:26][C:25]([CH3:36])=[N:24][N:23]=2)=[CH:18][CH:17]=1)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=NN=C(c2ccc(NC(=O)C(C)(C)C)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.3 %

Procedure:
1.56 ml (11.2 mmol) of triethylamine and 1.38 ml (11.2 mmol) of pivaloyl chloride were added to a solution of 3 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 160 ml of dichloromethane and the reaction mixture was stirred at 25° C. for one hour. The precipitate formed Was filtered, washed with 3×5 ml of dichloromethane, then with 3×20 ml of water and dried to yield 1.59 g of pure product, m.p. 225°-227° C. (decomp.). The other portion of the product was isolated from the organic phase. The filtrate was extracted with 3×20 ml of water, then with 3×15 ml of 4% aqueous sodium hydroxide solution, finally with 2×30 ml of water. The organic layer was subsequently dried and evaporated under reduced pressure. The crystalline residue was combined with the former product of 1.59 g and suspended in 20 ml of hot ethanol. The product was filtered after cooling, washed with 3×3 ml of ethanol and dried to yield 3.38 g (87.8%) of the pure product, m.p.: 225°-227° C. (decomp.).
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15].[Cl:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22]>>[Cl:17][CH2:18][CH2:19][NH:20][C:21]([N:16]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:11]1[O:4][C@@H:3]([CH3:2])[C@H:5]([OH:6])[C@@H:7]([OH:8])[C@H:9]1[OH:10])=[O:22]
Reactant: CCCCN
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Reactant: O=C=NCCCl
Product: CCCCN(C(=O)NCCCl)C1O[C@@H](C)[C@H](O)[C@@H](O)[C@H]1O
Yield: 64.3 %

Procedure:
3.3 g of L-rhamnose, 1.8 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 4.2 g of 1-(2-chloroethyl)-3-n-butyl-3-L-rhamnopyranosylurea are thereby obtained as colorless caramel.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].C[O-].[Na+].[C@:9]12([C:22](OCC)=O)[CH2:14][C@H:13]1[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2>CC1CCCO1>[CH3:2][C:1]1[N:3]=[C:22]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]3)[O:5][N:4]=1
Reactant: CCOC(=O)[C@]12C[C@H]1CN(C(=O)OC(C)(C)C)C2
Reactant: CC(N)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Product: Cc1noc([C@]23C[C@H]2CN(C(=O)OC(C)(C)C)C3)n1
Yield: 56.5 %

Procedure:
2-Methyl-tetrahydrofuran (40 mL), acetamide oxime (0.93 g, 0.0125 mol) and sodium methoxide (1.1 g, 0.020 mol) were added to (1R,5R)-3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (142) (1.27 g, 0.0050 mol) and the mixture was heated to reflux for 3 hours. Upon cooling the suspension was partitioned between ethyl acetate (100 mL) and water (25 mL). The organic layer was washed with water (25 mL), saturated sodium chloride (25 mL) and dried over Na2SO4. The mixture was concentrated and the residue was chromatographed over 25 g of silica gel with 15-25% ethyl acetate/hexanes, to obtain 0.75 g of clear colorless oil. MS (ESI) m/z 304 [M+K]+. 1H NMR (CDCl3) δ 1.16-1.17 (m, 1H), 1.46 (s, 9H), 1.60 (s, 1H), 1.72-1.75 (m, 1H), 2.36 (s, 3H), 3.49-3.51 (m, 1H), 3.65-3.79 (dd, 1H), 3.91-4.00 (m, 2H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9].C(I)C.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][CH2:8][O:5][C:1]([CH:2]([OH:3])[CH3:4])=[O:6].[C:7]([OH:11])(=[O:10])[CH2:8][OH:9]
Reactant: CC(O)C(=O)O
Agent: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCI
Product: CCOC(=O)C(C)O
Yield: 142.6 %

Procedure:
15 g of a lactic acid/glycolic acid copolymer having a weight-average molecular weight of about 7,500 (lactic acid/glycolic acid=75/25 (mol %)) (Wako Pure Chemical Industries, Ltd.) and a 7.8 g of ethyl iodide were dissolved in 150 ml of acetone. To thus obtained solution was added 1.38 g of potassium carbonate and then the resulting mixture was refluxed for 6 hours. After the resultant solution was cooled, inorganic substances were removed by filtration and then the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 100 ml of dichloromethane, washed 3 times with 100 ml of 10% ethanol-water, and then dried with magnesium sulfate. After magnesium sulfate was separated by filtration, the mixture was concentrated to dryness under reduced pressure to yield 12.5 g of the ethyl ester of lactic acid/glycolic acid copolymer.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[C:34]1([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>>[C:34]1([CH2:40][CH2:41][CH2:42][CH:43]2[CH2:44][CH2:45][N:46]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:47][CH2:48]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(COC(=O)[C@@H](c2ccccc2Cl)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Agent: Cl
Product: COc1ccc(COC(=O)[C@@H](c2ccccc2Cl)N2C[C@H](CN3CCC(CCCc4ccccc4)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 69 %

Procedure:
The title compound was prepared from 39 mg (0.085 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-(2-chlorophenyl)acetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 10, Step D) and 4-(3-phenylpropyl)piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 38 mg (69%) of the title compound: RF: 0.28 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz) δ 1.05-1.23 (m, 5H), 1.47-1.75 (m, 7H), 2.30-2.97 (m, 11H), 4.76 (s, 1H), 5.06 (s, 2H), 6.78-6.83 (m, 2H), 7.13-7.36 (m, 15H), 7.68 (m, 1H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N+:9]1[C:17]2[C:12](=[C:13]([F:21])[C:14]([F:20])=[C:15]([F:19])[C:16]=2[F:18])[C:11]([CH3:30])([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])[CH:10]=1)([OH:3])=[O:2].C(O[C:35](=O)[CH3:36])(=O)C>C(O)(=O)C>[F:21][C:13]1[C:14]([F:20])=[C:15]([F:19])[C:16]([F:18])=[C:17]2[C:12]=1[C:11]([CH3:30])([CH2:22][CH2:23][CH2:24][CH2:25][S:26]([OH:29])(=[O:28])=[O:27])/[C:10](=[CH:1]\[CH:4]=[CH:5]\[CH:6]=[CH:7]\[CH:8]=[N:9]\[C:35]1[CH:36]=[CH:13][CH:12]=[CH:11][CH:10]=1)/[N:9]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(CCCCS(=O)(=O)O)C=[N+](CCCCCC(=O)O)c2c(F)c(F)c(F)c(F)c21
Solvent: CC(=O)O
Product: CC1(CCCCS(=O)(=O)O)/C(=C\C=C\C=C\C=N\c2ccccc2)N(CCCCCC(=O)O)c2c(F)c(F)c(F)c(F)c21
Temperature: 120 °C

Procedure:
To 1-(5-carboxypentyl)-4,5,6,7-tetrafluoro-3-methyl-3-(4-sulfobutyl)-3H-indolium (24 mg) was added N-[5-(phenylamino)-2,4-pentadienylidene monohydrochloride (13 mg), acetic anhydride (4 ml) and acetic acid (2 ml). This mixture was heated to 120° C. for 1 hour 45 minutes after which time it was cooled to room temperature. This crude reaction mixture (ca. 5 mg/ml product) was used without purification as further described.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[C:8]([CH3:14])[C:6]=2[N:7]=1.[C:21](Cl)(=[O:23])[CH3:22].CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[S:10][C:9]([CH2:11][N:12]([CH3:13])[C:21](=[O:23])[CH3:22])=[C:8]([CH3:14])[C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CNCc1sc2c(N3CCOCC3)nc(Cl)nc2c1C
Reactant: CC(=O)Cl
Product: CC(=O)N(C)Cc1sc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2c1C
Yield: 40 %

Procedure:
1-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-methylmethanamine 56 from Example 11b was reacted with acetyl chloride (1.2 eq) followed by Suzuki coupling of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indazole 7 as per General Procedure K. Complete reaction was confirmed by LCMS and the reaction was concentrated in vacuo to give 101.9 mg of 408 after RP-HPLC purification (40% yield). MS (Q1) 437.2 (M)+.
Reaction SMILES: [NH:1]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.CI.[C:32](O)(=O)C.[OH-].[Na+]>O1CCCC1.C1OCCOCCOCCOCCOCCOC1.O>[N:1]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([CH3:32])[C@@H:2]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Reactant: CC(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CN(C(=O)OCc1ccccc1)[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 90 %

Procedure:
To a suspension of KH (19.3 g, 25% suspension in oil, 120 mmol) in tetrahydrofuran (100 mL) at 0° C. was slowly added (over 25 min) a solution of Cbz-D-Cha-Pro-OH (16.8 g, 41.7 mmol) in tetrahydrofuran (50 mL). During this addition period the internal temperature was monitored and maintained at less than 10° C. To this solution was then slowly added a solution of methyl iodide (5 mL, 80 mmol) and 18-crown-6 (661 mg, 2.5 mmol), again maintaining the internal temperature below 10° C. After 2 h acetic acid (10 mL) was added dropwise, followed by water (10 mL). The solution was then poured into cold water and the pH was adjusted to 9 with 2N NaOH. The aqueous base was washed twice with diethyl ether and then acidified to pH 2 with conc. HCl and extracted four times with chloroform. The chloroform extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo to afford 15.7 g (90%) of a pale yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.C[N:6](C)[CH:7]=[O:8].[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1C(O)=O>C1(C)C=CC=CC=1>[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1[C:7]([NH2:6])=[O:8]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C

Procedure:
Thionyl chloride (3.95 g) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (3.0 g) described in Reference Example 8 in toluene (55 ml), and stirred at 80° C. for an hour. The solvent and an excess amount of thionyl chloride were evaporated, tetrahydrofuran (55 ml) was added to the residue, 25% aqueous ammonia (44 ml) was added under ice-cooling and stirred at room temperature for two hours. After the reaction, 1N aqueous solution of sodium hydroxide was added, and the precipitated solid was filtered to give 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (2.9 g) as a white solid.
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(C)[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1.O>C1C=CC=CC=1.C(O)C#C>[C:1]([NH:9][CH:10]([CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[C:11]([O:13][CH2:25][C:20]#[CH:21])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(Cc1c[nH]cn1)C(=O)O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C#CCO
Solvent: O
Solvent: c1ccccc1
Product: C#CCOC(=O)C(Cc1c[nH]cn1)NC(=O)c1ccccc1

Procedure:
5 gm of 2-(benzoylamino)-3-(imidazol-4-yl)propanoic acid in 100 ml of benzene, 5 ml of propargyl alcohol, and 5.22 gm of p-toluenesulfonic acid.H2O was heated at reflux with the azeotropic removal of water by means of a Dean-Stark apparatus. After approximately 2 days of refluxing and the stoichiometric amount of water was produced, the reaction mixture was cooled, and a precipitate, the p-toluenesulfonic acid salt of the title compound was filtered out. The salt was taken up in water, the pH adjusted to 7.5 with 1.0N NaOH in a two phase system of water-dichloromethane. The layers were separated and the aqueous portion extracted 3×30 ml of CH2Cl2. The organic fractions were pooled, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][CH:27]=1)([O-:25])=[O:24].O>CN(C=O)C>[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([O:1][C@H:2]2[CH2:7][CH2:6][C@H:5]3[C@H:8]4[C@H:18]([CH2:19][CH2:20][C@:3]23[CH3:4])[C@:16]2([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]2)[CH2:10][CH2:9]4)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc([N+](=O)[O-])cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 17β-hydroxy4-methyl-5α-4-azaandrostan-3-one (1.07 g, 3.5 mmole) and p-nitrofluorobenzene (2.0 ml, 18 mmole) in DMF (15 ml) under N2 was added 95% Nail (180 mg, 7 mmole) in two portions during 10 mins. The mixture was stirred for 3 hours at room temperature and poured onto ice (50 g) and water (50 ml). The mixture was extracted with CH2Cl2 (30 ml×2). The organic layer was washed with brine and dried (Na2SO4). Removal of solvent gave the crude product which was purified via a flash silica gel column eluting with 1:1 ethyl acetate --CH2Cl2 to give the desired title product. Mp. 183°-184° C. (recrystallized from CH2Cl2 -hexane).
Reaction SMILES: [Li].[CH3:2][Cu]C.[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:27])([CH3:26])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[CH:28]1[CH2:33][C:32](=[O:34])[CH:31]=[CH:30][CH2:29]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH2:5]([O:12][C:13]1[CH:18]=[C:17]([C:19]([CH3:26])([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:16]=[CH:15][C:14]=1[C@H:28]1[CH2:29][C@H:30]([CH3:2])[CH2:31][C:32](=[O:34])[CH2:33]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC=CC(=O)C2)c(OCc2ccccc2)c1
Reactant: C[Cu]C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCC(C)(C)c1ccc([C@@H]2CC(=O)C[C@@H](C)C2)c(OCc2ccccc2)c1
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a 0° C. solution of dimethyl copper lithium (2.47 mmole) in ether (3 ml) and hexane (2 ml) was added dropwise a solution of 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-2-cyclohexen-1-one (500 mg, 1.24 mmole) in ether (1.5 ml). The reaction mixture was stirred for 15 minutes and then poured into saturated aqueous ammonium cloride (300 ml). The quenched reaction was extracted with three 50 ml portions of ether, the combined ether extracts washed with water, saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 475 mg (92%) of the title compound as an oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]2[C:17]=1[N:16]=C(C(O)=O)[CH:14]=[CH:13]2>>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:1]([C:2]([Cl:4])=[O:3])[CH:14]=[CH:13]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2cncc(Br)c2n1
Product: O=C(Cl)c1ccc2cncc(Br)c2n1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.5 equiv.) is added drop wise to a slurry of 8-Bromo-[1,6]naphthyridine-2-carboxylic acid (1 equiv., in 20 mL DMF) at 0° C. (ice bath) and stirred for 30 minutes. The reaction mixture is removed from the ice bath, stirred at room temperature for 3 h and then concentrated in vacuo to give a greenish colored solid, which is used immediately without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:21]1([CH3:25])[CH:22]=[CH:23][CH:24]=[C:19]([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH:20]=1
Reactant: Cc1cccc(-n2c([C@H](C)NC(=O)OC(C)(C)C)nc3cccnc32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(-n2c([C@H](C)N)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
To a solution of [(S)-1-(3-m-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tert-butyl ester (3.01 mmol) in DCM (25 mL) was added TFA (10 mL) and the mixture stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) to afford the title compound as a colourless oil (700 mg, 92% over three steps). LCMS (Method C): RT 1.91 min [M+H]+ 253.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[N+:6]([O-:9])[C:5]([C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:14]O>>[Cl:1][C:2]1[C:7]([Cl:8])=[N+:6]([O-:9])[C:5]([C:10]([O:12][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)c(Cl)[n+]1[O-]
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Cl)c(Cl)[n+]1[O-]
Temperature: 45 °C

Procedure:
A suspension of 5,6-dichloropyridine-2-carboxylic acid-N-oxide (5.0 g, 24.0 mmol) in methanol (100 mL) was saturated with HCl gas and the reaction mixture heated at 40-50° C. for one hour. The solvent was removed and the residue dissolved in diethyl ether/ethyl acetate. The organic solution was washed with water, saturated sodium bicarbonate solution, brine, dried, and concentrated to give methyl 5,6-dichloropyridine-2-carboxylate-N-oxide (4.0 g, 18.1 mmol). 1H NMR (DMSO-d6): δ 7.75 (s, 2H), 3.88 (s, 3H).