Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:22]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[S:29](=[O:32])(=[O:31])[CH2:30][C:21]=3[C:20]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])=[N:19]2)[CH2:13]1.[Na+].[I-]>C(#N)C.C(Cl)Cl>[N:35]1([C:33]([C:20]2[C:21]3[CH2:30][S:29](=[O:32])(=[O:31])[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]=3[N:18]([CH:14]3[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])[CH2:13]3)[N:19]=2)=[O:34])[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: O=C(c1nn(C2CCCN(CCCl)C2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CCCN1CCN1CCCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)C1
Yield: 9.9 %

Procedure:
A solution of 2-pyrrolidone (35 mg; 0.42 mmol; 2 eq.) with NaH (10 mg; 0.42 mmol; 2 eq.) in ACN at 0° C. is added to a solution of enantiomer B of 1-[1-(2-chloroethyl)piperidin-3-yl]-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg; 0.21 mmol; 1 eq.) and NaI (31 mg; 0.21 mmol; 1 eq.) in ACN (2 mL). Reaction mixture is heated to 60° C. for 18 h after which DCM is added and organic phase is washed with water and brine. It is dried over MgSO4 then purified by MD-Autoprep to give 11 mg (9%) of the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.05 (d, J=7.7 Hz, 1H), 8.00-7.82 (m, 2H), 7.81-7.67 (m, 1H), 4.89-4.64 (m, 3H), 4.00-3.83 (m, 2H), 3.83-3.56 (m, 8H), 3.22-3.12 (m, 1H), 2.99-2.82 (m, 1H), 2.67-2.34 (m, 4H), 2.29-2.15 (m, 2H), 2.15-1.54 (m, 8H). MS (ESI+): 528.5. HPLC (max plot) 97.6%; Rt 1.86 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14](O)=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:22][C:23]=1[NH2:24].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[NH:17][C:18]4[CH:19]=[C:20]([C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:22][C:23]=4[N:24]=3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCN(c2ncccc2Cl)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(C3CCN(c4ncccc4Cl)CC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the acid from step (b) above (0.48 g, 2 mmol) in DMF (20 mL) was added 3,4-diaminobenzotrifluoride (0.354 g, 2 mmol, Lancaster), followed by N,N-diisopropylethylamine (0.516 g, 4 mmol, Aldrich) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.912 g, 2.4 mmol, Aldrich). The reaction mixture was stirred at room temperature for 16 h, and then concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with hexane/EtOAc (3:7) to give the title compound as a purple solid. MS (ESI, pos. ion) m/z: 399 (M+1).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH2:8]([NH:10][C:11]([NH2:13])=[NH:12])[CH3:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]=1[C:33](Cl)=[O:34]>CC(C)=O>[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23]=1[C:33]([NH:13][C:11]([NH:10][CH2:8][CH3:9])=[NH:12])=[O:34]
Reactant: CCNC(=N)N
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCNC(=N)NC(=O)c1c(-c2ccccc2)noc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A mixture of 8.80 g of an aqueous sodium hydroxide solution (50%), ethylguanidine sulfate (14.98 g), and 100 ml of acetone, are stirred for 21/2 hrs at RT. The resulting mixture is then treated with anhydrous sodium sulfate (6.0 g) and stirring is continued for 1 hr. A solution of 5-methyl-3-phenyl-4-isoxazoloyl chloride (11.08 g) in 50 ml acetone is added dropwise and the resulting mixture is stirred overnight at RT. The reaction mixture is filtered, the filtrate diluted with 100 ml of saturated aqueous sodium bicarbonate and the acetone evaporated in vacuo. The aqueous residue is diluted with 100 ml H2O and extracted with two 100 ml portions of methylene chloride. The combined organic extract is dried, filtered and concentrated in vacuo. The residue is acidified with ethereal hydrochloric acid and evaporated in vacuo. The residue is stirred with 200 ml of diethyl ether, the solid collected and washed with diethyl ether. Recrystallization from acetonitrile affords 11.7 g of white crystalline product, M.P. 215° C.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22].Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O>[CH:36]1[C:37]2[CH:25]([CH2:24][O:23][C:21]([NH:1][C@H:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:22])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:32]=2[CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To (S)-4-amino-5-tert-butoxy-5-oxopentanoic acid (1.50 g, 7.38 mmol) in 1,4-dioxane (40 mL) chilled to 0° C., sodium carbonate (196 mg, 1.85 mmol) in water (20 mL) was added followed by Fmoc chloride (2.11 g, 8.16 mmol). The reaction was gradually warmed to ambient temperature and stirred at ambient temperature for 16 hours. After this time, the reaction was made slightly acidic (pH=6) with 2 M hydrochloric acid and the pH adjusted to ˜3 with 1 M citric acid (˜80 mL). The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography eluting with hexanes to a 3:2 ethyl acetate/hexane mixture to afford (S)-4-(((9H-fluoren-9-yl)methoxy)carbonylamino)-5-tert-butoxy-5-oxopentanoic acid (3.10 g, 99%) as a white solid: 1H NMR (300 MHz, CDCl3) δ carboxylic acid peak (1H) not observed as it was too broadened out, 7.76 (d, J=7.5 Hz, 2H), 7.61-7.58 (m, 2H), 7.42-7.26 (m, 4H), 5.45 (d, J=7.8 Hz, 1H), 4.48-4.19 (m, 4H), 2.51-2.34 (m, 2H), 2.28-2.14 (m, 1H), 1.99-1.88 (m, 1H), 1.47 (s, 9H); ESI MS m/z=448 [M+Na]+.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9](=[O:29])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])=[CH:16][C:15]=2[F:28])[O:11][CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].[CH2:32]([O:39][CH2:40][CH2:41]O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:32]([O:39][CH2:40][CH2:41][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:17]1[CH:16]=[C:15]([F:28])[C:14]([CH:10]([O:11][CH2:12][CH3:13])[C:9]([NH:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=2)=[O:29])=[C:19]([F:20])[CH:18]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: OCCOCc1ccccc1
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2O)cc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1c(F)cc(-c2ccccc2OCCOCc2ccccc2)cc1F

Procedure:
In analogy to example 22.1, (RS)-N-(4-cyano-benzyl)-2-(3,5-difluoro-2′-hydroxy-biphenyl-4-yl)-2-ethoxy-acetamide was reacted in a Mitsunobu reaction with 2-benzyloxy-ethanol, diethyl azodicarboxylate and triphenyl phosphine in THF to give (RS)-2-[2′-(2-benzyloxy-ethoxy)-3,5-difluoro-biphenyl-4-yl]-N-(4-cyano-benzyl)-2-ethoxy-acetamide. Yellow oil. MS 557.2 ([M+H]+)
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=O)[O:3]C1=O.[Br:13][C:14]1[C:15]([CH3:21])=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([Br:13])[C:15]=1[CH3:21])=[O:3]
Reactant: Cc1c(N)cccc1Br
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: Cc1c(Br)cccc1NC(=O)c1ccccc1N
Yield: 24.5 %

Procedure:
A suspension of 1H-benzo[d][1,3]oxazine-2,4-dione (5.00 g, 30.7 mmol) and 3-bromo-2-methylaniline (5.70 g, 30.7 mmol) in xylenes (50 mL) was heated at reflux for 8 h. The solvent was removed by distillation and the residue was purified by column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 0-50%), to give 2-amino-N-(3-bromo-2-methylphenyl)benzamide as an off-white solid (2.30 g, 24% yield).
Reaction SMILES: [C:1]([CH:3]([CH3:19])[CH2:4][N:5]1[CH2:10][CH2:9][C:8]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:2][CH2:1][CH:3]([CH3:19])[CH2:4][N:5]1[CH2:6][CH2:7][C:8]([C:17]#[N:18])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(C#N)CN1CCC(C#N)(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CN)CN1CCC(C#N)(c2ccccc2)CC1
Temperature: -20 °C

Procedure:
A solution of (+/−)-1-(2-cyanopropyl)-4-cyano-4-phenyl-piperidine (1.75 g, 6.91 mmol) in tetrahydrofuran (12 mL) was cooled to −78° C. and 1 M lithium aluminum hydride in tetrahydrofuran (3.9 ml) was added via syringe. The solution was warmed to −20° C. and after 4.5 hours, the reaction was worked up by sequential addition of water (0.20 mL), 2 M sodium hydroxide(0.40 mL), and water (0.20 mL). The reaction was then warmed to room temperature and diluted with ethyl acetate. The organic layer was washed with aq. sodium hydroxide and brine and dried over sodium sulfate. The filtered organic extract was concentrated to give an oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccno2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccno2)cc1

Procedure:
To a solution of 5-(4-methylphenyl)-isoxazole (17 g) and N-bromosuccinimide (19 g) in tetrachlormethane (500 ml) under nitrogen, bisbenzoyl peroxide (0.43 g) is added, and the mixture heated on reflux over night. The solvent is evaporated, and the residue purified by flash chromatography (silica gel, hexane/ethyl acetate 4:1) to give pure 5-(4-bromomethylphenyl)-isoxazole. NMR (CDCl3, 400 MHz) δ [ppm] 8.32 (d, 1.8 Hz, 1H), 7.78 (d, 8.2 Hz, 2H), 7.51 (d, 8.2 Hz, 2H), 6.54 (d, 1.8 Hz, 1H), 4.52 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.Br[CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:39]([CH2:38][CH2:37][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]1=[O:19])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCOc3ccccc3)c3ncccc23)c1
Reaction time: 10 h
Yield: 72.6 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (500 mg, 1.06 mmol) in DMF (10 ml) were added β-bromophenetole (256 mg, 1.28 mmol) and potassium carbonate (441 mg, 3.19 mmol), and the mixture was stirred at 40°-50° C. for 10 hours. The mixture was allowed to stand for cooling, and then poured into water. The mixture was extracted with ethyl acetate, and the extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1-3% methanol in chloroform), and crystallized from ether to give the title compound (446 mg, 0.77 mmol) as a colorless crystal.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH:12]12[CH2:20][CH:16]([CH2:17][NH:18][CH2:19]1)[CH2:15][N:14]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13]2>>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([CH:2]([OH:1])[CH2:3][N:18]2[CH2:19][CH:12]3[CH2:20][CH:16]([CH2:15][N:14]([C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22])[CH2:13]3)[CH2:17]2)=[CH:5][CH:6]=1)#[N:9]
Reactant: N#Cc1ccc(C2CO2)cc1
Reactant: CC(C)OC(=O)N1CC2CNCC(C2)C1
Product: CC(C)OC(=O)N1CC2CC(CN(CC(O)c3ccc(C#N)cc3)C2)C1

Procedure:
The crude reaction mixture from step (a) above was condensed with iso-propyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (5.2 g; see Example H above) according to the method described in Example 7 above to give the title compound in a 73% overall yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30]>>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([F:21])([F:33])[F:34])(=[O:31])=[O:30])[CH:7]=[CH:6]2
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2ccccc2C(F)(F)F)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.3 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 2-(trifluoromethyl)benzenesulfonyl chloride (27 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (5 mg, 17%) as a colorless solid. MS (ESI+) for C19H19F3N2O3S m/z 413 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)=[O:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>C1(C)C=CC=CC=1.CCOC(C)=O.CN(C=O)C>[N:24]1([C:8]([C:6]2[S:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)=[O:10])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=Cc1ccc(C(=O)O)s1
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(=O)N2CCCCC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A solution of 5-formylthiophenecarboxylic acid (9.0 g, 57.6 mmol) in toluene (100 mL) was treated with DMF (100 μL) followed by oxalyl chloride (9.9 mL, 115 mmol) and stirred at room temperature for 3 hr then evaporated in vacuo. The crude acid chloride was then dissolved in THF (100 mL), cooled in an ice bath, and treated with a THF solution (50 mL) containing triethylamine (10 mL, 72 mmol) and piperidine (6.3 mL, 63.4 mmol). The reaction was placed in a 5° C. refrigerator for 16 hr and then treated with a 1N HCl solution (200 mL) and EtOAc (200 mL). The organic portion was further washed with a saturated aqueous solution of NaHCO3 (100 mL) followed by a brine solution (100 mL), then dried over MgSO4, filtered, and evaporated in vacuo to afford product as an oil (12.87 g, 100%). 1H NMR (CDCl3) 1.64-1.71 (m, 6 H), 3.62 (br s, 4 H), 7.31 (d, J=4.0, 1 H), 7.71 (d, J=3.5, 1 H), 9.94 (s, 1 H). 13C NMR 24.6, 26.3 (br), 44.2 (br), 49.0 (br), 128.8, 135.4, 144.8, 146.1, 162.5, 183.3. LC/MS 4.78 min, [M+1]+ 224.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1>[CH2:25]([C:23]1[N:22]=[CH:21][NH:20][CH:24]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(Cc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-trityl-imidazole-4-carboxaldehyde (5 g, 14.8 mmoles) in THF (40 mL) is added dropwise a solution of 1M phenylmagnesium bromide in THF (17.7 mL, 17.7 mmoles). The reaction mixture is stirred at room temperature for 3 h, then it is poured into a saturated solution of NH4Cl. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is dissolved in concentrated HI solution (75 mL) and the reaction mixture is heated at reflux overnight. After cooling at room temperature, the reaction mixture is extracted three times with Et2O. The aqueous phase is basified by adding solid Na2CO3 to pH 7, solid NaHSO3 is added until the red colour disappeared and the aqueous phase is extracted three times with Et2O. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure to give 4-benzyl-1H-imidazole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12].[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][CH2:18][CH2:17][O:16][CH2:15][CH2:14][Cl:13]
Reactant: COc1ccc(O)c(Cl)c1
Reactant: ClCCOCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCCOCCCl)c(Cl)c1
Reaction time: 8 h

Procedure:
To a suspension of 9.6 g. of 50% sodium hydride in 250 ml. of dry dimethylformamide was added in portions 31.6 g. of 2-chloro-4-methoxyphenol. To this mixture was added 143 g. of bis(2-chloroethyl) ether, and the reaction mixture was heated at reflux with stirring for eight hours. The volatile solvent was removed, the residue partitioned between water and methylene dichloride, and the organic solution washed with water and dried over anhydrous magnesium sulfate. The product was twice distilled to give 2-[2-(2-chloro-4-methoxyphenoxy)ethoxy]ethyl chloride, b.p. 139°-140° C. (0.05 mm.).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C(O)C.C(O[C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:13]([C:16]#[N:17])[C:14]#[N:15])C>O>[NH2:15][C:14]1[O:3][N:2]=[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]=1[C:16]#[N:17]
Reactant: NO
Reactant: CCOC(=C(C#N)C#N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)noc1N

Procedure:
Hydroxylamine hydrochloride was suspended in water (30 ml) and added sodium hydroxide (4.4 g, 0.11 mole), then ethanol (40 ml) followed by batchwise addition of 2-(Ethoxy-phenyl-methylene)-malononitrile(21.7 g, 0.11 mole). Heated reaction mixture to 50° C. for 2 hours. Removed ethanol under vacuum and filtered precipitate. Redissolved precipitate in 50% ethyl acetate/hexanes and chromatographed on silica gel to give 8.2 g product after removal of solvent (yield: 40%).
Reaction SMILES: COC(C1C=CC(C(O)=O)=NC=1)=O.N1C=CC=CC=1CN.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][N:33]=1)=[O:31]>>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][N:33]=1)=[O:31]
Reactant: COC(=O)c1ccc(C(=O)NCc2ccccn2)nc1
Agent: COC(=O)c1ccc(C(=O)O)nc1
Agent: NCc1ccccn1
Product: O=C(O)c1ccc(C(=O)NCc2ccccn2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to pyridin-2-ylmethanamine via Procedure G. Crude methyl 6-(pyridin-2-ylmethylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-(pyridin-2-ylmethyl)pyridine-2,5-dicarboxamide. MS (Q1) 444.1 (M)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH:38]([F:40])[F:39])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH:38]([F:39])[F:40])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1OC(F)F
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1OC(F)F

Procedure:
In a similar manner as described for example A5, 2.78 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{-1-[2-(difluoromethoxy)phenyl]ethoxy}thiophene-2-carboxylate and 115 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.B([O-])([O-])O[C:19]1[S:20][C:21]([CH3:24])=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][C:21]1[S:20][C:19]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=3[CH:16]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(OB([O-])[O-])s1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2OCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2OCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.1 %

Procedure:
In toluene/ethanol/water (10/1/1) (24 ml) was dissolved methyl 7-bromo-2,3-dihydro-1-benzoxepine-4-carboxylate (560 mg), and to the mixture were added 5-methyl-2-thienyl borate (875 mg) and potassium carbonate (1.56 g). The mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphine palladium (260 mg), and the mixture was stirred at 100° C. for 24 hours and cooled to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the resulting residue was purified with silica gel column chromatography (hexane/acetone=12/1) to give methyl 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (345 mg).