Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH:32]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]1.C1(C)C=CC=CC=1>C(#N)C>[C:1]([C:5]1[N:6]=[C:7]([N:32]2[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: O[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (10 g, 29.7 mmol, Eq: 1.00) was dissolved in Acetonitrile (54.6 g, 70.0 ml). N-Ethyldiisopropylamin (7.84 g, 10.3 ml, 59.5 mmol, Eq: 2) was added dropwise over 5-10 min. After 10 min at RT, a solution of (S)-pyrrolidin-3-ol (2.94 g, 2.8 ml, 32.7 mmol, Eq: 1.1) in Acetonitrile (2.27 g, 2.91 ml) added dropwise over 30 min at 20° C. After 2 h30 reaction, toluene (86.5 g, 100 ml) was added and the reaction mixture was concentrated under reduced pressure to remove most of the acetonitrile. A 10% aqueous citric acid solution (100 ml) was added. The aqueous phase was separated and extracted with toluene (86.5 g, 100 ml). The organic phases were washed sequentially with half saturated aqueous NaHCO3 (50 ml) and half saturated aqueous NaCl (50 ml). The organic phases were combined dried over MgSO4 and rotavaped at 45° C./10 mbar. The crude product was taken up in ethanol (150 ml) and concentrated under reduced pressure. This was repeated twice in order to remove toluene and gave 11.1 g of the crude title compound as a light yellow solid/foam.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[C:10](OC)=[O:11])=[CH:2]1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C(OCC)(=O)C.O>[S:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])=[CH:2]1
Reactant: COC(=O)/C=C/C=C/c1ccsc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OC/C=C/C=C/c1ccsc1
Yield: 101.6 %

Procedure:
46 mg of methyl (E,E)-5-(3-thienyl)-2,4-pentadienoate was dissolved in 1 ml of tetrahydrofuran, and 0.59 ml of a 1M toluene solution of diisobutylaluminum hydride was added dropwise at -40° C. Water, 0.6 ml of 1N hydrochloric acid and ethyl acetate were added to the solution , and the organic layer separated was worked up in a customary manner to give 40 mg of (E,E)-5-(3-thienyl)-2,4-pentadien-1-ol as a colorless oil.
Reaction SMILES: [OH:1][C:2](C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[S:21](=[O:23])(=[O:22])[N:20](CC[Si](C)(C)C)[C:19](=[O:30])[CH2:18]2)=[C:13]([O:31]CC2C=CC=CC=2)[CH:12]=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[OH:31][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][N:8]=[C:2]=[O:1])[CH:16]=[CH:15][C:14]=1[N:17]1[S:21](=[O:22])(=[O:23])[NH:20][C:19](=[O:30])[CH2:18]1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCN)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C=NCCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1

Procedure:
A solution of 5-[4-(2-aminoethyl)-2-benzyloxyphenyl]-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.266 g, 0.46 mmol) (Example 67, step A) and diisopropylethylamine (0.177 mL, 1.02 mmol) in a minimum amount of CH2Cl2 is added dropwise over a period of 30 min to triphosgene (0.051 g, 0.17 mmol) dissolved in CH2Cl2 (10 mL). This solution is used directly in the next step.
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16].Cl[O-].[Ca+2].Cl[O-]>C(#N)C>[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CCCCCCCCC(O)CC
Agent: O=C([O-])O
Agent: [Ca+2]
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCC(=O)CC
Reaction time: 18 h

Procedure:
Sodium bicarbonate (8.81 g, 0.105 mol) was added to a solution of 15.0 g (0.075 mol) of 3,3-dimethyl-1,5-dioxaspiro<5.5>undecan-9-ol in 150 ml of acetonitrile. The reaction mixture was charged with 15.0 g of silica gel (MCB 60-200 mesh) and 15.0 g of calcium hypochlorite in sequence. The reaction mixture was stirred at a temperature in the range of 24° C. to 28° C. for about 18 hours and then warmed to 29° C. to 30° C. for 4 hours. The mixture was filtered and evaporated under vacuum. The residue was combined with 135 ml of toluene and 50 ml of water, and the resulting mixture was stirred for 45 minutes. The organic phase was separated, washed with 50 ml of a saturated sodium chloride solution and dried over 10.0 g of anhydrous sodium sulfate. A gas chromatograph of the sample showed 93.6% pure product. The organic phase was concentrated under vacuum to afford 13.97 g of 3,3-dimethyl-1,5-dioxaspiro<5.5>undecan-9-one.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@H:44]1[CH2:48][C@@H:47]([CH2:49][S:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[N:46]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[CH2:45]1.C(OCC)(=O)C>C(#N)C>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])=[C:18]([S:43][C@H:44]3[CH2:48][C@@H:47]([CH2:49][S:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:46]([C:57]([O:59][CH2:60][C:61]4[CH:62]=[CH:63][C:64]([N+:67]([O-:69])=[O:68])=[CH:65][CH:66]=4)=[O:58])[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](S)C[C@H]1CSc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4ccccc4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 5 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (2.24 g, 3.78 mmol) in acetonitrile (70 ml), DIPA (0.9 ml, 5.16 mmol) was added under cooling with ice, and then a solution of (3S,5S)-3-mercapto-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidine (1.39 g, 3.42 mmol) in acetonitrile (15 ml) was dropwise added thereto. The reaction solution was stirred at 5° C. overnight, and ethyl acetate (300 ml) was added to the reaction solution. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate), to give p-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(3S,5S)-1-p-nitrobenzyloxycarbonyl-5-(phenylthiomethyl)pyrrolidin-3-ylthio]-1-carbapen-2-em-3-carboxylate (1.55 g, yield: 60%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:12]=[O:13].[CH3:14][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[S:8][C:4]=2[C:3]=1[CH:12]=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nc2ccc(O)c(C=O)c2s1
Solvent: c1ccccc1
Solvent: CO
Product: COc1ccc2nc(C)sc2c1C=O

Procedure:
6-Hydroxy-2-methyl-benzothiazole-7-carboxaldehyde (75 mg, 0.362 mmol) was taken up in 30% methanol in benzene (7 mL) and treated with (trimethylsilyl)diazomethane (2.0M solution in hexanes) (0.5 mL, 1.0 mmol) for 2 hours at room temperature. The mixture was evaporated, and the title compound was purified by flash chromatography eluting with 25-30% ethyl acetate in hexane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25])#[N:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25])#[N:2]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C#N
Reaction time: 0.25 h
Yield: 68.4 %

Procedure:
40% Methanolic Triton B (0.24 mL, 0.53 mM) was added to a solution of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (140 mg, 0.41 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (130 mg, 0.82 mM) was added and the resultant mixture stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate/THF) to afford 116 mg (68%) of the {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 7.75 (d, 1H, J=8 Hz), 7.5-7.2 (m, 6H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 2H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.75 (s, 2H), 4.9 (s, 2H), and 3.8 (s, 3H). IR (KBr, cm−1) 2228, 1732, and 1675. MS (ES) m/e 412, 414.
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.Br[C:25]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]2[C:26]=1[CH2:27][N:28]([CH3:38])[C:29]2=[O:37].CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1.[CH3:57][C:58]1([CH3:78])[O:62][C@@H:61]([CH2:63][N:64]2[CH:68]=[C:67](B3OC(C)(C)C(C)(C)O3)[CH:66]=[N:65]2)[CH2:60][O:59]1>>[CH3:57][C:58]1([CH3:78])[O:62][C@@H:61]([CH2:63][N:64]2[CH:68]=[C:67]([C:25]3[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[C:30]4[C:26]=3[CH2:27][N:28]([CH3:38])[C:29]4=[O:37])[CH:66]=[N:65]2)[CH2:60][O:59]1
Reactant: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Reactant: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CN1Cc2c(-c3cnn(C[C@H]4COC(C)(C)O4)c3)ccc([N+](=O)[O-])c2C1=O
Yield: 99 %

Procedure:
Prepared analogously to Compound 3C replacing Compound 3D with Compound 1L and Compound 3E with 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 5E) to afford 1.96 g of the desired product (99%). 1H NMR (400 MHz, CDCl3) δ 7.79-7.85 (m, 2H), 7.74-7.80 (m, 1H), 7.65-7.73 (m, 1H), 4.46-4.58 (m, 3H), 4.36 (dd, J=5.05, 13.39 Hz, 2H), 4.14 (dd, J=6.44, 8.72 Hz, 1H), 3.83 (dd, J=6.06, 8.59 Hz, 1H), 3.24 (s, 3H), 1.34-1.44 (m, 6H). MS (ESI): m/z 373.16 [M+H]+. UPLC: tR=1.16 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([O:12]C)=[O:11])[CH2:9][CH2:8]2)[O:4][N:3]=1.O.[OH-].[Li+].[Cl-].[NH4+].Cl>CO.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:10]([OH:12])=[O:11])[CH2:8][CH2:9]2)[O:4][N:3]=1
Reactant: COC(=O)C1(c2cc(C)no2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: Cc1cc(C2(C(=O)O)CC2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To methyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate (100 mg, 0.552 mmol) was added a solution of lithium hydroxide monohydrate (32 mg, 0.76 mmol) in methanol (2 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 18 h. The solvent was reduced to about 1 mL in volume. A saturated aqueous solution of ammonium chloride (2 mL) was added followed by aqueous hydrochloric acid (1N) until pH was approximately 4. The mixture was extracted with ether (15 mL×2). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylic acid as a white solid (43 mg, 47%). The material was used without further purification. MS (ES+) (M+H) 168.0; LCMS retention time: 2.0 minutes (Method L). 1H NMR (500 MHz, CD3OD) δ 1.44-1.48 (m, 2H), 1.66-1.69 (m, 2H), 2.25 (s, 3H), 6.38 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.ClOC(C)(C)C.[CH2:15]([S:17][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])[CH3:16].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[NH:6][C:19](=[O:20])[C:18]2([CH2:23][CH2:22][OH:21])[S:17][CH2:15][CH3:16]
Reactant: CCSC1CCOC1=O
Reactant: Nc1ccc(Cl)cc1
Agent: CC(C)(C)OCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCSC1(CCO)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the stirred solution of 5.6 g p-chloroaniline in 150 ml of methylene chloride is added dropwise 4.7 ml of t-butyl hypochlorite in 20 ml of methylene chloride at -65°. After ten minutes, the solution of 5.75 g of 2-ethylmercaptobutyrolactone in 20 ml of methylene chloride is added dropwise and the temperature held at -65° for two hours. Then the solution of 6.1 ml of triethylamine in 20 ml of methylene chloride is added dropwise and the mixture is allowed to warm up to room temperature. 50 ml of water are added with stirring and the precipitate filtered off, to yield the 5-chloro-3-(2-hydroxyethyl)-3-ethylmercapto-2-oxindole melting at 132°-135°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([CH:20]=[O:21])=[CH:14][NH:15]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25]Br.C(OCC)(=O)C>O1CCCC1.[Cl-].[Na+].O>[CH3:22][N:23]([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24](=[O:27])[CH2:25][N:15]1[C:16]2[C:12](=[C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][CH:17]=2)[C:13]([CH:20]=[O:21])=[CH:14]1
Reactant: O=Cc1c[nH]c2cccc(OCc3ccccc3)c12
Reactant: CN(CCc1ccccc1)C(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN(CCc1ccccc1)C(=O)Cn1cc(C=O)c2c(OCc3ccccc3)cccc21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (1.31 g, 80% suspension in mineral oil, 43.8 mM) in 65 ml of tetrahydrofuran (THF), cooled in an ice bath, is added dropwise a solution of 4-benzyloxyindole-3-carboxaldehyde (10.2 g, 39.8 mM) in 55 ml of THF. The mixture is stirred in the cooling bath for an additional 30 minutes; N-methyl-N-phenethyl-2-bromoacetamide (15.3 g, 59.7 mM) is then added. The resulting mixture is stirred at room temperature for 18 hours. Ethyl acetate and 50% brine is added and the layers are separated. The organic layer is washed with brine, dried over magnesium sulfate and concentrated in vacuo to give crude product as a beige oil. Purification on preparative HPLC (silica gel column, 20% ethyl acetate in methylene chloride) gives N-methyl-N-phenethyl-2-(4-benzyloxy-3-formylindol-1-yl)acetamide. (m.p. 120°-122° C.)
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([CH:11]([OH:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][CH:10]=1)#[N:4].[CH:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[C:22]([C:28]#[N:29])[CH:21]=1.[I-].[K+].Cl>CCCCCC.CN(C=O)C.C(OCC)(=O)C>[C:3]([C:5]1[CH:6]=[C:7]([CH:11]([O:19][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:28]#[N:29])=[CH:21][CH:20]=2)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: CCOC(=O)CCC(O)c1cccc(C#N)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CCC(OCc1ccc(C#N)cc1)c1cccc(C#N)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Part C. Sodium hydride (0.76 mmol) (washed free of the mineral oil with hexane) was added to a solution of ethyl 3-(cyano)-gamma-(hydroxy)benzenebutanoate (0.15 gm, 0.64 mmol), a-bromo-p-tolunitrile (0.125 gm, 0.64 mmol) and potassium iodide in 5 mL DMF at 0° C. under a nitrogen atmosphere. The reaction was stirred for 2 hrs at 0° C. and was allowed to stir at ambient temperature overnight. The reaction solution was poured into 1N HCl and extracted with ethyl acetate. The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product as a viscous oil. The product was purified by flash chromatography on silica gel (75 mL) eluting toluene:ethyl acetate (v:v, 90:10) to give ethyl 3-(cyano)-gamma-[[4-(cyano)phenyl]methoxy]benzenebutanoate as a semisolid residue 0.10 gm (45% yield) MS 366(M+NH4)+ 1 H NMR (CDCl3): 7.72-7.47(m, 6H), 7.42(d, 2H), 4.5-4.3(m, 3H), 4.1(q, 2H), 2.42(m, 2H), 2.17-1.97(m, 2H), 1.23(t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9]O)=[CH:5][CH:4]=1)[CH3:2].C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:25]=[N+:26]=[N-:27])=[CH:5][CH:4]=1)[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1ccc(CO)cn1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(CN=[N+]=[N-])cn1
Yield: 82.7 %

Procedure:
After dissolving (6-ethyl-3-pyridyl)methanol (2.25 g, 16.4 mmol) in toluene (25 ml), diphenylphosphoryl azide (4.2 ml, 19.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.9 ml, 19.6 mmol) were added while stirring on ice, and the mixture was further stirred at room temperature for 18 hours. Water was added for treatment and extraction was performed with ethyl acetate. The extract was washed with brine and then dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (2.2 g) as a yellow oil. (84.5% yield)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Cl.[NH2:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(OCCO)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:14][CH2:15][C:16]3([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: NCC1(O)CCCCC1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: OC1(CNc2ccnc3cc(Cl)ccc23)CCCCC1
Reaction time: 16 h
Yield: 54.5 %

Procedure:
A solution of 20 g of 4,7-dichloroquinoline, 20 g of 1-aminomethyl-1-cyclohexanol hydrochloride and 3 equivalents of triethylamine in 80 ml of 2-ethoxyethanol was stirred at reflux until the reaction was complete. The reaction was complete after 16 hours, and upon dilution of the reaction mixture with water (300 ml), a solid precipitated out which was isolated by filtration. Recrystallization from ethanol gave 16 g of crystalline solid with a melting point of 205°-207° C.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O.C(OCC)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
ethyl 1-(1-(4-chlorobenzyl)-1H-benzo[d]imidazole-2-carbonyl)piperidine-4-carboxylate (60 mg, 0.141 mmol) and lithium hydroxide, H2O (23.65 mg, 0.564 mmol) were dissolved in THF (Ratio: 1.000, Volume: 0.25 ml) and Water (Ratio: 2, Volume: 0.500 ml). The reaction was stirred for two hours before it was diluted with water and diethyl ether. The aqueous phase was washed with diethyl ether twice. It was then acidified to pH ˜2 and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to obtain crude acid. No further purification was performed. (Yield: 54 mg, white solid). 1H-NMR (400 MHz, DMSO-d6) 12.28, 7.65, 7.36-7.18, 5.51, 4.36-4.27, 3.91-3.82, 3.12, 2.96, 1.92-1.83, 1.74-1.63, 1.50-1.17
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].Br[CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)C(OC)=O.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[C:5]2[O:12][C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][C:4]=2[CH:3]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: COC(=O)c1cc(Cl)cc(C=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(Cl)cc2cc(-c3ccccc3)oc12
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A mixture of 3.0 g of methyl 5-chloro-3-formyl-2-hydroxybenzoate, 3.44 g of methyl α-bromophenylacetate, 8.28 g of potassium carbonate and 50 ml of dimethylformamide is heated at 70°-80° C. for 15 minutes and further heated at 100° C. for 10 minutes. After cooling, water is added to the mixture, and the aqueous mixture is acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is dissolved in 50 ml of ethanol, and 4.5 g of potassium hydroxide are added to the solution. The mixture is refluxed for 1 hour and then evaporated to remove solvent. Water is added to the residue, and the aqueous mixture is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract is dried and evaporated to remove solvent. 150 ml of xylene and 30 mg of p-toluenesulfonic acid are added to the residue and the mixture is refluxed for 1 hour. The reaction mixture is evaporated to remove solvent and the residue is dissolved in ethyl acetate. The solution is washed, dried and evaporated to remove solvent. The residue is crystallized from isopropyl ether to give 2.32 g of 5-chloro-2-phenylbenzofuran-7-carboxylic acid.
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:8])[CH2:6][F:7])=[N+:2]=[N-:3].[C:9]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N+:17]([O-:19])=[O:18])#[C:10][CH3:11]>>[F:7][CH2:6][CH:5]([OH:8])[CH2:4][N:1]1[CH:11]=[C:10]([CH2:9][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[N+:17]([O-:19])=[O:18])[N:3]=[N:2]1
Reactant: CC#Cn1ccnc1[N+](=O)[O-]
Reactant: [N-]=[N+]=NCC(O)CF
Product: O=[N+]([O-])c1nccn1Cc1cn(CC(O)CF)nn1
Temperature: 60 °C

Procedure:
To a vial is added fluoroazide 17 (5.79 mmol) and 1-propynyl-2-nitroimidazole (5.79 mmol). The solution is heated at 60° C. overnight. The material is then purified on a silica gel column using EtOAc:Hex as the eluent. The material is then further purified via recrystallization using EtOAc:Hex to afford pale yellow crystals. Preparation of Compounds 5 and 21: