Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:7](=[O:14])[CH:8]=[CH:9][C:10](=[O:13])[C:11]=2[CH:12]=1)[CH3:2].CN(C)[N:18]=[CH:19][C:20]([CH3:22])=[CH2:21]>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]2[C:7](=[O:14])[C:8]3[C:9]([C:10](=[O:13])[C:11]=2[CH:12]=1)=[CH:21][C:20]([CH3:22])=[CH:19][N:18]=3)[CH3:2]
Reactant: C=C(C)C=NN(C)C
Reactant: CCc1cc2c([nH]c1=O)C(=O)C=CC2=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c([nH]c1=O)C(=O)c1ncc(C)cc1C2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
A suspension of 3-ethyl-1H-quinoline-2,5,8-trione (200 mg, 0.99 mmol) in chloroform (40 ml) is treated with 145 mg (1.3 mmol) of 2-methylpropenal dimethylhydrazone. The reaction was stirred at room temperature for 5 minutes and evaporated, and the residue was chromatographed on silica gel, eluting with ethyl acetate, to yield 120 mg (45%) of 7.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:14]([NH:17][C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:15][S:16][C@H:11]12)=[O:8].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CCCCCCC>CC(C)=O.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([OH:29])=[O:28])=[C:14]([NH:17][C:18]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(NC(=O)Sc3ccccc3)CS[C@H]12
Solvent: CCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(NC(=O)Sc3ccccc3)CS[C@H]12

Procedure:
To a cooled (5°) stirred solution of 68 mg. of benzhydryl 7-(2-thienylacetamido)-3-(phenylthio)carbonylamino-3-cephem-4-carboxylate in 1 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. The reaction mixture was allowed to stir with cooling for 20 minutes after which time was added approximately 30 ml. of n-heptane. The resulting solution was evaporated in vacuo to a low volume. An additional 5 ml. of n-heptane was added, and the resulting solution was stirred in an ice bath for 5 minutes. The solution was filtered, and the precipitate thereby obtained was dissolved in acetone. The acetone solution was then filtered, and the filtrate evaporated in vacuo to dryness. The solution obtained by dissolving the residue in ethyl acetate was extracted twice with aqueous sodium bicarbonate solution. The aqueous extracts were combined, layered with cold ethyl acetate and acidified with cold 1N.HCl. The ethyl acetate layer was separated, washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to dryness to provide 33 mg. of the title product as a white solid.
Reaction SMILES: C(N(CC)[C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][C@H:17]([NH:19][CH2:20][C@H:21]([OH:29])[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[CH3:18])C.[OH-:33].[K+]>O.C(O)C>[OH:29][C@H:21]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[CH2:20][NH:19][C@H:17]([CH3:18])[CH2:16][C:12]1[C:11]2[C:15](=[C:7]([O:6][CH2:5][C:4]([OH:33])=[O:30])[CH:8]=[CH:9][CH:10]=2)[NH:14][CH:13]=1
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC[C@H](O)c3ccc(O)cc3)c[nH]c12
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1ccc(O)cc1
Yield: 67.4 %

Procedure:
A solution of N,N-diethyl-2-(3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxyphenyl)ethylamino]propyl}-1H-indol-7-yloxy) acetamide (12 mg, 0.027 mmol) and potassium hydroxide (60 mg, 1.1 mmol) in water (0.5 mL) and ethanol (0.5 mL) is stirred at 60° C. for 6 hours. After cooling, the mixture is concentrated and acidified by addition of water (30 mL) and acetic acid. The resultant is purified by reversed phase column chromatography (COSMOSIL 75C18-OPN (Nacalai Tesque) (octadecyl-silica gel, particle diameter: 75 μm, hereinafter, the same), water→water/methanol=10/ 1) to give the desired (3-{(2R)-2-[(2R)-2-hydroxy-2-(4-hydroxyphenyl)ethylamino]propyl}-1H-indol-7-yloxy)acetic acid (7 mg, yield: 68%).
Reaction SMILES: CO[C:3](=[O:24])[CH:4]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=1)=O.[C:25]([O:29][C:30](=[O:41])[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38](=[NH:40])[NH2:39])[CH2:34][CH2:33]1)([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:25]([O:29][C:30](=[O:41])[NH:31][CH:32]1[CH2:33][CH2:34][N:35]([C:38]2[NH:40][C:3](=[O:24])[C:4]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([F:15])[CH:8]=3)[N:39]=2)[CH2:36][CH2:37]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)C(C(=O)c1ccc(C#N)c(F)c1)c1ccc(OC)cc1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=N)N)CC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3ccc(C#N)c(F)c3)nc(N3CCC(NC(=O)OC(C)(C)C)CC3)[nH]c2=O)cc1
Yield: 3.5 %

Procedure:
A mixture of 3-(4-cyano-3-fluoro-phenyl)-2-(4-methoxy-phenyl)-3-oxo-propionic acid methyl ester (1.8 g, 5.5 mmol), (1-carbamimidoyl-piperidin-4-yl)-carbamic acid tert-butyl ester (2.6 g, 9.2 mmol), DIEA (2.4 g, 18.3 mmol) in toluene (50 mL) was refluxed overnight. The solvent was concentrated in vacuo. The residue was suspended in MeOH and the solids were filtered to give 100 mg (4%) of the title compound. [M+H] Calc'd for C28H30FN5O4, 520. Found, 520.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([CH3:31])[CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)=[C:26]([CH3:31])[CH:25]=1
Reactant: Cc1cc(F)ccc1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1cc(F)ccc1Nc1nc(NCc2ccccn2)nc(C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (4-fluoro-2-methylphenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.01 (s, 3H), 2.07 (s, 3H), 2.15 (s, 3H), 4.30 (bs, 2H), 6.68 (bs, 1H), 6.84-6.89 (m, 1H), 6.98-7.10 (m, 2H), 7.17 (t, J=7.3 Hz, 2H), 7.57-7.67 (m, 2H), 8.43 (d, J=4.2 Hz, 1H); MS (ESI) m/z 338.8 (M+1)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]5[O:22][CH2:21][O:20][C:18]5=4)[CH:13]=[C:12]4[C:23](=[O:37])[N:24]([CH2:26][CH2:27][CH2:28][O:29]CC5C=CC=CC=5)[CH2:25][C:11]=34)=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C1COCC1.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]5[O:22][CH2:21][O:20][C:18]5=4)[CH:13]=[C:12]4[C:23](=[O:37])[N:24]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:25][C:11]=34)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1c2cc3ccc4c(c3c(-c3ccc5c(c3)OCO5)c2CN1CCCOCc1ccccc1)OCO4
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C1c2cc3ccc4c(c3c(-c3ccc5c(c3)OCO5)c2CN1CCCO)OCO4
Yield: 69.4 %

Procedure:
The mixture of 20 (16 mg, 0.032 mmol) and 10% Pd/C (4 mg) in dry THF (3 mL) was stirred for 20 h at room temperature under 1 atm of hydrogen. The Pd/C was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using CH2Cl2/acetone (3:1 to 2:1, v/v) to yield 21 (9 mg, 69%) as a white solid. mp 213-215° C.; 1H NMR (CDCl3) δ 8.31 (s, 1H, H4), 7.67 (d, 1H, H5, J=8.4 Hz), 7.28 (d, 1H, H6, J=8.4 Hz), 6.82-6.92 (m, 3H, H2′+H5′+H6′), 6.07 (AB, 2H, 3′,4′-OCH2O—, Δδ=8.7 Hz, J=1.2 Hz), 5.93 (AB, 2H, 7,8-OCH2O—, Δδ=4.8 Hz, J=1.2 Hz), 4.28 (q, 2H, lactam-CH2—, J=4.8 Hz), 3.77 (t, 2H, NCH2(CH2)2OH, J=4.8 Hz), 3.59 (t, 2H, N(CH2)2CH2OH, J=4.8 Hz), 2.65 (br s, 1H, OH), 1.81 (quintet, 2H, NCH2CH2CH2OH, J=4.8 Hz); MS (EI) m/z 405 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](CCl)[CH:12]=[O:13].[OH-].[Na+].[CH2:18](O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:18]=[C:12]([OH:13])[CH:11]=[N:10]1
Reactant: O=CC(CCl)=NNc1ccc(Cl)cc1Cl
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cnn(-c2ccc(Cl)cc2Cl)c1
Yield: 87 %

Procedure:
27.0 g of 3-chloropyruvaldehyde 2,4-dichlorophenylhydrazone is suspended in 100 ml of ethanol. To the suspension is added at room temperature 12 g of sodium hydroxide dissolved in 10 ml of water. After stirring the mixture for 2 hours ethanol is distilled off, and water is added to the resultant residue to dissolve it. Insolubles are removed by filtration, and the filtrate is neutralized with glacial acetic acid. The precipitate is recovered by filtration, washed with water and dried. Recrystallization from toluene results in 17.3 g of the subject compound in the yield of 87%. m.p. 148° to 149° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: ClC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(OC2CCCC2)cn1
Temperature: 65 °C
Yield: 54.6 %

Procedure:
A mixture of 2-chloropyrimidin-5-ol (1 g, 7.66 mmol), chlorocyclopentane (2.39 mL, 22.98 mmol) and potassium carbonate (3.18 g, 22.98 mmol) in N,N-dimethylformamide were heated at 65° C. for 16 h at ambient temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (0-25% ethyl acetate/hexanes) to afford 2-chloro-5-(cyclopentyloxy)pyrimidine (831 mg, 4.18 mmol, 54.6% yield) as a white solid. MS (LC/MS) R.T.=2.32; [M+H]+=199.23.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][N:53]2[CH2:58][C:57]3[CH:59]=[C:60](/[CH:63]=[CH:64]/[C:65](O)=[O:66])[CH:61]=[N:62][C:56]=3[NH:55][C:54]2=[O:68])[CH2:47][CH2:46]1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:44][N:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][N:53]2[CH2:58][C:57]3[CH:59]=[C:60](/[CH:63]=[CH:64]/[C:65](=[O:66])[N:11]4[CH2:12][CH:9]([O:8][CH2:7][C:3]5[S:2][CH:6]=[CH:5][CH:4]=5)[CH2:10]4)[CH:61]=[N:62][C:56]=3[NH:55][C:54]2=[O:68])[CH2:47][CH2:46]1
Reactant: c1csc(COC2CNC2)c1
Reactant: CN1CCN(CCN2Cc3cc(/C=C/C(=O)O)cnc3NC2=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(CCN2Cc3cc(/C=C/C(=O)N4CC(OCc5cccs5)C4)cnc3NC2=O)CC1
Reaction time: 48 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (38 mg, 0.18 mmol), EDCI (35 mg, 0.18 mmol), HOBt (26 mg, 0.18 mmol) and diisopropylethylamine (54 μL, 0.31 mmol) were successively added to a solution of (E)-3-(3-(2-(4-methylpiperazin-1-yl)ethyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)acrylic acid hydrochloride (54 mg, 0.12 mmol) in dimethylformamide (6 mL) at room temperature. The reaction mixture was stirred for 2 days and then diluted by addition of ethyl acetate (50 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methano/ammoniac (1:0:0.1 to 9:1:0.1) as eluent. After several triturations of the compound in diethylether and pentane and a recrystallisation from acetone, the title product was obtained as an off-white solid (2 mg, 3%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:10])=[O:11])=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: CC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)propan-2-one (2.2 g, 0.01 mol) in dimethylformamide (10 mL) was added 1,3-dibromopropane (7.6 mL, 0.07 mol), potassium carbonate (2.3 g, 0.01 mol) and potassium iodide (0.7 g, 0.004 mol). The mixture was stirred at room temperature for 72 hours. Water was added into the reaction vessel and the crude was extracted with ethyl acetate. The organic layer was washed with water and brine, dried, filtered and evaporated to dryness. The crude obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 100% to 10%), obtaining the title compound (54%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].C(NC(C)C)(C)C>O1CCOCC1.[Cu](I)I.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:22]1([C:20]#[C:21][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: I[Cu]I
Solvent: C1COCCO1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NC1(c2ccc(C#Cc3ccccc3)cc2)CCC1
Temperature: 90 °C
Yield: 52.1 %

Procedure:
A mixture of tert-butyl 1-(4-bromophenyl)cyclobutylcarbamate (1.53 g, 4.7 mmol), ethynylbenzene (2.5 mL, 22.6 mmol), copper iodide (36 mg, 0.24 mmol) and diisopropylamine (3.2 mL, 22.6 mmol) in dioxane (3 mL) was degassed for 30 min, followed by the addition of bis(tri-tert-butylphosphine)palladium (144 mg, 0.36 mmol). The resulting mixture was heated at 90° C. for 16 h, after cooled down to RT, concentrated to dryness. The crude residue was purified by column chromatography (eluting with 10% DCM in heptane) to give the title compound (0.85 g, 52%). 1H NMR (500 MHz, CDCl3): 7.58-7.54 (m, 4H), 7.48-7.43 (m, 2H), 7.39-7.20 (m, 3H), 2.55-2.40 (m, 4H), 2.15-2.10 (m, 1H), 1.93-1.84 (m, 1H), 1.45-1.20 (br s, 9H).
Reaction SMILES: [CH3:1][O:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:20].[BH4-].[Na+]>CO>[CH3:1][O:2][N:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[OH:13])=[CH:11][C:6]=2[N:5]=[C:4]1[CH3:20]
Reactant: COn1c(C)nc2cc(C(=O)c3ccccc3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COn1c(C)nc2cc(C(O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
(a-4) To a stirred solution of 3.4 parts of (1-methoxy-2-methyl-1H-benzimidazol-5-yl) phenylmethanone in 64 parts of methanol were added 0.6 parts of sodium tetrahydroborate. After stirring for 30 minutes at room temperature, the methanol layer was evaporated. Water was added to the residue and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from 45 parts of ethyl acetate. The product was filtered off and dried, yielding 2.8 parts (80%) of 1-methoxy-2-methyl-α-phenyl-1H-benzimidazole-5-methanol (int. 51).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C@@H:23]([CH3:37])[C@@H:24]([CH3:36])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].[N+:44]([C:47]1[N:48]=[CH:49][NH:50][CH:51]=1)([O-:46])=[O:45]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH2:25][C@H:24]([CH3:36])[C@H:23]([CH3:37])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:50]3[CH:51]=[C:47]([N+:44]([O-:46])=[O:45])[N:48]=[CH:49]3)[CH:15]=2)[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCBr)c2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C[C@H](C)[C@H](C)Cc2ccc(OC)c(OCCOCCOCCOCCn3cnc([N+](=O)[O-])c3)c2)cc1OC
Yield: 88 %

Procedure:
The Standard Procedure 2 was followed by use of 5b (130.8 mg, 0.2241 mmol, 1.0 equiv), potassium carbonate (63.6 mg, 0.460 mmol, 2.1 equiv), and 4-nitroimidazole (6a, 50.2 mg, 0.444 mmol, 2.0 equiv). After workup and purification with column chromatography (100% EtOAc as eluant), 7c (121.3 mg, 0.1971 mmol) was obtained in 88% yield as a yellow gummy oil: 1H NMR (CDCl3, 400 MHz) δ 0.80 (d, J=6.0 Hz, 6H, 2×CH3), 1.71-1.72 (m, 2H, 2×CH), 2.22-2.28 (m, 2H, 2×ArCH), 2.69-2.73 (m, 2H, 2×ArCH), 3.61-3.85 (m, 21H, 3×OCH3+6×OCH2), 4.08-4.12 (m, 4H, CH2N+CH2O), 6.61 (s, 1H, ArH), 6.65-6.68 (m, 3H, 3×ArH), 6.74-6.77 (m, 2H, 2×ArH), 7.46 (d, J=1.0 Hz, 1H, nitroimidazole C5-H), 7.87 (d, J=1.0 Hz, 1H, nitroimidazole C2-H); 13C NMR (CDCl3, 100 MHz) δ 15.97, 16.00, 38.54, 38.59, 39.01, 39.04, 48.02, 55.59, 55.69, 55.77, 68.26, 69.30, 69.49, 70.32, 70.37, 70.40, 70.49, 110.87, 111.58, 112.07, 114.57, 120.17, 120.77, 121.47, 134.30, 134.40, 136.45, 146.80, 147.33, 147.69, 147.76, 148.48; IR (neat) 2924 (s), 2868 (s), 1607 (w), 1589 (w), 1516 (s), 1456 (m), 1335 (s), 1260 (s), 1236 (s), 1028 (s) cm−1; HRMS (FAB) m/z calcd for C32H46N3O9 (M+H)+: 616.3234. found: 616.3239.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(CNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a solution of 4-aminobenzenemethanamine (1.5 g, 12.3 mmol) in 20 mL CH2Cl2 was added benzylchloroformate (1.57 mL, 11 mmol), followed by triethylamine (Et3N) (1.5 mL, 11 mmol) at room temperature. White percipitates was observed immediately. The reaction was stirred at room temperature for 10 minutes and removed Et3N salt by filtration. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The EtOAc layer was washed with a sat. solution of KHSO4, a sat. solution of NaHCO3, concentrated in vacuo and subjected to a silica-gel column using CHCl3 /CH3 OH=25/1 ratio as an eluting solvent to give title compound (43% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([C:36](O)=[O:37])[CH:27]=1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:36]([C:28]3[CH:27]=[C:26]([O:25][CH3:24])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)=[O:37])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc(C(=O)O)nc2ccccc12
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: COc1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(C)sc2-c2cccc(F)c2)nc2ccccc12

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 4-methoxy-quinoline-2-carboxylic acid. LC-MS (basic): tR=0.96 min; [M+H]+=517.2.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:25])=[C:5]([C:21]([O:23]C)=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH2:14][CH2:13][CH2:12]2)[CH3:2].[I-].[Li+]>CCOC(C)=O>[CH2:1]([C:3]1[C:4]([OH:25])=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH2:14][CH2:13][CH2:12]2)[CH3:2]
Reactant: CCc1c(-c2ccc3c(c2)CCCN3C)[nH]c(=O)c(C(=O)OC)c1O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc3c(c2)CCCN3C)[nH]c(=O)c(C(=O)O)c1O
Temperature: 65 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a suspension of methyl 5-ethyl-4-hydroxy-6-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (34 mg, 0.1 mmol) in EtOAc (1 mL) was added lithium iodide (40 mg, ca. 0.3 mmol, 3.0 eq) at room temperature. The mixture was heated to 65° C. and stirred for 1 h. The reaction mixture was diluted by EtOAc (2 mL) then quenched with 1N HCl (0.5 mL). The precipitate was collected by filtration then washed with Et2O to afford the title compound as a yellow solid (20 mg, 0.061 mmol, 61%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].I[CH2:10][CH:11]([CH3:13])[CH3:12].CC1(C)CCCCC1=O>>[CH2:10]([C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8])[CH:11]([CH3:13])[CH3:12]
Reactant: CC1CCCCC1=O
Reactant: CC(C)CI
Agent: CC1(C)CCCCC1=O
Product: CC(C)CC1(C)CCCCC1=O

Procedure:
The alkylation of 2-methylcyclohexanone with 1-iodo-2-methyl-propane takes place in a manner similar to that described above for the preparation of 2,2-dimethyl-cyclohexanone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:41]([C:37]3[CH:36]=[C:35]4[C:40](=[CH:39][CH:38]=3)[N:32]([CH2:31][C:28]3[CH:27]=[CH:26][C:25]([C:20]5[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:30][CH:29]=3)[C:33]([CH3:45])=[C:34]4[CH3:44])=[O:42])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3ccc4c(c3)OCO4)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using benzo[d][1,3]dioxol-5-ylmethanamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 533 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[C:20](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([O:18][CH3:19])[CH:12]=[CH:11][C:7]=1[C:8]([O:10][CH3:20])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=O)O)c(NCCCCl)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1NCCCCl
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.3 %

Procedure:
To a mixture of 2-[(3-chloropropyl)amino]-4-methoxy-3-nitrobenzoic acid (1.77 g, 6.13 mmol) and potassium carbonate (847 mg, 6.13 mmol) in N,N-dimethylformamide (18 mL) was added iodomethane (0.38 mL, 6.10 mmol) at room temperature. After stirring at room temperature for 14 hr, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×5) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound (1.60 g, 5.29 mmol, 86%) as a yellow amorphous.