Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:21]([C@@:22]4([CH3:28])[CH2:23][CH2:24][C@H:25]([OH:27])[CH2:26][C:2]124)[CH2:20][CH2:19][C@@:18]1([CH3:29])[C@H:6]3[CH2:7][CH2:8][C@@H:9]1[C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35].C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:26][C@@H:25]([OH:27])[CH2:24][CH2:23][C@:22]1([CH3:28])[C@@H:21]1[C@H:5]([C@H:6]3[C@:18]([CH3:29])([CH2:19][CH2:20]1)[C@@H:9]([C@H:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: NCCCCN
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C[C@@H](NCCCCN)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 60.8 %

Procedure:
5,6α-epoxicholestan-3β-ol (8.9 g, 22.1 mmol, 1 eq) and putrescine (3.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-(4-aminobutylamino)-cholestan-3β-ol as a white solid (6.6 g, 61%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 19% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(N(CC)CC)C>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:10][CH2:11][C:12](=[C:15]3[C:16]4[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=4[CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=4)[CH2:13][CH2:14]2)=[CH:30][CH:31]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 92.3 %

Procedure:
1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) was N-acetylated by acetic anhydride using triethyl amine as base. Yield 92.3%
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[CH:25]=[CH2:26].CCOCC>CN(C=O)C>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:26][CH:25]=[CH2:24])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Oc2ccccc2)ccc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccccc2)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Acetyl-4-phenoxyphenol (4.22 g, 18.5 mmol) and cesium carbonate (15.0 g, 46.0 mmol) are taken in DMF (50 mL) and treated with allyl bromide (2.24 g, 18.5 mmol). The mixture is stirred overnight at room temperature. Ether is added and the mixture is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to give 2-acetyl-1-allyloxy-4-phenoxybenzene as a yellow solid.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]CC.[Na+].O.[N+:12]([CH3:15])([O-:14])=[O:13]>C(O)C>[N+:12]([CH2:15][C:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:14])=[O:13]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of cyclopentanone (40.0 mL, 452 mmol) in nitromethane (36 mL) and ethanol (14 mL) was added a solution of sodium ethoxide in ethanol (2.67 M, 8.5 mL, 23 mmol). The solution was stirred for five days at room temperature. Water (400 mL) was added, and the mixture was extracted with ethyl acetate (2×350 mL). The combined organic extracts were washed with water (2×200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The starting materials and solvent were removed from the product by distillation under reduced pressure to yield 8.3 g of 1-(nitromethyl)cyclopentanol as a yellow liquid.
Reaction SMILES: C(C1C=C2C(=CC=1)N(OC(OC(C)(C)C)=O)C(=O)[C@@H](NC(=O)OC(C)(C)C)C2)C1C=CC=CC=1.[CH2:35]([C:42]1[CH:43]=[C:44]([C:68]([N+:71]([O-:73])=[O:72])=[CH:69][CH:70]=1)[CH2:45][C@@H:46]([C:61]([O:63]C(C)(C)C)=[O:62])[N:47]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:35]([C:42]1[CH:43]=[C:44]([C:68]([N+:71]([O-:73])=[O:72])=[CH:69][CH:70]=1)[CH2:45][C@@H:46]([C:61]([OH:63])=[O:62])[NH2:47])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1cc(Cc2ccccc2)ccc1[N+](=O)[O-])N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H]1Cc2cc(Cc3ccccc3)ccc2N(OC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1cc(Cc2ccccc2)ccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
tert-Butyl {(3S)-6-benzyl-1-[(tert-butoxycarbonyl)oxy]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}carbamate (81) To a solution of tert-butyl 3-benzyl-N-(diphenylmethylene)-6-nitro-L-phenylalaninate (79) (150 mg, 0.288 mmol) in dichloromethane was added trifluoroacetic acid in equal volume at 0° C., and the reaction was allowed to stir at RT for 18 h. Solvents were removed under reduced pressure, and the residue was taken in water (50 mL), and washed with EtOAc (3×50 mL). The aqueous layer was concentrated under reduced pressure to provide 3-benzyl-6-nitro-L-phenylalanine (80) as a solid (70.2 mg, 59%). LCMS m/z 301.0 (M+1). This crude product (70.2 mg, 0.234 mmol) was dissolved in a 1:1 mixture of THF and MeOH and treated with sodium acetate (325 mg, 2.34 mmol) and tin(II) chloride dihydrate (269 mg, 1.17 mmol) and stirred for 4 h at 0° C. To the reaction mixture was added triethylamine (0.33 mL, 2.4 mmol) and (BOC)2O (132 mg, 0.585 mmol), and the reaction was allowed to warm to RT and stir for 18 h. The reaction mixture was filtered, and the filtrate was washed with water (3×100 mL), washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 80% EtOAc in heptane) yielded the product as a solid (40 mg, 36%). 1H NMR (500 MHz, CDCl3) δ 1.47 (br s, 9H), 1.56 (br s, 9H), 2.86-3.00 (m, 1H), 3.33-3.43 (m, 1H), 3.94 (s, 2H), 4.47-4.55 (m, 1H), 5.57 (br s, 1H), 6.9-7.1 (v br s, 1H), 7.04 (s, 1H), 7.11 (br d, J=8 Hz, 1H), 7.18 (d, J=7.6 Hz, 2H), 7.21-7.25 (m, 1H), 7.31 (dd, J=7.8, 7.3 Hz, 2H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[C:13]([Cl:22])[C:12]=2[Cl:23])[N:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25].O>CS(C)=O>[N:1]([C:6]1[N:10]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[C:13]([Cl:22])[C:12]=2[Cl:23])[N:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1cnn(-c2c(Cl)cc(C(F)(F)F)c(Cl)c2Cl)c1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.2 %

Procedure:
1.0 g (0.015 mol) of sodium azide is added to 3.0 g (0.007 mol) of 5-bromo-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole in 50 ml of dimethylsulphoxide, the mixture is stirred at room temperature for 15 hours, poured into 150 ml of water and extracted several times with chloroform and ethyl acetate, the combined organic phases are dried over magnesium sulphate and concentrated in vacuo and the oily crude produc is purified by chromatography (silica gel; mobile phase: chloroform/acetone 9:1). 0.68 g (24% of theory) of 5-azido-4-nitro-1-(2,3,6-trichloro-4-trifluoromethyl-phenyl)-pyrazole of melting point 84° C.-88° C. is obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21]C4C=CC(C(O)=O)=CC=4OC)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CC2N(C)C(=O)C(F)(F)CN(C3CCCC3)C=2N=1.[CH3:54][N:55]([CH3:66])[CH2:56][CH2:57][O:58][C:59]1[CH:65]=[CH:64][C:62](N)=[CH:61][CH:60]=1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:62]4[CH:64]=[CH:65][C:59]([O:58][CH2:57][CH2:56][N:55]([CH3:66])[CH3:54])=[CH:60][CH:61]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Product: CN(C)CCOc1ccc(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 4-(2-(dimethylamino)ethoxy)aniline. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.79 (m, 6 H) 1.93 (br. s, 2 H) 2.20 (s, 6 H) 2.59 (t, J=5.81 Hz, 2 H) 3.32 (s, Hz, 3 H) 3.88-4.10 (m, 4 H) 4.68 (t, J=8.34 Hz, 1 H) 6.85 (d, J=8.84 Hz, 2 H) 7.55 (d, J=9.09 Hz, 2 H) 8.18 (s, 1 H) 9.20 (s, 1 H). [M+H] calc'd for C23H30F2N6O2, 461; found 461.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH:12]=C)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].S([O-])([O-])=[O:15].[Na+].[Na+].O>C(O)(C)(C)C>[C:1]([O:5][C:6]1[N:7]=[C:8]([CH:12]=[O:15])[CH:9]=[N:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: C=Cc1cncc(OC(C)(C)C)n1
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)Oc1cncc(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
After adding 7.20 g of AD-mix-5 to 60 ml of 50% aqueous tert-butanol, a solution of 1.00 g of 2-tert-butoxy-6-vinylpyrazine in tert-butanol (5 ml) was added and the mixture was stirred overnight at room temperature. Next, 8.40 g of sodium sulfite was added to the reaction solution, the mixture was stirred at room temperature for 1 hour, and then water was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in 40 ml of methanol, an aqueous solution of 2.35 g of sodium periodate (20 ml) was added while stirring on ice, and stirring was continued at room temperature for 40 minutes. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (954 mg, 96% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:10]1[C@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C@@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:12][NH:11]1)#[N:9].[C:33](OC(=O)C)(=[O:35])[CH3:34].C(=O)(O)[O-].[Na+]>ClCCl>[C:33]([N:11]1[CH2:12][C@H:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=2[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]1[C:8]#[N:9])(=[O:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1C#N
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.8 %

Procedure:
Triethylamine (1.29 mL, 9.25 mmol) was added to a solution of tert-butyl [(3R,6S)-2-cyano-6-(2,3-difluorophenyl)azepan-3-yl]carbamate (0.65 g, 1.85 mmol) in dichloromethane (20 mL) at 0° C. Acetic anhydride (0.53 mL, 5.55 mmol) was added and the mixture was allowed to warm to ambient temperature. After 16 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (99% dichloromethane/ethyl acetate→70% dichloromethane/ethyl acetate) gave the title compound (144 mg). MS 394.1 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@@H:7]2[CH2:6][C@@H:5]([CH2:10]3)[CH2:4]1.C1(C2NC3C(=CC=[C:31](C=3)[O:32]C)C=2CCN=1)C.COCC[C@@H]1[C@@H]2N3CCC4C5C=CC=CC=5NC=4[C@]2(C(OC)=O)CC(C3)C1.CC[C@@H]1[C@@H]2N3CCC4C5C=CC=CC=5NC=4[C@]2(C(OC)=O)C[C@@H](C3)C1>>[CH3:1][CH2:2][C@@H:3]1[C@@H:8]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19]([O:32][CH3:31])[CH:20]=[CH:21][C:16]=5[NH:15][C:14]=4[C@@H:7]2[CH2:6][C@@H:5]([CH2:10]3)[CH2:4]1
Reactant: COc1ccc2c3c([nH]c2c1)C(C)=NCC3
Reactant: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccccc5c4CCN(C2)[C@@H]13
Agent: CC[C@H]1C[C@@H]2CN3CCc4c([nH]c5ccccc45)[C@](C(=O)OC)(C2)[C@H]13
Agent: COCC[C@H]1CC2CN3CCc4c([nH]c5ccccc45)[C@](C(=O)OC)(C2)[C@H]13
Product: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccc(OC)cc5c4CCN(C2)[C@@H]13

Procedure:
Ibogamine (20-40 mg/kg), harmaline (10-40 mg/kg) and desethycoronaridine (10-40 mg/kg) were obviously tremorigenic for 3-4 h and no attempt was made to compare these drugs quantitatively. However, visual observations and videotape recordings of 18-methoxycoronaridine (40 mg/kg) and both R- and S-enantiomers of both ibogamine (40 mg/kg) and coronaridine (40 mg/kg) indicated very little if any tremorigenic activity. The effects of these latter drugs were therefore assessed using the automated testing procedure developed to quantitate tremors. Ibogains (40 mg/kg) and saline (1 ml/kg) were used as positive and negative controls, respectively. While ibogaine produced a significant increase in movements indicative of tremors, the 18-methoxycoronaridine and the ibogamine and coronaridine enantiomers had no effects that differed significantly from the effects of saline.
Reaction SMILES: [CH3:1][CH:2]([OH:10])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:10][CH:2]([C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)[CH3:1])[C:15]=1[C:16]#[N:17]
Reactant: CC(O)c1ccc(F)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.1 %

Procedure:
A solution of alpha-methyl-4-fluorobenzyl alcohol (0.7 ml; 5.5 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (220 mg; 5.5 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, and stirred for 45 minutes. In another vessel, a solution of 2,6-difluorobenzonitrile (765 mg, 5.5 mmol) in dimethylformamide was chilled to 0° C., and activiated anion was added over 20 minutes. Mixture was then stirred 2 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 1.1 g of 2-fluoro-6-[1-(4-fluorophenyl)-ethoxy]-benzonitrile (78% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][O-:13].[Na+].O>CO>[CH3:12][O:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A roundbottom flask was charged with a solution of 6-chloro-2-methyl-3-nitropyridine (12.0 g, 69.36 mmol) in methanol (100 ml). Sodium methanolate (5.6 g, 103.70 mmol) was added and the resulting solution was stirred at room temperature for 24 hours. The mixture was poured into 100 ml of water and the solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18](Cl)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>N1C=CC=CC=1>[CH3:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[O:1][C:2]2=[O:10])=[O:19])[CH2:14][CH2:13]1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: CC1CCN(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1CCN(C(=O)n2c(=O)oc3cccnc32)CC1

Procedure:
100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one, 235 mg (1.45 mmol) of 4-methylpiperidine-1-carbonyl chloride and 101 μl (2.18 mmol) of triethylamine were stirred in 5 ml of pyridine at room temperature for 3 h. The reaction mixture was concentrated, and the residue was dissolved in water and extracted with ethyl acetate. The organic phase was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 6 mg (3%), M+H+: 262.12.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:31]([CH2:42][O:43][CH2:44][CH3:45])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl.O>[NH2:47][C:26]1[C:25]2[N:30]=[C:31]([CH2:42][O:43][CH2:44][CH3:45])[N:32]([CH2:33][C:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])([CH3:36])[CH3:35])[C:24]=2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:29][C:28]=2[N:27]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 8 h

Procedure:
mCPBA (11.2 g, 39.2 mmol) was added to a solution of N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (prepared as described in Parts A-D of Example 52, 17.2 g, 35.6 mmol) in dichloromethane (350 mL). The solution was stirred overnight and additional mCPBA (approximately 1-2 g) was added. After 20 minutes, concentrated ammonium hydroxide (150 mL) was added. The mixture was stirred for 10 minutes and p-toluenesulfonyl chloride (8.20 g, 42.8 mmol) was added in portions. The mixture was stirred at ambient temperature for 2 days, then was filtered. A white solid was obtained, which was slurried in water, filtered, and dried to yield 11.7 g of N-{2-[4-amino-7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide. A small sample, 500 mg, was purified to yield 300 mg of analytically pure N-{2-[4-amino-7-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, mp 264-266° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[N:7]([CH3:14])[C:6]4=[O:15])[CH2:29][CH2:30]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4cc(Cl)ccc43)CC2)c2ccccc21
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.75 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 2,65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred at 70°-80° C. for 2 hours. The reaction mixture is cooled, poured onto water and the precipitated product is filtered off. It is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 3 parts (43%) of 5-chloro-1-{1-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 166.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17](=O)[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:20]([NH2:22])=[O:21].C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]([NH:22][CH:20]=[O:21])[CH3:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: NC=O
Solvent: O=CO
Product: CC(NC=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 190 °C
Reaction time: 7 h
Yield: 60 %

Procedure:
A mixture of 1-[1-(3-bromo-phenyl)-1H-benzoimidazol-5-yl]-ethanone (7.5 g, 23.8 mmol), formamide (9.5 ml, 23.8 mmol) and formic acid (22.4 ml, 595 mmol) was stirred at 190° C. for 7 hours. The cooled mixture was decanted. The residue was rendered alkaline by addition of saturated, aqueous sodium carbonate and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate and concentrated in vacuo. The concentrate was eluted through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (9:1:0.1 v/v/v) to afford the desired product (60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([Cl:27])=[O:18])=[CH:10]1
Reactant: O=C(O)c1ccc(=O)n(-c2c(F)cccc2F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(=O)n(-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
To a suspension of 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (795 mg) in CH2Cl2 (8 mL) were added DMF (0.025 mL) and ethanedioyl dichloride (603 mg) at 0° C. under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hr. The volatile materials were removed by evaporation in vacuo to give 1-(2,6-difluorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarbonyl chloride (810 mg).