Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]4[CH2:24][CH2:23][CH2:22][O:21]4)[CH:14]=3)[C:9]2=[O:25])=[CH:4][C:3]=1[F:26].[CH3:27][N:28]([CH3:35])[C:29]1([CH3:34])[CH2:33][CH2:32][NH:31][CH2:30]1>>[CH3:27][N:28]([CH3:35])[C:29]1([CH3:34])[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:19][C@H:20]5[CH2:24][CH2:23][CH2:22][O:21]5)[CH:14]=4)[C:9]3=[O:25])=[CH:4][C:3]=2[F:26])[CH2:30]1
Reactant: CN(C)C1(C)CCNC1
Reactant: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(Br)c(F)c1
Product: CN(C)C1(C)CCN(c2ccc(-n3ccc4cc(OC[C@H]5CCCO5)ccc4c3=O)cc2F)C1

Procedure:
2-(4-Bromo-3-fluorophenyl)-6-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one and dimethyl-(3-methyl-pyrrolidin-3-yl)-amine were reacted according to Method R1. In this way the product was obtained with molecular weight 465.57 (C27H32FN3O3); MS (ESI): 466 (M+H+).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[OH-].[Na+].[I-].[Na+].[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2)=[O:18].[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][C:31]=1[CH2:40]Cl>O1CCOCC1.O>[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[N:32][C:31]=1[CH2:40][C:22]1[C:21]2[C:25](=[CH:26][CH:27]=[C:19]([C:17]([O:16][CH3:15])=[O:18])[CH:20]=2)[NH:24][C:23]=1[CH3:28]
Reactant: ClCc1ncc2ccccc2c1Cl
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2[nH]c(C)c(Cc3ncc4ccccc4c3Cl)c2c1
Temperature: 100 °C
Reaction time: 56 h
Yield: 19.2 %

Procedure:
To a mixture of L-tartaric acid (0.600 g), sodium hydroxide (0.160 g), 1,4-dioxane (4 ml) and water (4 ml), added are sodium iodide (0.15 g) and 5-(methoxycarbonyl)-2-methylindole (0.378 g). Then, a 1,4-dioxane (2 ml) solution of 4-chloro-3-(chloromethyl)isoquinoline (0.50 g) is added thereto, and stirred at 100° C. for 56 hours. The reaction mixture is concentrated, and water is added to the residue, which is then extracted with ethyl acetate. The organic layer is dried and concentrated, and the resulting residue is purified through silica gel column chromatography to obtain 3-((4-chloroisoquinolin-3-yl)methyl)-5-(methoxycarbonyl)-2-methylindole (69) (0.14 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]#[N:8])[N:4]=[CH:3]1.[CH2:9]([Mg]Br)[CH3:10].B(F)(F)F.[OH-].[Na+]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2([NH2:8])[CH2:10][CH2:9]2)[N:4]=[CH:3]1
Reactant: CC[Mg]Br
Reactant: Cn1cnc(C#N)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Product: Cn1cnc(C2(N)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-Methyl-1H-imidazole-4-carbonitrile (0.5 g, 4.6 mmol, 1 eq) was dissolved in THF, and to which titanium isopropoxide (1.6 g, 5.6 mmol, 2.5 eq) was added dropwise over 15 minutes. The mixture was stirred for 15 minutes at room temperature, and then ethyl magnesium bromide (1.6 g, 11.5 mmol, 2.5 eq) was added at room temperature over 15 minutes. The reaction mixture was stirred for 1 h. BF3 etherate (0.8 g, 5.6 mmol, 2.2 eq) was added and the mixture stirred at room temperature for 1 h. 1 N NaOH solution was added to the mixture to bring the pH to 9-10. Reaction mass was filtered through celite and the filtrate washed with DCM. The organic mixture was concentrated and the residue purified by flash chromatography on silica gel using 10% chloroform/methanol. Yield: 0.6 g 1H NMR (400 MHz, CDCl3): δ 0.97 (t, J=3.4 Hz, 2H), 1.00 (t, J=3.4 Hz, 2H), 3.63 (s, 3H), 7.28 (s, 1H), 7.31 (s, 1H). LCMS: (ES+) m/z=138.2 (M+H).
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH2:11][OH:12])[CH:8]=[CH:9][CH:10]=1)([F:4])[CH3:3].C(OCC)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]=[O:12])([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc(CO)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(F)(F)c1cccc(C=O)c1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Add a solution of [3-(1,1-Difluoro-ethyl)-phenyl]-methanol (3.47 mmol) in dichloromethane (10.5 mL) dropwise to a suspension of 3,3,3-triacetoxy-3-iodophthalide (3.64 mmol) in dichloromethane (10.5 mL) at room temperature. Stir for 30 minutes. Add diethyl ether (10 mL) and 5% aqueous sodium bicarbonate (10 mL) containing sodium thiosulfate (3 g). Mix well for 20 minutes. Separate the layers, and extract the aqueous with ethyl ether. Combine the organic layers, wash with brine, dry over sodium sulfate, filter, and evaporate to give a yellow solid. Purify over silica (40 g) eluting with 0 to 50% dichloromethane in hexanes. Evaporate until most solvent is removed being careful not to drive off the volatile product. Dry additionally by blowing a nitrogen stream over the product to give the title compound in 70% yield. 1HNMR (400.43 MHz, CDCl3): δ 10.03 (s, 1H), 8.00 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.75 (d, J=7.0 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H), 1.98-1.89 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[N:10]=[N:11][NH:12][N:7]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(-c2nn[nH]n2)cc1
Yield: 76 %

Procedure:
4-Bromobenzonitrile (20 g, 110 mmol), sodium azide (7.9 g, 121 mmol) and NH4Cl (6.5 g, 121 mmol) in DMF (340 mL) were heated at 90° C. under argon. After 2 days the reaction mixture was concentrated and then diluted with water (300 mL). After adding enough 1M NAOH to render the mixture basic (litmus paper) it was washed with ether (4×25 mL). The aqueous portion was acidified to pH 3 with 1N HCl, the precipitated product was collected by suction filtration and then washed with water. The crude product was recrystallized from ethanol to give crystalline 5-(4-bromophenyl)-2H-tetrazole (19.2 g. 83.6 mmol) in 76% yield, mp. 271°-273° C.
Reaction SMILES: FC1C=CC(C2C3C(=CC=CC=3)N(C(C)C)C=2/C=C/CO)=CC=1.[CH3:24][O:25][C:26](=[O:36])[C:27]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)=[O:28].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:24][O:25][C:26](=[O:36])[C:27](=[O:28])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CC(C)n1c(/C=C/CO)c(-c2ccc(F)cc2)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccccc1

Procedure:
As in Example 15, (E)-3-[3-(4-fluorophenyl)-1-(1-methylethyl)- 1H-indol-2-yl]-2-propen-1-ol (1.0 g) was reacted with 4-hydroxyphenylglyoxylic acid methyl ester (0.585 g) in the presence of diethyl azodicarboxylate (0.71 g) and triphenylphosphine (1.06 g) in tetrahydrofuran (30 mL). The crude reaction product, isolated in the usual manner, was purified by flash chromatography over silica gel (130 g; ethyl acetate-hexane; 1:4) to furnish 0.61 g of (E)-4-[3-[3-(4-fluorophenyl)-1-(1-methylethyl)-1H-indol-2-yl]-2-yl]-2-propenyloxy]-alpha-oxobenzeneacetic acid methyl ester as a yellow oil. A portion (0.2 g) was rechromatographed over silica gel (diethyl ether-hexane; 1:19) to furnish 0.225 g of the analytically pure ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31]O)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:31][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: COc1ccc(CO)cc1OC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(=O)N(c3cnn(Cc4c(C)noc4C)c3)C2=O)cc1OC
Reaction time: 0.08 h

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) (275 mg, 1 mmol), (3,4-dimethoxyphenyl)methanol (201 mg, 1.2 mmol), N,N,N,N-tetramethylazodicarboxamide (344 mg, 2 mmol) were dissolved in 2 mL anhydrous THF. Tributylphosphine (404 mg, 2 mmol) was added and the reaction mixture was placed in a microwave reactor for 5 minutes at 90° C. The reaction was filtered, concentrated and purified by HPLC (10-95% Acetonitrile/Water, 25 minutes) to afford the title compound. Yield: 25 mg, 6%. 1H NMR (DMSO, 400 MHz): δ2.119 (s, 3H), 2.385 (s, 3H), 3.724 (J=6.4 d, 6H), 3.946 (s, 2H), 4.435 (s, 2H), 5.178 (s, 2H), 6.885 (m, 3H), 7.776 (s, 1H), 8.166 (s, 1H). MS M+H calculated 426.1. Found 426.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.06 uM.
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N+:9]([O-])=O)[CH:6]=[CH:7][CH:8]=1.O.Cl>C(O)(C)C>[F:1][S:2]([F:12])([F:13])([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[NH2:9]
Reactant: O=[N+]([O-])c1cccc(S(F)(F)(F)(F)F)c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Nc1cccc(S(F)(F)(F)(F)F)c1

Procedure:
Reduced iron powder (8.60 g) was added to a stirred solution of 3-pentafluorosulphanylnitrobenzene (2.65 g) in a mixture of isopropanol (27 ml), water (6 ml) and concentrated hydrochloric acid (0.3 ml). The resulting mixture was heated under reflux for 1 hour, and was then allowed to cool slightly before being filtered through Hyflo. The Hyflo was washed with more isopropanol, and the combined filtrates were evaporated under reduced pressure. The residue was dissolved in a little diethyl ether and the solution was treated with solid sodium hydrogen carbonate, then dried over magnesium sulphate. After filtration to remove the inorganics the solution was evaporated under reduced pressure, and the oily residue was distilled in a Kugelrohr apparatus. The title compound was collected as a colourless oil, bp 110° C. (oven temperature) at 12 mmHg, which crystallised on standing, yield 1.90 g, mp 32°-35° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCc1cc(OC(F)(F)F)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
2-Benzyloxy-5-trifluoromethoxy-benzaldehyde (1.40 g) is dissolved in ethanol (30 ml) and thereto is added sodium borohydride (189 mg) and the mixture is stirred at room temperature for 30 minutes. To the reaction solution are added aqueous ammonium chloride solution and ethyl acetate and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give (2-benzyloxy-5-trifluoromethoxy-phenyl)methanol (1.10 g).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(C(C)C)C(C)C)C.N1(C(N2C=CN=C2)=O)C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]2[C@@H:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[N:38]([C@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:37](=[O:55])[C@@H:36]([CH2:56][C:57](O)=[O:58])[CH2:35]2)[CH:31]=[CH:32][CH:33]=1.[NH4+].[Cl-]>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:30]([C@H:34]2[CH2:35][C@H:36]([CH2:56][C:57]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:58])[C:37](=[O:55])[N:38]([C@@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C@@H:39]2[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)[C@@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)NS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanesulfonamide (0.02 g, 0.2 mmol), N-ethyl-N-isopropylpropan-2-amine (0.05 ml, 0.3 mmol), di(1H-imidazol-1-yl)methanone (0.04 g, 0.2 mmol) and 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3, 0.030 g, 0.06 mmol) were combined in 2 mL of THF. After being stirred at 25° C. for 12 h, sat. NH4Cl solution was added and the reaction mixture was extracted with EtOAc. The combined organic layers were successively washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase HPLC (10 to 90% AcCN/H2O with 0.1% TFA in 45 min) to give the title compound as a white solid.
Reaction SMILES: C[N+](C)=CCl.[Cl-].P(Cl)(Cl)(Cl)=O.[Br:12][CH2:13][C:14](=[O:30])[C:15](=[N:19][O:20][CH2:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C:16]([OH:18])=O.Cl.[NH2:32][CH:33]1[C:58](=[O:59])[N:35]2[C:36]([C:42]([O:44][CH:45]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[O:43])=[C:37]([CH:40]=[CH2:41])[CH2:38][S:39][C@H:34]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[Br:12][CH2:13][C:14](=[O:30])[C:15](=[N:19][O:20][CH2:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C:16]([NH:32][CH:33]1[C:58](=[O:59])[N:35]2[C:36]([C:42]([O:44][CH:45]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:43])=[C:37]([CH:40]=[CH2:41])[CH2:38][S:39][C@H:34]12)=[O:18]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(CON=C(C(=O)O)C(=O)CBr)OCC(Cl)(Cl)Cl
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)CBr)[C@H]2SC1
Temperature: 5 °C
Yield: 89 %

Procedure:
Vilsmeier reagent prepared from phosphorus oxychloride (7.1 ml) and N,N-dimethylformamide (6.0 ml) was suspended in dry tetrahydrofuran (25 ml). To this suspension was added 4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyric acid (25 g), and the mixture was stirred at 5° C. for an hour to prepare the activated acid solution. The solution was added at a time to a solution of benzhydryl 7-amino3-vinyl-3-cephem-4-carboxylate hydrochloride (16.2 g) and trimethylsilylacetamide (40 g) in ethyl acetate (140 ml) at -30° C., and the mixture was stirred at -15° to -5° C. for an hour. The reaction mixture was washed with a saturated aqueous sodium bicarbonate and a saturated aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyramido]-3-vinyl-3-cephem-4-carboxylate (26.0 g).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH3:6][C:7](=[O:10])[CH2:8][CH3:9]>P(=O)(O)(O)O>[CH3:9][C:8]([C:7](=[O:10])[CH3:6])=[CH:2][C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: CCC(C)=O
Agent: O=P(O)(O)O
Product: CC(=O)C(C)=CC(=O)O

Procedure:
Prepared from glyoxylic acid (16.1 g, 0.18 mol), 2-butanone (45.6 g, 0.63 mol) and orthophosphoric acid (30 ml). 1H n.m.r. δ (CDCl3) 2.07, s, 3H, CH3; 2.40, s, CH3; 6.57, s, 1H, H2. 13C n.m.r. δ (CDCl3): 13.2, CH3; 26.2, CH3; 125.2, C2; 152.6, C3; 171.2, C1; 199.8, C4.
Reaction SMILES: [C:1]1([C:7](=[N:17]O)[C:8](=[N:15]O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[C:20](=S)=[S:21]>C(O)C>[C:1]1([C@H:7]2[C@H:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:15][C:20](=[S:21])[NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C(C(=NO)c1ccccc1)c1ccccc1
Reactant: S=C=S
Agent: [Na]
Solvent: CCO
Product: S=C1N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Reaction time: 3 h

Procedure:
11.5 g of D,L-1,2-diphenylethylenediamine (melting point 70°-71°), which is obtainable by reduction of benzil dioxime with sodium in ethanol, are dissolved in 230 ml of carbon disulfide. The solution is stirred for 3 hours and evaporated to dryness. The residue is taken up in a mixture of 40 ml of ethanol and 40 ml of water, 0.6 ml of concentrated hydrochloric acid is added and the mixture is refluxed for 48 hours. It is then evaporated to dryness and the residue is recrystallised from a mixture of ethanol and acetone. Trans-4,5-Diphenylimidazolidine-2-thione with a melting point of 223°-225° is obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f3) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:5]([O:7][CH3:8])=[O:6].CI.[C:22]([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])([CH3:22])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 90.5 %

Procedure:
Following similar methods to those described in Preparation 324 using 2-(4-bromo-2-nitro-phenyl)-malonic acid dimethyl ester (10 g, 30 mmol), MeI (2 mL, 33 mmol) and K2CO3 (4.6 g, 33 mmol) gave the title compound (9.4 g) as a yellow solid. MS: [M+H]+=346.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[O:10]=[C:11]1[NH:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25][N:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.N1C=CC=CC=1>C(O)(=O)C>[O:29]=[C:26]1[NH:25][N:24]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:14]3[CH:13]=[CH:12][C:11](=[O:10])[NH:16][N:15]=3)=[CH:18][CH:19]=2)[CH2:28][CH2:27]1
Reactant: O=C1CCC(c2ccc(C3=NNC(=O)CC3)cc2)=NN1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(-c3ccc(=O)[nH]n3)cc2)=NN1

Procedure:
A solution of pyridinium bromide perbromide (0.6 g) in hot acetic acid (50 ml) was added dropwise over 10 minutes to a refluxing mixture of 1,4-bis(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzene (0.5 g) and pyridine (0.3 ml) in glacial acetic acid (100 ml). After addition the clear brown solution was stirred under reflux for 3 hours and was cooled and filtered. The filtrate was concentrated to small volume (ca 10 ml) and was treated with distilled water (100 ml) to yield a brown solid which was collected, washed with ethanol and ether and then dried. The crude material is recrystallised from acetic acid to afford the title compound, m.p. greater than 250° C., H NMR: δ (DMSOd6); 2.45 (2H, t), 2.95 (2H, t), 7.00 (1H, d), 7.88 (4H, m), 8.08 (1H, d) and 10.88 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[O:20]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:28]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1cccc(Oc2ccccc2)c1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc(Oc2ccccc2)c1

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 3-phenoxybenzoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-phenoxybenzamide as a white powder, m.p. 105.0-107.0° C. 1H NMR (300 MHz, DMSO-d6) δ8.54 (t, J=5.4 Hz, 1H), 8.34 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.1, 1.2 Hz, 1H), 7.58-7.29 (m, 9H), 7.19-7.13 (m, 2H), 7.04-6.99 (m, 2H), 4.65 (t, J=7.2 Hz, 2H), 3.28 (m, 2H), 1.89 (quintet, J=7.2 Hz, 2H), 1.58 (quintet, J=7.2 Hz, 2H); MS (EI) m/e 451.2012 (451.2008 calcd for C27H25N5O2).
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(O)(=O)CC[C:13]([OH:15])=[O:14]>>[C:13]([OH:15])(=[O:14])[CH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCC(=O)O
Reactant: O=C(O)CCCC(=O)O
Product: O=C(O)CCCCC(=O)O

Procedure:
The mother liquor with the urea-succinic acid adduct removed was treated with a column of the same strongly acidic ion exchange resin to remove urea. After 120 g. of water was further distilled off, the treated liquid was cooled to and allowed to stand at 15° C. to deposit crude adipic acid. 11.9 g. of crude adipic acid was obtained by filtration. The obtained crude adipic acid contained 2.1% by weight of glutaric acid and 1.3% by weight of succinic acid and may be recycled to a purification step in the production of adipic acid to obtain pure adipic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[C:48]1[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[N:49]=1.[CH2:55]([N:62]1[CH2:66][CH2:65][C@@H:64]([NH2:67])[CH2:63]1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:55]([N:62]1[CH2:66][CH2:65][C@@H:64]([NH:67][C:48]2[CH:53]=[N:52][CH:51]=[C:50]([Cl:54])[N:49]=2)[CH2:63]1)[C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: Clc1cncc(Cl)n1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Clc1cncc(N[C@@H]2CCN(Cc3ccccc3)C2)n1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
Palladium(II) acetate (75 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (313 mg) in dioxane (5 mL) was stirred at ambient temperature for 15 minutes. To this suspension was added 2,6-dichloropyrazine (1.00 g), (3R)-(−)-1-benzyl-3-aminopyrrolidine (1.42 g), and cesium carbonate (3.28 g), and the mixture was heated at 80 C for 8 hours. The resulting mixture was allowed to cool to ambient temperature, poured into water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform/methanol=96/4 v/v) to give N-[(3R)-1-benzyl-3-pyrrolidinyl]-6-chloro-2-pyrazinamine (1.00 g) as a yellow solid.