Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6]([CH2:8]P(=O)(OCC)OCC)[N:7]=1)[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH2:1]([C:3]1[S:4][C:5]([CH3:17])=[C:6](/[CH:8]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:7]=1)[CH3:2]
Reactant: CCOP(=O)(Cc1nc(CC)sc1C)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCOC)c(C)s1
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of diethyl [(2-ethyl-5-methyl-1,3-thiazol-4-yl)methyl]phosphonate (4.16 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.66 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (3.48 g) was added to the reaction mixture, and the mixture was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (5:95-25:75, v/v) to give 2-ethyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-5-methyl-1,3-thiazole as a yellow oil (3.56 g, yield 68%). NMR (CDCl3) δ: 1.38 (3H, t, J=7.6 Hz), 2.45 (3H, s), 2.98 (2H, q, J=7.6 Hz), 3.63 (3H, s), 5.55 (2H, s), 7.09 (1H, d, J=15.8 Hz), 7.14-7.33 (2H, m), 7.35-7.46 (2H, m), 7.55-7.65 (1H, m), 7.82 (1H, s).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][CH2:32][CH2:33][NH2:34]>CCCCO>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[CH2:31][CH2:32][CH2:33][NH:34][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: COc1ccc(Br)c(CCCN)c1
Solvent: CCCCO
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(NCCCc3cc(OC)ccc3Br)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (200 mg, 0.58 mmol, 1.00 equiv), 3-(2-bromo-5-methoxyphenyl)propan-1-amine (1.14 g, 2.35 mmol, 4.00 equiv, 50%), n-BuOH (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 245 mg (83%) of methyl 3-(3-(2-bromo-5-methoxyphenyl)propylamino)-2-phenylquinoxaline-6-carboxylate as a yellow semi-solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
2-Chloropyridine4-carbonyl chloride (0.143 g) was added to a stirred mixture of N-(3-amino4-methylphenyl)-2-morpholinopyridine4 carboxamide (0.211 g), triethylamine (0.164 g) and methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40° C. There was thus obtained the title compound (0.276 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.24 (d, 2H), 7.34 (d, 1H) 7.81 (s, 1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.26 (d, 1H), 8.6 (d, 1H); Mass Spectrum M+H+ 452 and 454.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[CH:14]1([CH2:17][OH:18])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:18][CH2:17][CH:14]1[CH2:16][CH2:15]1
Reactant: OCC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCC1CC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-Nitrophenyl chloroformate (0.56 g, 2.8 mmol) was added to a mixture of cyclopropyl carbinol (0.20 g, 2.8 mmol) and triethylamine (0.58 mL, 4.2 mmol) in methylene chloride (5 mL). The mixture was stirred at r.t. for 2 h. After removal of solvent, the residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product.
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C@@H:20]([CH3:25])[C:21]([F:24])([F:23])[F:22])[C:16]([CH:26]3[CH2:28][CH2:27]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[CH2:5][C:6](O)=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH4+:30]>>[NH2:30][C:6](=[O:7])[CH2:5][C:4]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][C@@H:20]([CH3:25])[C:21]([F:23])([F:24])[F:22])[C:16]([CH:26]2[CH2:27][CH2:28]2)=[CH:15][N:14]=1)=[O:12])([CH:1]1[CH2:2][CH2:3]1)[CH3:9]
Reactant: [NH4+]
Reactant: C[C@H](Oc1cc(C(=O)NC(C)(CC(=O)O)C2CC2)ncc1C1CC1)C(F)(F)F
Agent: [Cl-]
Product: C[C@H](Oc1cc(C(=O)NC(C)(CC(N)=O)C2CC2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-3-[[5-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carbonyl]amino]butanoic acid (example 247b) and ammonium chloride as starting materials and isolated (150 mg, 72%); MS (ESI, m/z): 400.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:19]>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl

Procedure:
Reaction of commercially-available 2-chloro-3,5-dinitrobenzoic acid (X) with SOCl2 gave 2-chloro-3,5-dinitrobenzoyl chloride (XI: Z=Cl), which was quenched with ammonia to give 2-chloro-3,5-dinitrobenzamide (XI: Z=NH2). A solution of this amide (1.00 g, 4.07 mmol) and Et3N (1.42 g, 10 mmol) in p-dioxane (30 mL) was treated with N,N-bis(2-chloroethyl)amine hydrochloride (1.45 g, 8.14 mmol) at 50° C. for 18 h. The mixture was then poured into water and extracted with EtOAc to give an oil, which was chromatographed on silica gel. Elution with EtOAc/petroleum ether (1:1) gave 2-[N,N-bis(2-chloroethyl)amino]-3,5-dinitrobenzamide (19) (Ie: R=CONH2) (1.15 g, 80%), mp (CHCl3 /petroleum ether) 123°-124° C. 1H NMR (CH3SOCD3) δ 8.70 (d, J=2.7 Hz, 1 H, H-4), 8.49 (d, J=2.7 Hz, 1 H, H-6), 7.68, 7.35 (2xbr, 2H, CONH2), 3.80, 3.61 (2xt, J=6.9 Hz, 8 H, NCH2CH2Cl). 13C NMR δ 167.94 (CONH2), 147.27 (C-2), 147.20, 142.84 (C-3,5), 137.70 (C-1), 128.40, 123.24 (C-4,6), 55.84 (CH2N), 42.28 (CH2Cl). Anal. (C11H12Cl2N4O5) C,H,N,Cl.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(C2CCCN2)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(C)cc2C)cc1

Procedure:
The title compound, white solid, m.p. 130° C. and MS: m/e=329 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(2,4-dimethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:23][NH:24][O:25][CH3:26]>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:24]([O:25][CH3:26])[CH3:23])=[O:22])=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CNOC
Reactant: CC1Cc2cc(CCOc3ccc(N=C=O)cc3)ccc2O1
Solvent: Cc1ccccc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc3c(c2)CC(C)O3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
1.8 g of 4-[2-(2,3-dihydro-2-methyl-5-benzofuranyl)ethyloxy]phenyl isocyanate was dissolved into 20 ml of toluene, and 2.0 g of N,O-dimethylhydroxylamine dissolved in 5 ml of toluene was slowly added dropwise thereto at room temperature. After the mixture was stirred at room temperature for 2 hours, toluene was distilled off and the residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (2/3) as a developer to obtain 1.8 g of Compound No. 42 shown in Table 2.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[O:8])=[O:5])[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:23])[NH:18][C:19](=[NH:22])[O:20][CH3:21])=[CH:12][CH:11]=1>O1CCCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([N:18]=[C:19]([NH:22][C:7](=[O:8])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[O:20][CH3:21])=[O:23])=[CH:14][CH:15]=1
Reactant: COC(=N)NC(=O)Nc1ccc(Cl)cc1
Reactant: CCOC(=O)N=C=O
Solvent: C1CCOC1
Product: CCOC(=O)NC(=O)NC(=NC(=O)Nc1ccc(Cl)cc1)OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
12 Parts ethoxycarbonyl isocyanate was added dropwise to 23 parts of methyl 4-(4-chlorophenyl)allophanimidate (prepared as above) in 230 parts of tetrahydrofuran at 20°C. The mixture was stirred for six hours at room temperature and then evaporated under reduced pressure. The residue was triturated with boiling 1-chlorobutane, cooled, and the solid collected by filtration affording 16 parts of ethyl 4-[1-(4-chlorophenylcarbamoylimino)-1-(methoxy)methyl]allophanate, m.p. 140.5-142°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]([C:16]([NH:18][CH:19]([CH2:34]C1C=CC=CC=1)[CH:20]([OH:33])[C:21]([F:32])([F:31])[CH:22]([NH2:30])[CH2:23]C1C=CC=CC=1)=[O:17])([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[CH2:41]([S:44](Cl)(=[O:46])=[O:45])[CH2:42][CH3:43].C(N(CC)CC)C>>[CH2:41]([S:44]([NH:30][CH:22]([C:21]([F:31])([F:32])[CH:20]([OH:33])[CH:19]([NH:18][C:16](=[O:17])[C@:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10])[CH3:34])[CH3:23])(=[O:46])=[O:45])[CH2:42][CH3:43]
Reactant: CCCS(=O)(=O)Cl
Reactant: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(N)Cc1ccccc1)(c1ccccn1)C(C)C
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NC(C)C(F)(F)C(O)C(C)NC(=O)[C@](NC(=O)OC)(c1ccccn1)C(C)C
Yield: 65 %

Procedure:
Reaction of the resultant compound from Example 269 and 1 equivalent of propane-sulfonyl chloride and 1.1 equivalent of triethylamine provided the desired product in 65% yield. Mass spectrum: (M+H)+ =661. 1H NMR (CDCl3) δ0.80 (d, 3H), 0.88 (m, 2H), 0.95 (d, 3H), 1.10 (t, 3H), 2.0 (m, 3H), 2.40 (m, 2H), 2.85-3.15 (m, 4H), 3.30 (m, 1H), 3.50 (m, 1H), 3.95 (m, 1H), 4.90 (m, 1H), 5.25 (m, 3H), 6.12 (br d, 1H), 7.20 (m, 12H), 7.70 (m, 1H), 8.60 (m, 1H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[F:15][C:16]([F:37])([F:36])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)=[CH:19][CH:18]=1>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:37])([F:36])[F:15])=[CH:18][CH:19]=2)[N:24]=[C:25]([C:33]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=3)[N:14]=2)[N:26]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.75 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.099 g, 38%). MS (ISN) 514.1 [(M−H)−]; mp 204° C.
Reaction SMILES: [CH:1]([C:4]1[CH2:8][C:7](=[O:9])[N:6]([C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH3:12])[CH3:11])[N:5]=1)([CH3:3])[CH3:2].[OH-].[Ca+2].[OH-].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCOCC1>[OH:9][C:7]1[N:6]([C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)([CH3:12])[CH3:11])[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:8]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CC(C)C1=NN(C(C)(C)c2ccccc2)C(=O)C1
Reactant: CCOC(=O)Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C(C)C)nn(C(C)(C)c2ccccc2)c1O
Temperature: 45 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
3-Isopropyl-1-(2-phenylpropan-2-yl)-1H-pyrazol-5(4H)-one (1.22 g, 5.00 mmol) and calcium hydroxide (435 mg, 7.50 mmol) were suspended in dioxane (20 mL), heated to 45° C. and stirred for 1 hour. After the stirring, the reaction solution was allowed to cool to room temperature, and after dropwise addition of ethyl chloroformate (597 mg, 5.50 mmol), stirred at 90° C. for 6 hours. After completion of the reaction, the resulting light brown suspension was poured into ice-cold 3 M hydrochloric acid and extracted with chloroform (20 mL×5). The resulting organic layer was washed with 0.06 M hydrochloric acid (50 mL×2), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 40 g, ethyl acetate:hexane=1:19 to 1:9) to give 650 mg of the desired product as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][N:4]=1.[H][H]>[Pd].CO>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: CN(C)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CN(C)c1ccc(N)cn1
Yield: 139.6 %

Procedure:
A solution of dimethyl-(5-nitro-pyridin-2-yl)-amine (100 mg, 0.47 mmol) and 10% palladium on carbon (0.05 g) in methanol (5 mL) was shaken under 50 psi hydrogen atmospheres at room temperature for 3 h. The reaction mixture was then filtered through a plug of celite and the filtration pad was washed with ethyl acetate. The organic layers were collected, concentrated, and dried to give N2,N2-dimethyl-pyridine-2,5-diamine (90 mg crude) as a light red oil, which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][C:6]1=[O:16].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][C:6]1=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CN(C)CCN1C(=O)CCc2cccc(F)c21
Agent: O=S(=O)(O)O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (2.86 g, 12.11 mmol) was weighed into a round bottom flask equipped a stir bar. To this was added concentrated sulfuric acid (30 mL) and the flask was cooled to −5° C. in an ice/salt bath. To this stirring solution was added nitric acid (90%, 615.5 μL, 13.2 mmol) and the resulting mixture was stirred for 30 min. The reaction mixture was then quenched with ice and NaOH(aq). The product was extracted with CH2Cl2 (3×). The combined organics were dried, filtered and concentrated then chromatographed on silica using 0-10% (2M NH3 in MeOH) in dichloromethane, giving the desired product. Yield: 1.1 g, 32%, product still contains some impurities). 1H NMR (CDCl3) δ 2.20 (s, 6H), 2.48 (t, 2H, J=7.0 Hz), 2.67 (t, 2H, J=7.0 Hz), 2.98 (t, 2H, J=7.0 Hz), 4.16 (t, 2H, J=7.0 Hz), 7.89 (m, 2H). ESI-MS: 282 (MH+, 100), 237 (50), 192 (27).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](O)(=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:27](=[O:33])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: O=C(O)CCC(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: O=C(O)CCC(=O)Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1
Yield: 7.9 %

Procedure:
To a solution of 1.0 g (2.66 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 25 ml CH2Cl2 were added 320 mg (3.2 mmol) succinic acid and 390 mg (3.2 mmol) dimethylaminopyridine and the reaction mixture was refluxed for 20 hours. The reaction mixture was concentrated to 10 ml and was purified by chromatography over silica gel to give 100 mg (0.21 mmol, 7.4%) succinic acid mono-{(3S,4S)-4-[2-(4-benzyl -3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl} ester as colorless oil.
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:19][NH:18][C:4]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Agent: I
Solvent: CCO
Product: CNC(=Nc1ccccc1N1CCOCC1)N1CCCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210), pyrrolidine (1 ml) and ethanol (40 ml) was heated under reflux for two weeks to yield an oil which was purified by chromatography on a neutra alumina column eluted with a 1:1 mixture of dichloromethane and hexane and then a 1:9 mixture of methanol and dichloromethane to give N-methyl-N'-(2-morpholinophenyl)pyrrolidine-1-carboxamidine which was converted into its monofumarate salt (m.p. 168°-171° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl-].[Cl-].[Cl-].[Al+3].[C:15]1([C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[CH:27][N:26]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>ClCCCl>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:27]1[N:26]=[C:25]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12)=[O:6]
Reactant: O=C(O)c1ccccc1I
Reactant: c1ccc2c(-c3ncc4ccccn34)cccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1I)c1nc(-c2cccc3ccccc23)n2ccccc12
Reaction time: 0.17 h
Yield: 18.4 %

Procedure:
To a solution of 2-iodobenzoic acid (487 mg, 1.83 mmol) in 1,2-dichloroethane (20 mL) was added aluminum trichloride (266 mg, 2.00 mmol). The mixture was allowed to stir for 10 min. then a solution of 3-naphthalen-1-yl-imidazo[1,5-a]pyridine (212 mg, 0.87 mmol) in 1,2-dichloroethane (5 mL) was added. The mixture was stirred at ambient temperature for 30 min. then washed with saturated aqueous sodium bicarbonate and the organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (76 mg, 18%). 8.37 (1H), 8.18 (1H), 8.10 (2H), 7.92 (1H), 7.85 (1H), 7.71 (2H), 7.56 (5H), 7.20 (1H), 7.07 (1H); m/z (M+H)=475.1.
Reaction SMILES: C[Li].O1CCCC1.[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([NH:27][C:28]([C:31]#N)([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)C>[CH2:8]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C#N)Nc1cccnc1N1CCN(Cc2ccccc2)CC1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)Nc1cccnc1N1CCN(Cc2ccccc2)CC1

Procedure:
Methyllithium (61 ml, 85 mmol) as a 1.4M solution in diethyl ether is added to 30 ml tetrahydrofuran and cooled to -78°. 1-Benzyl-4-[3-(1-cyano-1-methylethylamino)pyridyl]-piperazine (PREPARATION 95, 7.14 g, 21.28 mmol), dissolved in 30 ml cooled tetrahydrofuran, is cannulated into the methyllithium solution, rinsing in with 10 ml THF. The reaction is stirred at -78° and allowed to warm to 20°-25° overnight. The reaction is cautiously quenched with water, then extracted from water with methylene chloride. The extract is dried over sodium sulfate and concentrated. The concentrate is chromatographed on a 500 g silica gel column, eluting with ethyl acetate/hexane (2/3, v/v), the appropriate fractions are pooled and concentrated to give the title compound, NMR (300 MHz, CD3OD) 7.44, 7.43-7.07, 6.84-6.80, 3.49, 2.92, 2.52, 1.28 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.Cl[CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCNc1ccc(Cl)c(Cl)c1

Procedure:
In the manner given in Example 5, 3,4-dichloroaniline, 1-chloro-2-dimethylaminoethane hydrochloride and sodium carbonate are heated in toluene to give N,N-dimethyl-N'-(3,4-dichlorophenyl)ethylenediamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11]N)=[O:10])[CH:6]=[CH:5][N:4]=1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][C:13](=[O:19])/[CH:14]=[CH:15]\[C:16]([OH:18])=[O:17])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COc1cc(C(=O)NN)ccn1
Solvent: C1CCOC1
Product: COc1cc(C(=O)NC(=O)/C=C\C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxypyridine-4-carbohydrazide 8 (167 mg, 1.0 mmol) in 10 mL of THF was added maleic anhydride (110 mg, 1.1 mmol). The mixture was stirred at ambient temperature for 2 h. After removal of the solvent, the residue was diluted with 10 mL of dichloromethane. The solid was collected by filtration to give (Z)-4-(2-methoxypyridine-4-carboamido)-4-oxobut-2-enoic acid 9 as a solid. Yield: 190 mg, 71%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([O:17]C)=[O:16])=[C:13]([CH2:19][O:20][CH3:21])[NH:12][C:11](=[O:22])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Li+]>O.C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH2:19][O:20][CH3:21])[NH:12][C:11](=[O:22])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCC1=C(C(=O)OC)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Yield: 90 %

Procedure:
A stirred mixture of one mole equivalent of methyl (4R)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (10.0 g, 32.0 mmol) and lithium hydroxide (2 equivalents, 1.53 g, 64.0 mol) in H2O-THF (2:1, 300 mL) was heated at reflux temperature for 1 h. The reaction mixture was concentrated, dissolved in water, washed with ethyl acetate and acidified (1 N HCl) to pH 3-4 (pH paper). The precipitated product was collected, washed with water and dried under reduced pressure to give the desired product in 90% yield.