Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:40](Cl)(=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:43])[CH2:41][CH3:42])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 16.7 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (85 mg, 0.15 mmol) in dichloromethane (2 mL) was added propanoyl chloride (15.6 mg, 0.17 mmol). Triethylamine (30 mg, 0.30 mmol) was added, and the resultant mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 25 to 55% over 15 min, UV detection at 214 nm) to give 15.7 mg (17%) of the title compound as an off white solid. MS (ES) m/e 625.1 [M+H]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1.[CH:50]1([CH2:53][NH2:54])[CH2:52][CH2:51]1.O>CN1C(=O)CCC1.C(Cl)Cl>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7]([NH:54][CH2:53][CH:50]3[CH2:52][CH2:51]3)[N:6]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: NCC1CC1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(NCC4CC4)nc23)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (36 mg) was suspended in NMP (0.2 ml). Cyclopropylmethylamine (88 uL) was added and the mixture stirred at room temperature for 15 minutes. Water and methylene chloride were added and the resulting precipitate was filtered. After triturating in a mixture of ethyl acetate and hexanes, (Z)-5-((4-(cyclopropylamino)-2-(cyclopropylmethylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione was isolated as a yellow solid). LCMS (ES): >95% pure, m/z 355 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(C(CNS(C)(=O)=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.5 %

Procedure:
To 4-[2-Amino-1-(2-fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (1.45 g, 4.48 mmol) in MeCl2 (10 mL) was added methanesulfonyl chloride (0.51 g, 4.48 mmol) and pyridine. The reaction was allowed to stir at room temperature for 18 h. The reaction mixture was then diluted with EtOAc (50 mL) and washed with H2O (50 mL) and brine (50 mL). The organic phase was concentrated to dryness yielding 1.43 g (80%) product.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][C:19]=3[CH:20]=2)=[O:15])=[CH:6][CH:5]=1.[NH2:34][OH:35].[OH-].[Na+]>CO.O1CCCC1.O>[OH:35][NH:34][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:21][C:19]=3[CH:20]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1ccc(OCCNC(=O)c2cc3cc(OCCN4CCCC4)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-{2-[5-(2-pyrrolidin-1-ylethoxy)benzofuran-2-carbonylamino]-ethoxy}-benzoic acid methyl ester (169 mg, 0.37 mmol) in methanol (8 ml) and tetrahydrofuran (4 ml) was added hydroxylamine in water (2.9 ml of a 50 wt. % solution) and 4.0 M aqueous solution of sodium hydroxide (0.65 ml). After stirring for 18 h, the organics were removed and the aqueous solution was cooled in an ice/water bath and the pH was adjusted to ˜8 with 4.4 ml 1.0 M hydrochloric acid to give precipitates. The heterogeneous solution was warmed to room temperature and acetonitrile was added till the precipitates dissolved. The solution was chromatographed on C-18 reverse phase HPLC. Fractions with absorbance at 214 nm, were collected, frozen, and lyophilize to give the title compound (31 mg). 1H NMR (400 MHz, DMSO-d6) δ: 11.05 (s, 1H), 10.4 (s, 1H), 8.91 (s, 2H), 7.70 (d, 2H, J=7.4), 7.59 (dd, 1H, J=3.7, 9.1 Hz), 7.51 (d, 1H, J=3.7 Hz), 7.35 (s, 1H), 7.13 (d, 1H, J=9.0 Hz), 7.00 (d, 2H, J=7.4 Hz), 4.37 (m, 2H), 4.18 (m, 2H), 3.62 (m, 6H), 3.12 (m, 2H), 2.02 (m, 2H), 1.89 (m, 2H). EM (calc.): 453.2; MS (ESI) rate (M+1H)+: 454.1, (M−1H)−: 452.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:31])/[C:20]([O:22]CCCCCCCC)=[O:21])[C:10]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:9]([CH3:37])[NH:8][C:7]=1[CH3:38])=[O:5])[CH3:2]>C(Cl)Cl.CC(C)=O>[CH2:35]([O:34][C:32]([C:10]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[CH:18]=[C:19](\[CH3:31])/[C:20]([O:22][CH:6]([CH3:4])[CH2:7][CH3:38])=[O:21])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:38])[NH:8][C:9]=1[CH3:37])=[O:33])[CH3:36]
Reactant: CCCCCCCCOC(=O)/C(C)=C/c1ccccc1C1C(C(=O)OCC)=C(C)NC(C)=C1C(=O)OCC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1/C=C(\C)C(=O)OC(C)CC

Procedure:
2(e) (E)-4-(2-(3-Octyloxy-3-oxo-2-methyl-1-propenyl)phenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester T.l.c. (methylene chloride/acetone, 100:15) Rf 0.52
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([N:15]([CH3:35])[CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:24][CH2:23]4)[C:12]([C:36]([F:39])([F:38])[F:37])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[Li+].[OH-].O.[CH2:43]1COC[CH2:44]1>CO>[CH2:43]([CH:29]([C@H:25]1[C:26]2[C:22](=[CH:21][C:20]([O:19][CH2:18][CH2:17][CH2:16][N:15]([C:13]3[C:12]([C:36]([F:37])([F:38])[F:39])=[CH:11][CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=4)[N:14]=3)[CH3:35])=[CH:28][CH:27]=2)[CH2:23][CH2:24]1)[C:30]([OH:32])=[O:31])[CH3:44]
Reactant: C1CCOC1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN(C)c3nc(-c4ccc(CC)cc4)ccc3C(F)(F)F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(N(C)CCCOc3ccc4c(c3)CC[C@H]4C(CC)C(=O)O)n2)cc1

Procedure:
Following the procedure described in Example 308 and starting with ethyl ((1S)-5-[(3-{[6-(4-ethylphenyl)-3-(trifluoromethyl)-2-pyridinyl](methyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 319, 10 mg, 0.018 mmol), LiOH (0.1 mg, 0.004 mmol) in THF (1 mL), MeOH (1 mL), and water (0.5 mL), the title compound was obtained (0.0024 g, 51%). 1H NMR (400 MHz, CD2Cl2) δ 7.98 (d, 2H), 7.85 (d, 1H), 7.35-7.25 (m, 3H), 7.01 (d, 1H), 6.72 (d, 1H), 6.65 (dd, 1H), 4.02 (t, 2H), 3.83 (t, 2H), 3.47 (qt, 1H), 3.08 (s, 3H), 2.90-2.68 (m, 5H), 2.42-2.30 (m, 2H), 2.15 (qt, 2H), 1.78-1.68 (m, 1H), 1.33 (m, 3H); LC-MS: RT=4.50 min, (M+H)+ 513.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH2:17])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1.[Cl:23][C:24]1[N:25]=[CH:26][N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:28]=1[C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([O:8][C:9]2[C:10]([F:18])=[C:11]([CH2:16][NH:17][C:29]([C:28]3[N:27]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])[CH:26]=[N:25][C:24]=3[Cl:23])=[O:30])[CH:12]=[CH:13][C:14]=2[Cl:15])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of ({3-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (690 mg, 1.454 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (403 mg, 1.454 mmol) and HOBT (267 mg, 1.745 mmol) in DMF (4 ml) was added EDC (335 mg, 1.745 mmol) and the reaction mixture was stirred at RT for 45 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material (942 mg) was used directly in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.77 (t, 1H), 8.32 (d, 1H), 7.98 (s, 1H), 7.45-7.56 (m, 1H), 7.41 (t, 1H), 7.31 (d, 1H), 5.49 (s, 2H), 4.48 (d, 2H), 3.38 (t, 2H), 0.74 (t, 2H), −0.09 (s, 9H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C@H:18]([OH:20])[C@@H:17]2[C@H:15]1[C@H:16]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>O1CCCC1>[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:19][C@H:18]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:17]2[C@H:15]1[C@H:16]2[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](OS(C)(=O)=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Yield: 126.2 %

Procedure:
Methanesulfonyl chloride (224.61 μL, 2.90 mmol) is added to di-tert-butyl (1S,2S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (400 mg, 967 μmoles) and triethylamine (472 μL, 3.39 mmol) in tetrahydrofuran (4.84 mL) at 0° C. and stirred. Cooling bath is removed and the reaction is allowed to warm to room temperature and stirred overnight. Dilute with water and saturated aqueous sodium bicarbonate then extract with ethyl acetate. The combined organics are washed with brine, dried over sodium sulfate, filtered, and concentrated to under reduced pressure to give the title compound (600 mg, 1.22 mmol, 100%).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[Si]([O:20][CH2:21][C:22]([CH3:59])([CH3:58])[O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4[C:45]([C:50]#[N:51])=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:40][C:39]=3[F:52])[C:33]([CH2:53][CH2:54][CH3:55])=[N:32][C:31]=2[CH2:56][CH3:57])=[CH:26][CH:25]=1)(C(C)(C)C)(C)C>C(OCC)(=O)C>[CH2:56]([C:31]1[N:32]=[C:33]([CH2:53][CH2:54][CH3:55])[N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[C:50]3[NH:51][C:4](=[O:7])[O:5][N:3]=3)=[CH:40][C:39]=2[F:52])[C:35](=[O:36])[C:30]=1[C:27]1[CH:26]=[CH:25][C:24]([O:23][C:22]([CH3:59])([CH3:58])[CH2:21][OH:20])=[CH:29][CH:28]=1)[CH3:57]
Reactant: CCCc1nc(CC)c(-c2ccc(OC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)(C)CO)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1F
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogen carbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (0.74 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuran solution (1 mol/L, 2.4 mL) was added, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated from the reaction mixture under reduced pressure. The residue was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.39 g, 82%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[CH3:11][C:12](=O)[CH2:13][CH2:14][C:15](=O)[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Br:9][C:5]1[C:4]([CH3:10])=[N:3][C:2]([N:1]2[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]2[CH3:11])=[N:7][C:6]=1[CH3:8]
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1nc(N)nc(C)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.00 g (9.89 mmol) of 2-amino-5-bromo-4,6-dimethylpyrimidine in 16 mL of anhydrous toluene was added 1.36 mL (11.5 mmol) of 2,5-hexanedione followed by 96 mg (0.50 mmol) of p-toluenesulfonic acid. The reaction mixture was heated and stirred at reflux for 12 h. The reaction mixture was poured into 150 mL of water and then extracted with 200 mL of ethyl acetate. The organic solution was washed with 150 mL of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 5:1 hexanes-ethyl acetate afforded the expected product as light yellow crystals: yield 2.23 g (81%); mp 64-65° C.; silica gel TLC Rf 0.65 (6:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 2.34 (s, 6H), 2.67 (s, 6H) and 5.89 (s, 2H); 13C NMR (CDCl3) δ 14.5, 14.5, 24.9, 24.9, 108.7, 108.7, 118.6, 129.5, 129.5, 155.3, 155.3 and 166.9; mass spectrum (APCI), m/z 280.0458 (M+H)+ (C12H15N3Br requires 280.0449).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6](=[O:14])[C:7]([C:12]#[N:13])=[CH:8]OCC)[CH2:3][CH2:2]1.[C:25]([N:28]1[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]1=[O:35])(=[NH:27])[NH2:26]>COCCOC>[C:12]([C:7]([C:6](=[O:14])[N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)=[CH:8][NH:27][C:25](=[NH:26])[N:28]1[CH2:32][C:31]([CH3:33])([CH3:34])[NH:30][C:29]1=[O:35])#[N:13]
Reactant: CCOC=C(C#N)C(=O)N(CC1CC1)c1cccc(C(F)(F)F)c1
Reactant: CC1(C)CN(C(=N)N)C(=O)N1
Solvent: COCCOC
Product: CC1(C)CN(C(=N)NC=C(C#N)C(=O)N(CC2CC2)c2cccc(C(F)(F)F)c2)C(=O)N1
Reaction time: 48 h
Yield: 47 %

Procedure:
A solution of 8.2 g of (unpurified, about 90% pure) 2-cyano-3-ethoxyacrylic acid N-isopropyl-N-(3-trifluoromethylphenyl)amide (compound IV: R4 =CH(CH3)2 ; R5, R6 =H; R7 =C2H5) in 20 ml of abs. DME was added dropwise to a suspension of 3.91 g (25 mmol) of 1-amidino-4,4-dimethyl-2-oxoimidazolidine in 16 ml of abs. DME at 20°, and the mixture was stirred at 22°-24° for 4.5 hours. The mixture was then evaporated in vacuo at a maximum bath temperature of 25°. The oily residue was taken up in 250 ml of ether and extracted six times with 25 ml of water each time. The etherial solution was then dried over MgSO4, filtered and evaporated in vacuo (<26°). The residue (12.7 g) was partially crystalline. The latter was taken up in 40 ml of ether, 2 ml of pentane were added, the mixture was left to stand at 4°-6° for 2 days and subsequently the crystals were filtered off with suction. Drying (over P4O10 at 20°-24°, 6-8 mbar, 48 hours) resulted in 5.12 g (=47% yield) of TLC-pure compound II (R1, R2 =CH3 ; R3, R5, R6 =H; R4 =CH(CH3)2), melting point 121°-122° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][C:30]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH3:34])[C:31](O)=[O:32].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:31](=[O:32])[C:30]([CH3:29])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH3:34])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)C(C)(C)c4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4′-(4-Aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.038 g, 0.1 mmol), α,α-dimethylphenylacetic acid (0.020 g, 0.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) (0.023 g, 0.12 mmol), 1-hydroxybenzotriazole (HOBt) (0.016 g, 0.12 mmol), and triethylamine (0.56 mL, 0.4 mmol) were combined in CH2Cl2 (1 mL) and stirred at room temperature overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:5](=[CH:6][C:7]([N+:19]([O-:21])=[O:20])=[C:8]([CH3:18])[C:9]=2[C:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:16])[N:4]=1
Reactant: C1CNCCN1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N3CCNCC3)c2nc1OC
Reaction time: 2 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and piperazine 138 mg (1.60 mmol). Reaction was continued for 2 hours, and the crude product was eluted through a flash column (8% methanol in chloroform): 250 mg (86%), mp 150-152° C.; 1H NMR (CDCl3): δ 8.30 (s, 1H), 4.05 (s, 3H), 3.96 (s, 3H), 3.81 (t, 4H, J=4.9, 5.1 Hz), 2.96 (t, 4H, J=5.1, 4.9 Hz),2.54 (s, 3H), 1.84 (br s, 1H); MS (APCI): m/z 362 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:10]([NH2:14])[CH2:11][CH2:12][CH3:13].O>C1(C)C=CC=CC=1>[CH2:10]([NH:14][C:1]([CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)=[O:8])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN
Reactant: O=C(Cl)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)C1CCNCC1
Reaction time: 8 h
Yield: 14.4 %

Procedure:
Isonicotinoyl chloride (100.0 g) was added over 1 hour to a solution of n-butylamine (51.6 g) in toluene (600 ml) at 0°. The mixture was allowed to stand overnight, heated on a steam bath for 1/2 hour, then water was added. The aqueous layer was separated, basified to about pH 12 (NaOH), and extracted with ethyl acetate (2 times). The combined organic extracts were dried (MgSO4), evaporated and the resulting residue (36.0 g) dissolved in acetic acid (400 ml) and hydrogenated at 50 p.s.i./30° in the presence of platinum oxide. The catalyst was removed by filtration, the solution evaporated to dryness, the residue basified to about pH 12 (Na2CO3), and extracted with chloroform. The chloroform extracts were dried (Na2SO4) and evaporated to give 4-(N-n-butylcarbamoyl)piperidine, (18.7 g), m.p. 75°-79°. The oxalate salt was prepared in isopropanol from the free base and oxalic acid and was recrystallised from isopropanol/ethyl acetate, m.p. 143°-144° .
Reaction SMILES: [ClH:1].C(N(CC)CC)C.C(#N)CCCCC#N.[C:17]([Cl:21])([Cl:20])([Cl:19])Cl.[C:22]([Cl:25])([Cl:24])=[CH2:23]>[Ni]>[Cl:24][C:22]([Cl:1])([Cl:25])[CH2:23][C:17]([Cl:21])([Cl:20])[Cl:19]
Reactant: C=C(Cl)Cl
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cl
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: N#CCCCCC#N
Product: ClC(Cl)(Cl)CC(Cl)(Cl)Cl
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A 400 mL Hastelloy™ C nickel alloy shaker tube was charged with anhydrous cuprous chloride (1.39 g, 0.014 mole), triethylamine hydrochloride (1.93 g, 0.014 mole), adiponitrile (52.0 g, 0.481 mole), carbon tetrachloride (151.0 g, 0.982 mole), and vinylidene chloride (47.5 g, 0.490 mole). The tube was sealed, cooled in a dry ice bath, evacuated, and purged with nitrogen several times. The tube was placed in a heating jacket and agitation begun. The tube was heated to 120° C. over the course of 1.3 hours and then held at 119-122° C. for one hour; during this time the pressure rose to a maximum of 83 psig (674 kPa) and then dropped to 41 psig (384 kPa) at the end of the heating period. The tube was then cooled to ambient temperature.