Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>CO>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:6]=2)[CH:13]=1
Reactant: COC(=O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COc2cccnc2)cc1-c1ccccc1
Yield: 98.9 %

Procedure:
To a solution of 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid methyl ester (3.4 g, 10.6 mmol), prepared as in Example 228C, in methanol (30 mL) was added aqueous 4N sodium hydroxide and the reaction mixture was heated at reflux for 6 hours. The methanol was distilled of in vacuo and the residue was taken up in water. The aqueous solution was taken to pH 4 with HCl and the resulting precipitate was filtered off and dried to give 4-(3-pyridyloxymethyl)-2-phenylbenzoic acid (3.2 g).
Reaction SMILES: [CH3:1][C:2]([N+:5]([O-:7])=O)([CH3:4])[CH3:3].C(O)(=O)C.[NH:12]1[CH:16]=[C:15]([CH:17]=O)[CH:14]=[N:13]1>C(O)C.[Zn]>[NH:12]1[CH:16]=[C:15]([CH:17]=[N+:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[O-:7])[CH:14]=[N:13]1
Reactant: O=Cc1cn[nH]c1
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[N+]([O-])=Cc1cn[nH]c1
Temperature: 5 °C

Procedure:
To a suspension of 1,1-dimethylnitroethane (546.0 mg, 5.29 mmol) and zinc (515.5 mg, 7.89 mmol) in ethanol (3.0 ml) was added acetic acid (950.0 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 45 minutes. After cooling the mixture to 5° C. again, pyrazole-4-carbaldehyde (255.4 mg, 2.66 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (chloroform/methanol=10/1).
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][Mg]Br>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14]([CH3:23])=[N:15][C:16]3[C:21]([C:22]=2[CH3:26])=[CH:20][CH:19]=[CH:18][N:17]=3)=[O:12])=[CH:24][CH:25]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2ncccc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc2ncccc2c(C)c1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
N-(4-tert-butylbenzyl)-2-methyl-1,8-naphthyridine-3-carboxamide (150 mg, 0.45 mmol) was dissolved in THF (anh, 8.0 ml) under N2. Methylmagnesium bromide (4.5 ml of a 1M sln) was added dropwise. The mixture was stirred at r.t. for 2.0 h. The reaction was quenched with NH4Cl (sat). The product was extracted with EtOAc, dried (MgSO4), filtered and concentrated. The residue was dissolved in CHCl3 and O2 (94%) was bubbled through the solution for 3.0 h. The mixture was concentrated and purified by flash chromatography CH2Cl2/MeOH (96:4→95:5) yielding 50.0 mg of the title compound (32%). 1H NMR (CDCl3) δ 8.80 (m, 1H), 8.13 (m, 1H), 7.44 (d, 2H), 7.41 (d, 2H), 7.35 (m, 1H), 7.02 (t, 1H), 4.74 (d, 2H), 2.73 (s, 3H), 2.49 (s, 3H), 1.34 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH2:29](O)[CH2:30][CH2:31][CH:32]=[CH2:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:33][CH2:32][CH2:31][CH:30]=[CH2:29])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CCCCO
Reactant: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Product: C=CCCCN(c1cc2nn(-c3ccc(Cl)cc3)c(C(=O)NC)c2cc1C1CC1)S(C)(=O)=O
Yield: 69 %

Procedure:
Synthesized under alkylation conditions by reacting 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (200 mg, 0.48 mmol) with 4-penten-1-ol (0.1 mL). Work up and purification afforded (i) (161 mg, 69%). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=0.5 Hz, 1H), 7.56-7.48 (m, 4H), 7.37 (s, 1H), 5.88-5.66 (m, 2H), 5.03-4.93 (m, 2H), 3.73 (t, J=7.8 Hz, 2H), 3.05 (s, 3H), 3.01 (d, J=4.9 Hz, 3H), 2.49-2.37 (m, 1H), 2.15-2.05 (m, 2H), 1.85-1.62 (m, 2H), 1.15-1.04 (m, 2H), 1.04-0.93 (m, 1H), 0.67-0.52 (m, 1H). ESI-MS m/z calculated for [M+H]+: 487.2. found: 487.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[CH3:25][C:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][CH2:27]1
Reactant: CC1(N)CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2(C)CC2)cn1
Yield: 83 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 1-methylcyclopropylamine hydrochloride instead of methylamine, to the title compound (97 mg, 83%) which was obtained as a white solid. MS: m/e=362.5 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:7])[CH2:5][CH3:6])[CH3:3].[CH3:8][N:9]([CH:11](OC)OC)[CH3:10]>>[CH3:10][N:9]([CH3:8])/[CH:11]=[C:5](\[CH3:6])/[C:4](=[O:7])[CH:2]([CH3:3])[CH3:1]
Reactant: CCC(=O)C(C)C
Reactant: COC(OC)N(C)C
Product: C/C(=C\N(C)C)C(=O)C(C)C

Procedure:
2-Methyl-3-pentanone (5 g, 49.9 mmol) and DMF-DMA (10 mL, 74.9 mmol) were heated together in a sealed tube for 4 days. The reaction was concentrated in vacuo to afford an orange oil that was used directly in the next reaction (1.64 g, 21%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>C(OCC)(=O)C>[ClH:27].[CH3:26][N:21]([S:22]([CH3:25])(=[O:24])=[O:23])[C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CN(c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1)S(C)(=O)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1ccc(CC2CCNCC2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-4-{4-[methyl(methylsulfonyl)amino]benzyl}piperidine (1.2 g, 3.15 mmol) was dissolved in ethyl acetate (5 mL). To the solution was added 4N-hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 2 hours. The resulting crystals were collected by filtration, washed with ethyl acetate (5 mL) and dried to give the titled compound (851 mg) as colorless powdery crystals.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].C([O-])(O)=O.[Na+].[N+:22]([O-])([OH:24])=[O:23]>>[C:1]([NH:4][CH:5]([C:11]1[CH:12]=[CH:13][C:14]([N+:22]([O-:24])=[O:23])=[CH:15][CH:16]=1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)NCC(NC(C)=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)NCC(NC(C)=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h
Yield: 61 %

Procedure:
3 g, 0.014 mol of N,N'-Diacetyl-1-phenylethylenediamine was added slowly to 10 ml of 90% HNO3 at -40°. After stirring 5 hr at -40°, the solution was poured over ice and neutralized with NaHCO3. The product was extracted into ethyl acetate, and that was dried with MgSO4 and then evaporated to dryness under reduced pressure. The product was recrystallized from acetone/hexane, yielding 2.2 g (61%) of N,N'-Diacetyl-1-(p-nitrophenyl)-ethylenediamine mp 178°-180°. Anal. (C12H15N3O4) C, H, N were within 0.4% of theoretical.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:32])([F:31])[O:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][O:15][C:16]2[CH:28]=[CH:27][C:19]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl[C:34]1[S:35][C:36]2[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:37]=2[N:38]=1>CN(C)C=O>[F:32][C:8]([F:31])([F:7])[O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][O:15][C:16]2[CH:28]=[CH:27][C:19]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:34]4[S:35][C:36]5[CH:42]=[C:41]([OH:43])[CH:40]=[CH:39][C:37]=5[N:38]=4)[CH2:23][CH2:22]3)=[CH:18][CH:17]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc2nc(Cl)sc2c1
Reactant: FC(F)(F)Oc1ccc(COc2ccc(CC3CCNCC3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc2nc(N3CCC(Cc4ccc(OCc5ccc(OC(F)(F)F)cc5)cc4)CC3)sc2c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Potassium carbonate (1.02 g) and 4-[4-(4-trifluoromethoxybenzyloxy)benzyl]piperidine were added to an N,N-dimethylformamide solution (10 ml) of 2-chlorobenzothiazol-6-ol (1.37 g) and the mixture was stirred at 80° C. for 2 days. After being cooled to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→2:1) to afford the title compound as a white powder (2.1 g).
Reaction SMILES: [Na].Br.Br[CH2:4][CH2:5][NH2:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1>C(O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:4][CH2:5][NH2:6])=[CH:10][CH:9]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: NCCBr
Agent: Br
Agent: [Na]
Solvent: CCO
Product: NCCSc1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
A solution of sodium metal (22.5 mg, 0.98 mmol) in ethanol (2.0 mL) was treated with 2-bromoethylamine hydrobromide (100.0 mg, 0.49 mmol) and 4-chlorobenzenethiol (71.0 mg, 0.49 mmol), heated to 75° C. for 18 hours, and concentrated. The concentrate was partitioned between water (2.0 mL) and diethyl ether (5.0 mL) and the organic phase was dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 188 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:23]=[CH:22][C:12]([CH2:13]P(=O)(OCC)OCC)=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12](/[CH:13]=[CH:32]/[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:22][CH:23]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(C)cc3s2)cc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccccc4)cc3)sc2c1
Yield: 61.1 %

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methylbenzothiazol-2-yl)benzylphosphonate (0.30 g, 0.80 mmol) in dry THF (15 ml), potassium t-butoxide (0.10 g, 0.88 mmol) and benzaldehyde (0.085 g, 0.80 mmol) in dry THF (5 ml) to give the title compound (0.16 g, 60%) as a pale yellow solid after work-up and flash chromatography (2:1 Hexane/EtOAc).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[CH3:22]I.[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:19][CH2:20]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1
Reactant: CI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC12CC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a stirred solution of 2′-chloro-9′-cyclohexyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 271; 849 mg, 2.767 mmol) in DMA (60 mL) under nitrogen was added methyl iodide (190 μL, 3.044 mmol). The mixture was cooled on an ice/water bath and sodium hydride (60% mineral oil dispersion; 122 mg, 3.044 mmol) added in one portion. The reaction mixture was stirred on the ice/water bath for 1 hour, the cooling bath removed and allowed it to warm to room temperature. After 1.5 hours the solvent was evaporated and the residue treated with an excess of water. This afforded a solid, which was filtered off and washed well with water and then dried by dessication under high vacuum over P2O5 overnight. To yield the title compound as an off-white solid (887 mg, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:3]=1[C:4]([C:6]1[CH:18]=[C:17]2[C:9]([N:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=3)[C:11]3[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12)=[O:5].[C:38](Cl)(=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:10]2[C:9]3[C:17](=[CH:18][C:6]([C:4](=[O:5])[C:3]4[C:32]([CH3:37])=[CH:33][C:34]([CH3:36])=[CH:35][C:2]=4[CH3:1])=[C:7]4[CH:31]=[CH:30][CH:29]=[CH:28][C:8]4=3)[C:16]3[C:11]2=[CH:12][CH:13]=[C:14]([C:38](=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH:15]=3)=[CH:24][CH:23]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3cc(C(=O)c4c(C)cc(C)cc4C)c4ccccc4c32)cc1
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccc(C(=O)CC(C)C)cc3c3cc(C(=O)c4c(C)cc(C)cc4C)c4ccccc4c32)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-{4-[5-(2,4,6-trimethyl-benzoyl)-benzo[a]carbazol-11-yl]-phenyl}-ethanone (383 mg, 0.795 mmol) in CH2Cl2 (10 mL) are added isovaleroyl chloride (120 mg, 0.995 mmol) and AlCl3 (350 mg, 2.62 mmol) at 0° C. After stirring for 2 hours, the reaction mixture is poured into ice-water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with CH2Cl2 to obtain an off-white solid (345 mg; 76%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 1.02 (d), 2.22 (s), 2.34 (m), 2.43 (s), 2.78 (s), 2.94 (d), 7.00 (s), 7.14 (d), 7.33 (t), 7.48 (d), 7.64-7.68 (m), 7.98 (d), 8.31 (d), 8.43 (s), 8.67 (s), 9.47 (d).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][CH:30]=2)([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C(c2ccc([N+](=O)[O-])cc2)(c2ccc([N+](=O)[O-])cc2)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(C(c2ccc(N)cc2)(c2ccc(N)cc2)c2ccc(N)cc2)cc1

Procedure:
In a Parr reactor, tetrakis(4-nitrophenyl)methane (17.0 grams, 34.0 mmol; prepared as described in Example B) and palladium, 10 weight percent on activated carbon (2.1-5 grams, 2.00 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) were added to tetrahydrofuran (450 milliliters). The reactor was closed, and the mixture was stirred under 200 pounds per square inch (13.6 atmospheres) of hydrogen pressure for 72 hours at room temperature. The mixture was then filtered through CELITE, solvent was removed from the filtrate by evaporation under reduced pressure, and the resulting white solid was triturated in chloroform. The solid was then recovered by filtration, washed with chloroform again, and dried under reduced pressure at room temperature to give the targeted tetrakis(4-aminophenyl)methane as a white powder in a quantitative yield (12.9 grams).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[N:23][N:24]([CH2:26][C@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2C(OC(C)(C)C)=O)[CH:25]=1.Cl.O1CCOCC1>CC(O)C>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[N:23][N:24]([CH2:26][C@H:27]3[CH2:31][CH2:30][CH2:29][NH:28]3)[CH:25]=2)=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1cc(N)cn1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1[C@H](Nc2nc(Nc3cnn(C[C@H]4CCCN4)c3)ncc2Cl)[C@H]2C=C[C@@H]1C2
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
(1S,2S,3R,4R)-3-(2,5-Dichloropyrimidin-4-ylamino)bicyclo[2.2.1]hept-5-ene-2-carboxamide (100 mg, 0.334 mmol) and (R)-tert-butyl 2-((4-amino-1H-pyrazol-1-yl)methyl)pyrrolidine-1-carboxylate (116 mg, 0.435 mmol) were combined with 2-propanol (2 ml) and 4N HCl in dioxane (0.084 ml, 0.334 mmol) in a sealed tube and the reaction was heated to 85° C. for 4 hours. The reaction mixture was concentrated to dryness, and the residue was treated with trifluoroacetic acid (3 mL). After stirring at room temperature for 30 minutes, the reaction mixture was again concentrated to dryness and the residue was suspended in saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with CH2Cl2 (2×10 mL) and ethyl acetate (2×10 mL). The organic extracts were combined, dried (Na2SO4) filtered, and concentrated. The residue was purified by flash chromotography (Analogix, 4 g column, 15 mL/minutes, 0 to 20% methanol (containing 5% NH4OH)/CH2Cl2 over 25 minutes) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.30-1.44 (m, 2H) 1.53-1.81 (m, 3H) 2.11 (d, J=8.82 Hz, 1H) 2.51-2.56 (m, 1H) 2.75-2.85 (m, 3H) 2.86-2.89 (m, 1H) 3.37-3.47 (m, 1H) 3.93-4.01 (m, 2H) 4.12 (t, J=7.12 Hz, 1H) 6.31-6.39 (m, 2H) 7.25 (s, 1H) 7.52 (s, 1H) 7.65-7.83 (m, 3H) 7.89 (s, 1H) 9.10 (s, 1H); MS (ESI(+)) m/e 429 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:11][C:10](=[O:12])[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])=[N+:8]([O-])[C:7]=1[O:18][CH3:19])=[O:5])C.[OH-].[Na+].Cl>CO>[CH2:13]([C:9]1[C:10](=[O:12])[NH:11][C:6]([C:4]([OH:5])=[O:3])=[C:7]([O:18][CH3:19])[N:8]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1[nH]c(=O)c(CC(C)C)[n+]([O-])c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1nc(CC(C)C)c(=O)[nH]c1C(=O)O
Temperature: 25 °C

Procedure:
932 Milligrams of 6-ethoxycarbonyl-3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one 4-oxide in 21 ml of methanol and 10 ml of an aqueous solution of 1N-sodium hydroxide were mixed and stirred at room temperature for hours. The reaction mixture was acidified by adding hydrochloric acid, and the precipitated crystals were collected by filtration, and the crystals were dissolved in chloroform-methanol, next the solvent was removed by distillation to obtain 830 mg of 3-isobutyl-5-methoxy-1,2-dihydropyrazin-2-one-6-carboxylic acid 4oxide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][CH2:29][O:30][C:23]=3[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][CH2:29][O:30][C:23]=4[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:27])[CH2:18][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:29][CH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:27])[CH2:18][N:19]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:29][CH2:30][OH:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CNCC1CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN(CCO)CC1CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Yield: 46.8 %

Procedure:
2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(cyclohexylmethyl)-2-oxoethanamine (296 mg) was dissolved in acetonitrile (10 mL). To the reaction liquid were added 2-bromoethanol (400 mg), potassium carbonate (555 mg), and potassium iodide (133 mg), followed by stirring under heating at reflux for 16 hours. Thereafter, the solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](cyclohexylmethyl)amino}ethanol (155 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:4]([OH:6])=O.Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[OH:1][CH2:2][C@@H:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:4]([NH:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: NOCc1ccccc1
Reactant: C=CCCCC[C@H](CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CCCCC[C@H](CO)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-2-(hydroxymethyl)-7-octenoic acid (1.12 g, 6.51 mmol), O-benzyl hydroxylamine hydrochloride (1.04 g, 6.51 mmol) and 4-dimethylamino-pyridine (1.90 g, 15.62 mmol) in dichloromethane (30 mL) at 0° C. was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.50 g, 7.81 mmol). After stirring at room temperature overnight, the reaction was then quenched with 1N aqueous HCl solution (25 mL) and extracted using dichloromethane (25 mL×2). The organic extracts were washed with water, brine, and dried over MgSO4. Removal of the solvent under reduced pressure yielded the title compound. MH+278.
Reaction SMILES: C(=O)([O-])[O-].[Mg+2:5].[S:6]([OH:16])(=[O:15])([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)=[O:7]>>[S:6]([O-:16])(=[O:15])([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:7].[Mg+2:5].[S:6]([O-:16])(=[O:15])([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Mg+2]
Product: Nc1ccc(S(=O)(=O)[O-])cc1

Procedure:
Magnesium sulfanilate was prepared by reacting magnesium carbonate with sulfanilic acid in a mole ratio of 1:2 by heating to remove water and carbon dioxide.