Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1-n1cnc(C)c1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
1-(2-Methoxy-4-nitro-phenyl)-4-methyl-1H-imidazole (2.52 g, 10.8 mmol) dissolved in ethanol (110 mL) was stirred under an atmosphere of hydrogen at 20° C. for 3.5 h in the presence of 10% palladium on charcoal (0.25 g). The catalyst was filtered off and washed with ethanol. The solvent of the filtrate was evaporated under reduced pressure. The crude product was purified on silica gel using dichloromethane/methanol (19:1 v/v) as eluent. The fraction containing the product was suspended in diethyl ether, stirred for 15 min, filtered and dried to yield the title compound (1.72 g, 78%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH:12]=[CH:13][CH:14]=2)=[O:9])=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCn1cccc1C(=O)c1ccc(N)cc1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
Iron powder (0.52 g) was added in three portions to a stirred solution of 2-(4-nitrobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole (0.59 g. 1.7 mM) in acetic acid at 65° C. Heating was continued for 2 hours and solvent was evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with water, dried (Mg SO4) and evaporated, to give 2-(4-aminobenzoyl)-1-(2-trimethylsilylethoxymethyl)pyrrole as an oil (0.5 g). MS: 317 (MH+). NMR: −0.18 (9H, s); 0.74 (2H, t) 3.38 (2H, t); 5.64 (2H, s); 5.95 (2H, s); 6.16 (1H, m); 6.59 (2H, d) 6.6 (1H, m); 7.3 (1H, m); 7.57 (2H, d).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:20](=[O:41])[N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:6][NH:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:41]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccc2ccccc2c1)c1nc(C)no1
Yield: 94.5 %

Procedure:
N-methyl-N-((1R)-1-{N-methyl-N-[(1R)-1(3-methyl[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl)carbamic acid tertbutyl ester (2.4 g, 4.2 mmol) was dissolved in a mixture of trifluoroacetic acid (40 ml) and dichloromethane (40 ml) at 20° C. After 10 min the reaction mixture was concentrated in vacuo and coevaporated from dichloromethane (80 ml). The residue was crystallised from ethyl acetate to give 1.9 g of (2R)-2-methylamino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[C:10]([Mg]Cl)#[CH:11].S(=O)(=O)(O)O>O1CCCC1>[CH3:6][C:5]([OH:7])([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:8][CH3:9])[C:10]#[CH:11]
Reactant: CCC(C)CCC(C)=O
Reactant: C#C[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C#CC(C)(O)CCC(C)CC
Yield: 93 %

Procedure:
128 g (1 mole) of 5-methyl-heptan-2-one are added in the course of 1 hour, with stirring, to 1 liter of a 1.1 molar solution of ethynyl-magnesium chloride in tetrahydrofuran at 10° C. After allowing about a further hour's reaction, the mixture is worked up. To do so, 2 N sulfuric acid is added, whilst cooling with ice, until two clear phases are present. The organic phase is then separated off and washed neutral with water, if necessary, and the tetrahydrofuran is distilled off at 50° C./67 mbar. The residue is subjected to fractional distillation. 143 g of main fraction, boiling at 50°-52° C./0.01 mbar, are obtained; nD25 =1.4411. This corresponds to a yield of 93%. Scent: predominantly floral, woody, herbal, minty with a spicy, slightly animal after-scent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13](Cl)=[O:14])=[CH:11][C:10]([C:16]([F:19])([F:18])[F:17])=[N:9]1.C(Cl)(Cl)Cl.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH2:32])(=[O:27])=[O:26]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][NH:32][C:13]([C:12]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:14])(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cccc(CNC(=O)c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 21 %

Procedure:
To a round bottom flask was added 2-(2-chlorophenyl)-5-trifluoromethyl-2H-pyrazole-3-carbonyl chloride (160 mg, 0.520 mmol) in a solution of anhydrous CHCl3 (10 mL). To the reaction solution was added 3-methylsulfonyl benzylamine (122 mg, 0.661 mmol), TEA (150 μL, 1.10 mmol), and DMAP (67 mg, 0.549 mmol). The reaction solution was allowed to stir at 60° C. for 5 hrs. The reaction solution was diluted with EtOAc (150 mL), poured into a separatory funnel and washed with aq. NH4Cl. The partitioned organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure on the rotavapor. The crude material was chromatographed through a silica gel column using a solvent gradient of 100% hexane to 30% EtOAc to afford 50 mg of title compound (20%). 1H NMR (CDCl3): δ 7.83 (m, 1H), 7.79 (s, 1H), 7.48-7.58 (m, 4H), 7.42-7.46 (m, 2H), 7.05 (s, 1H), 6.66 (t, J=6 Hz, 1H), 4.58 (d, J=6 Hz, 2H), 3.03 (s, 3H); MS (ES): 458.1 [M+H]+.
Reaction SMILES: [O-]CC.[Na+].[Na].Br[CH:7]([CH2:20][Br:21])[CH2:8][C:9]1[CH:10]=[C:11]([F:19])[CH:12]=[CH:13][C:14]=1[O:15]C(=O)C>C(O)C>[Br:21][CH2:20][CH:7]1[CH2:8][C:9]2[CH:10]=[C:11]([F:19])[CH:12]=[CH:13][C:14]=2[O:15]1
Reactant: CC(=O)Oc1ccc(F)cc1CC(Br)CBr
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Fc1ccc2c(c1)CC(CBr)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sodium ethoxide solution, prepared in the conventional manner starting from 15.2 parts of sodium in 100 parts of ethanol, is added dropwise to a mixture of 231 parts of 3-(2,3-dibromopropyl)-4-acetoxy-fluorobenzene in 800 parts of ethanol (exothermic reaction: temperature rises to 50° C.). Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled to room temperature, filtered from some insoluble matter and the filtrate is evaporated. The residue is divided between water and ether. The aqueous layer is separated and extracted once more with ether. The combined ethereal phases are dried over calcium chloride, filtered and evaporated. The oily residue is distilled in vacuo, yielding 102 parts of 2-bromomethyl-2,3-dihydro-5-fluorobenzofuran; bp. 100° -105° C. at 1.5 mm. pressure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:21])[C:19]=1[Cl:20])[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[C:19]([Cl:20])=[C:18]([Cl:21])[CH:17]=1)=[O:9]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: O=C(Nc1cc(Cl)c(Cl)c(Cl)c1)c1cc(Br)ccc1O
Yield: 78.6 %

Procedure:
Using 5-bromosalicylic acid and 3,4,5-trichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(=O)O[CH2:13][CH2:12][O:11]1.[H-].[Na+]>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH2:13][CH2:12][OH:11]
Reactant: O=C1OCCO1
Reactant: Oc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: OCCOc1cc(F)cc(F)c1

Procedure:
In a sealed Pyrex tube, a mixture of 3,5-difluorophenol (2.19 g, 16.8 mmol), ethylene carbonate (1.0 g, 11.4 mmol), a catalytic amount of NaH (60% in mineral oil) in DMF (1 mL) was reacted in a Labwell MW-10 microwave reactor at 50 W for 3 min. The reaction mixture was diluted with toluene and washed with 5% aqueous NaOH. The organic phase was dried (MgSO4) and concentrated: This gave 1.59 g (80%) of the title compound as a light red oil. MS m/z 174 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:21])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:39][O:40][C:41](=[O:45])[C:42](Cl)=O>C1COCC1>[CH3:39][O:40][C:41]([C:42]1[N:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:4]2[C:5]([C:8](=[O:21])[C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][CH2:12]1)=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[O:45]
Reactant: CS(=O)(=O)C1CCN(CCC(=O)c2ccc(F)cc2Nc2ccccc2)CC1
Reactant: COC(=O)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1c(CN2CCC(S(C)(=O)=O)CC2)c(=O)c2ccc(F)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of 1-(4-fluoro-2-phenylamino-phenyl)-3-(4-methanesulfonyl-piperidin-1-yl)-propan-1-one (500 mg) in THF (8 mL) under N2 was added NaHMDS (3.1 mL, 1 M in THF). After 5 min, chloro-oxoacetic acid methyl ester (0.28 mL) was added, and the mixture stirred for 2 h at 0° C., then for 1 h at RT. The reaction mixture was quenched with NH4Cl (sat'd aq), extracted with EtOAc, and chromatographed (0-20% MeOH/DCM) to provide 7-fluoro-3-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (301 mg, Compound 126). M+H=473; mp=190.0-191.0° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([CH3:13])[C:9]=1[O:10][CH2:11][CH3:12])[NH2:6])[CH3:2].[C:14](Cl)(Cl)=[O:15]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([N:6]=[C:14]=[O:15])[CH:7]=[C:8]([CH3:13])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1c(C)cc(N)cc1CC
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1c(C)cc(N=C=O)cc1CC
Temperature: 25 °C
Yield: 101.9 %

Procedure:
A mixture of 3-ethyl-4-ethoxy-5-methylaniline (1.8 g) in toluene (20 ml was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-ethyl-4-ethoxy-5-methylphenyl isocyanate (2.1 g). The thus obtained crude substance was added to an isopropanol solution (20 ml) containing triethylamine (1 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with toluene. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using toluene as the eluent to give isopropyl N-(3-ethyl-4-ethoxy-5-methylphenyl)carbamate (Compound No. 93) ((2.4 g) in a yield of 91% (calculated from the starting 3-ethyl-4-ethoxy-5-methylaniline). M.P., 68°- 69.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([O:16]C)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1OCc1ccccc1
Yield: 91.3 %

Procedure:
To a solution of methyl 3-(benzyloxy)-2-thiophenecarboxylate (7.85 g, 31.61 mmol) in MeOH (32 mL) and THF (16 mL) was added 2 N NaOH (21 mL), and the mixture was stirred at reflux for 10 hrs, and then concentrated under reduced pressure. The residue was diluted with water, washed with ether. The separated aqueous phase was acidified with 5N HCl. The precipitated solid was collected by filtration, washed with hexane, and dried under reduced pressure at 60° C. to give 3-(benzyloxy)-2-thiophenecarboxylic acid as a yellow solid (6.76 g, yield; 91%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[OH-].[Na+].CN(C)[CH:23]=[O:24]>>[Cl:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[C:8]=1[N:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: Clc1cccc(Cl)c1-n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cccn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
Under ice-cooling, 7.67 g of phosphorus oxychloride was added dropwise to 4 g of N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes, and 2.1 g of 1-(2,6-dichlorophenyl)-1H-pyrrole was added thereto. The resulting mixture was stirred at 60° C. for 2 hours, allowed to cool to room temperature, and then poured into ice water. The mixture was adjusted to pH 4 by an addition of a 2N aqueous sodium hydroxide solution, and then extracted with ethyl acetate two times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.80 g of 1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:32][S:33]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[CH:41]=[C:40]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (0.45 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.48 g, 83%). MS (ISP) 580.3 [(M+H)+]; mp 200° C.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:11][CH2:12][C@H:13]([OH:18])[C:14](OC)=[O:15])[CH:5]=1)(=[O:3])[NH2:2].[NH3:19].CO>>[NH2:19][C:14](=[O:15])[C@@H:13]([OH:18])[CH2:12][NH:11][C:6]1[N:7]=[C:8]([Cl:10])[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=1
Reactant: N
Reactant: COC(=O)[C@@H](O)CNc1cc(C(N)=O)nc(Cl)n1
Solvent: CO
Product: NC(=O)c1cc(NC[C@H](O)C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of the (S)-methyl 3-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)-2-hydroxypropanoate (0.421 g, 1.53 mmol) and 7M ammonia in MeOH (10 mL, 70 mmol) were heated in a sealed tube at 50° C. overnight. The precipitated solid was filtered off from the warm reaction mixture, rinsed once with 5 mL MeOH, and air-dried to give (S)-6-((3-amino-2-hydroxy-3-oxopropyl)amino)-2-chloropyrimidine-4-carboxamide as a light tan powder (0.372 g, 1.43 mmol, 94% yield). LC/MS: m/z=260.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]CC)=[O:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][C:2]1([C:17]([OH:19])=[O:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: CCOC(=O)C1(C)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylate (2.920 g, 9.99 mmol) in THF (12.50 mL) and MeOH (12.5 mL) was added 2 M aqueous solution of LiOH (25 mL, 50 mmol). The resulting yellow solution was stirred at rt for 22 hrs. The reaction was adjusted to pH=5 with 3N aqueous HCl. The solution was extracted with EtOAc (3×). The combined EtOAc extracts were washed with saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The obtained yellow solid was dried under high vacuum to give the desired product, 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylic acid (2.650 g, 9.53 mmol, 95% yield) as a yellow solid. Anal. Calcd. for C13H16N2O4 m/z 264.2, found: 265.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J=9.34 Hz, 2H), 6.89 (d, J=9.34 Hz, 2H), 4.13 (d, J=12.64 Hz, 1H), 3.64 (ddd, J=12.50, 4.53, 4.40 Hz, 1H), 3.10-2.99 (m, 1H), 2.94 (d, J=13.19 Hz, 1H), 2.33-2.18 (m, 1H), 1.88-1.69 (m, 2H), 1.53-1.37 (m, 1H), 1.25 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:8])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[CH3:13]N(C=O)C>O1CCCC1>[C:1]([O:5][C:6](=[O:8])[NH:7][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
(1S,2S)-3-(tert-butyl-diphenyl-silanyloxy)-1-furan-2-yl-2-methyl-propyl)-carbamic acid tert-butyl ester 2.5.1a (3.9 g, 7.9 mmol, 1.0 equiv) was added to a suspension of 60% sodium hydride (0.94 g, 23.5 mmol, 3.0 equiv) in dry tetrahydrofuran (30 mL) at 0° C. under nitrogen. After stirring at 0° C. for 15 min, to this solution was added methyl iodide (3.7 g, 16.0 mL, 26.0 mmol, 3.3 eqiuv) and DMF (3 mL). The reaction mixture was then stirred at room temperature for 3 hours. The reaction was quenched with sat. ammonium chloride aq. solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give obtain (1S,2S)-3-(tert-Butyl-diphenyl-silanyloxy)-1-furan-2-yl-2-methyl-propyl)-methyl-carbamic acid tert-butyl ester (4.0 g, 100%). 1H NMR (400 MHz, CDCl3) 0.84 (m, 3H); 1.00 (s, 9H); 1.50 (s, 9H); 2.33 (m, 1H); 2.71 (m, 3H); 3.47 (m, 3H); 5.26 (m, 1H); 6.09 (m, 1H); 5.93 (s, 1H); 6.16 (m, 1H); 6.26 (m, 1H)
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([CH3:10])[NH:7][C:8]=1[Br:9].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>>[Br:3][C:4]1[N:5]=[C:6]([CH3:10])[N:7]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[C:8]=1[Br:9]
Reactant: Cc1nc(Br)c(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(Br)c(Br)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
A 901 mg portion of 60% sodium hydride was added little by little to ice-cold N,N-dimethylformamide (50 ml) containing 4.91 g of 4,5-dibromo-2-methylimidazole. The reaction mixture was stirred at room temperature for 1 hour. 2-(Trimethysilyl)ethoxymethyl chloride (3.75 g) was added dropwise to the mixture on ice, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, and the mixture was washed subsequently with a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica-gel column chromatography (eluent, hexane:ethyl acetate=3:1) to obtain 7.6 g of colorless oily material of 4,5-dibromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[C:12](SC)=[N:11][CH:10]=2)=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cnc(SC)n2C(C)C)cc1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(-c2cncn2C(C)C)cc1

Procedure:
A mixture of 7.5 parts of 5-(4-methoxyphenyl)-1-(1-methylethyl)-2-(methylthio)-1H-imidazole, 10 parts of Raney-nickel catalyst and 80 parts of ethanol is stirred and refluxed for 2h. The catalyst is filtered off and another 10 parts of Raney-nickel catalyst is added. The whole is stirred for 2 hours at reflux temperature. The Raney-nickel catalyst is filtered off and the filtrate is evaporated, yielding 4 pants of 5-(4-methoxyphenyl)-1-(1-methylethyl)-1H-imidazole as a solid residue.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]3)=[CH:17][CH:16]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc3c(c2)CCCC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Hydroxy-1-tetralone (52.1)(3.24 g, 20 mmol) and 4-methoxybenzyl chloride (52.2) (3.13 g, 20 mmol) were dissolved in DMF (20 mL). Cs2CO3 (7.17 g, 22 mmol) was added to the mixture, and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was used without further purification for the next step. MS ESI (pos.) m/e: 283 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10](=O)[NH:11][N:12]=1.P(Br)(Br)([Br:16])=O.C([O-])(O)=O.[Na+]>>[Br:16][C:10]1[N:11]=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1ccc(-c2ccccn2)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1ccc(-c2ccccn2)nn1
Temperature: 0 °C
Yield: 75 %

Procedure:
1 g (5.78 mmol) of 6-(pyridin-2-yl)-2H-pyridazin-3-one 7 and an excess (5 g) of phosphorus oxybromide are refluxed for 12 hours. The reaction mixture is poured into 100 ml of ice-cold water and then neutralized, dropwise, with a saturated aqueous solution of NaHCO3. After extraction with dichloromethane (3×30 ml) the organic phase is dried over MgSO4 and then concentrated under reduced pressure, to give the brominated pyridazine 8b with a yield of 75%.