Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH2:17])[CH2:16][CH2:15][CH2:14]2)[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[C:27]([O:31][C:32](=O)[O:33]C(C)(C)C)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]2([NH:17][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])[CH2:16][CH2:15][CH2:14]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1(C2CC(=O)N(Cc3ccccc3)C2)CCC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C2CCN(Cc3ccccc3)C2)CCC1
Reaction time: 12 h
Yield: 26 %

Procedure:
A 1.50 g (6.14 mmol) portion of 1-benzyl-4-(1-aminocyclobutyl)-2-pyrrolidone (fr. 2) was dissolved in 200.0 ml of tetrahydrofuran to which, with cooling in an ice bath, was subsequently added 932 mg (24.56 mmol) of lithium aluminum hydride in small portions. After 12 hours of stirring with heating under reflux, the reaction solution was cooled in an ice bath and mixed with 932 μl of water in small portions, 932 μl of 15% sodium hydroxide aqueous solution and 932 μl of water in that order. After 30 minutes of stirring at room temperature, insoluble material was removed by filtration and the solvent was evaporated. To the thus obtained syrup were added 70.0 ml of acetonitrile and then 1.69 ml (7.37 mmol) of di-tert-butylcarbonate at room temperature, followed by overnight stirring. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (230-400 mesh silica gel 150 ml, 5% methanol-chloroform) to yield 525 mg (26%) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH:22]1(N)C2C(=CC=CC=2)CCC1>>[CH2:1]([C:3]1[C:4]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:22]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: NC1CCCc2ccccc21
Product: CCc1cnc(CC)c(NC2CCCc3ccccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.81, 7.38, 7.19, 5.49, 4.56, 2.87, 2.69, 2.57, 2.12, 1.98, 1.91, 1.32; 13C NMR (100 MHz, CDCl3) δ 153.69, 151.42, 140.81, 138.70, 138.29, 129.85, 129.56, 129.18, 127.49, 126.58, 48.71, 30.07, 29.94, 28.56, 26.07, 20.42, 13.96, 11.16; HRMS (FAB) calcd for C18H23N3+H 282.1970, found 282.1975.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([Sn](C)(C)C)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:29][C:30]1[N:35]=[C:34](Cl)[CH:33]=[C:32]([Cl:37])[N:31]=1>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:34]5[CH:33]=[C:32]([Cl:37])[N:31]=[C:30]([NH2:29])[N:35]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc([Sn](C)(C)C)ccc32)n1)c1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4cc(Cl)nc(N)n4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 424, starting from 2-[(S)-1-Phenylethylamino]-4-[5-trimethylstannylbenzimidazol-1-yl]pyrimidine and 2-amino4,6-dichloropyrimidine. Mass spectrum (ESI) 443.4 (M+).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH3:11])[C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]1=[O:18])=[O:5].[CH3:32]N(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.F[B-](F)(F)F.C[O+](C)C>ClCCl>[CH3:32][O:1][C@@H:2]([C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH3:11])[C@H:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:8][C:7]1=[O:18])=[O:5]
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.6 %

Procedure:
Following a literature method (Diem, M. J.; Burow, D. F.; Fry, J. L. Journal of Organic Chemistry 42(10), 1977, 1801-1802), to a solution of tert-butyl (2S)-2-{(1R,2R)-1-hydroxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}pyrrolidine-1-carboxylate (0.70 g, 1.6 mmol, from Reference Example 5) in anhydrous dichloromethane (5 mL) is added N,N,N′,N′-tetramethyl-1,8-naphthalenediamine (0.62 g, 2.9 mmol), followed by trimethyloxonium tetrafluoroborate (0.35 g, 2.4 mmol). The resulting reaction mixture is stirred for 24 hours at room temperature, quenched by the addition of ice water (25 mL), and then filtered through a diatomaceous earth pad. The filtrate is evaporated under reduced pressure and then partitioned between diethyl ether and water. The aqueous phase is extracted thrice with diethyl ether. The combined organic extracts are washed with 1M aqueous potassium bisulfate solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.69 g (97%) of tert-butyl (2S)-2-{(1R,2R)-1-methoxy-2-methyl-3-[(4R,5S)-4-methyl-2-oxo-5-phenyl-1,3-oxazolidin-3-yl]-3-oxopropyl}pyrrolidine-1-carboxylate as a foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([NH2:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[N:18]1[C:25](Cl)=[N:24][C:22](Cl)=[N:21][C:19]=1[Cl:20]>CC(C)=O.O>[Cl:20][C:19]1[N:18]=[C:25]([NH:8][CH:6]2[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)[N:24]=[C:22]([NH:8][CH:6]2[CH2:7][C:2]([CH3:11])([CH3:1])[NH:3][C:4]([CH3:10])([CH3:9])[CH2:5]2)[N:21]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)CC(Nc2nc(Cl)nc(NC3CC(C)(C)NC(C)(C)C3)n2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
62.4 g of 2,2,6,6-tetramethyl-4-amino-piperidine in 200 ml of acetone and, at the same time, 42.4 g of sodium carbonate dissolved in 100 ml of water are added to a finely dispersed suspension of cyanuric chloride, prepared by adding 36.9 g of the latter in 200 ml of boiling acetone to 400 ml of ice water. The temperature is kept at 0°-5° C. by means of external cooling. After the addition is complete, the reaction mixture is allowed slowly to warm to room temperature and is stirred at this temperature for 3 hours. Filtering and recrystallisation of the product from ethyl acetate/hexane gives 46.3 g of a white crystalline product, melting point 270° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3].Br[CH2:22][CH:23]1[CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:6]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][N:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:16]([F:19])([F:17])[F:18])[C:7]2=[O:20])[CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCC1
Reactant: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)[nH]1
Product: CC(C)Cc1cn(-c2ccccc2C(F)(F)F)c(=O)n1CC1CCC1

Procedure:
This material was obtained in analogy to the procedure outlined in example 23 from 4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one (obtained in example 18, 200 mg) by alkylation with bromomethylcyclobutane (115 mg). 3-Cyclobutylmethyl-4-isobutyl-1-(2-trifluoromethyl-phenyl)-1,3-dihydro-imidazol-2-one was obtained as a light yellow oil (9 mg). MS (ESI): 353.2 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:8]=2[NH:9]C(=O)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C>[C:1]1([C:7]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:8]=2[NH2:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(Br)cc1-c1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(Br)cc1-c1ccccc1
Yield: 98.8 %

Procedure:
2-Phenyl-4-bromo-N-acetylaniline (7.79 g, 26.85 mmol) was dissolved in ethanol (100 mL), 2 N hydrochloric acid (33.56 mmol, 67.12 mL) was added dropwise under ice bath, and the mixture was heated under reflux overnight. The solution was concentrated under reduced pressure and to the residue were added ethyl acetate (50 mL) and water (40 mL) for extraction. The organic layer was dried over sodium sulfate and, after filtration, concentrated under reduced pressure. The residue was purified by a silica gel column to obtain 2-phenyl-4-bromoaniline (6.58 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][NH2:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4cccc(Cl)c4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3cccc(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.055 g, 69%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp 211-214° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[CH3:2][N:3]([CH3:11])[CH:4]1[CH2:9][CH2:8][C:7](=[N:13][OH:14])[CH2:6][CH2:5]1
Reactant: CN(C)C1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CN(C)C1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
A mixture of 1.78 gm (10 mMol) of 4-dimethylaminocyclohexanone hydrochloride and 0.70 gm (10 mMol) of hydroxylamine hydrochloride in 25 mL ethanol was treated with 3 mL pyridine and then heated at reflux for 30 minutes. The reaction mixture was then cooled to room temperature and stored at 4° C. for 18 hours. The resulting crystalline solid was collected and washed with cold ethanol. The solid was then dissolved in water and the aqueous solution made basic by the addition of potassium carbonate. The aqueous phase was then extracted with dichloromethane which contained a small amount of isopropanol. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to provide a crystalline solid. This solid was recrystallized from ethanol to provide 1.05 gm (67%) of the desired oxime.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:41])[NH:29][C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Br:40])[CH:35]=1)([CH3:33])[CH2:31][OH:32])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28](=[O:41])[NH:29][C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Br:40])[CH:35]=1)([CH3:33])[CH:31]=[O:32])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C=O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
Dess-Martin periodinane (3.55 g, 8.36 mmol) was added portionwise over 5 minutes to a solution of rac-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-carbamic acid tert-butyl ester (2.3 g, 6.97 mmol) in dry DCM (45 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and at room temperature for 1 hour. The reaction mixture was quenched with NaHCO3 (aq. sat. solution) followed by NaHSO3 (aq. sat. solution). Then Et2O was added and the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and the aqueous layer was further extracted with Et2O. The combined organic layers were separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; DCM). The desired fractions were collected and concentrated in vacuo to yield rac-[1-(3-bromo-phenyl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (2 g, 88% yield) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:22]([NH2:24])=[O:23])=[C:8]1[C:18]([NH:20][CH3:21])=[O:19].[CH3:25][C:26]1[O:30][N:29]=[C:28]([C@:31]([OH:35])([C:33]#[CH:34])[CH3:32])[N:27]=1>>[F:16][C:15]1[CH:14]=[C:13]2[C:4]([C:5]3[N:9]([CH:10]4[CH2:17][CH:12]2[CH2:11]4)[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:7]([C:22]([NH2:24])=[O:23])[N:6]=3)=[CH:3][C:2]=1[C:34]#[C:33][C@@:31]([OH:35])([C:28]1[N:27]=[C:26]([CH3:25])[O:30][N:29]=1)[CH3:32]
Reactant: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: CNC(=O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(C#C[C@@](C)(O)c3noc(C)n3)cc1-2

Procedure:
9-Bromo-10-fluoro-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide (125 mg) was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol similar to as described in General Procedure G to afford 14.5 mg of 10-fluoro-9-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-3-N-methyl-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-3,4-dicarboxamide following reverse phase hplc purification. MS (Q1) 465 (M)+. 1H NMR (400 MHz, DMSO) δ 10.58 (q, J=4.1 Hz, 1H), 8.86 (d, J=7.5 Hz, 1H), 8.28 (s, 1H), 7.74 (s, 1H), 7.33 (d, J=10.0 Hz, 1H), 6.79 (s, 1H), 6.13-6.05 (m, 1H), 3.74-3.63 (m, 1H), 3.18-3.05 (m, 2H), 2.78 (d, J=4.6 Hz, 2H), 2.62 (s, 3H), 1.87 (s, 3H), 1.68 (d, J=12.3 Hz, 2H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[N:6]([C@@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:19])[CH:16]=2)[N:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10]1)=[N+:7]=[N-:8]>FC(F)(F)C(O)=O>[N:6]([C@@H:9]1[CH2:18][C:17]2[C:12](=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=[C:15]([Br:19])[CH:16]=2)[N:11]([C:20]([O:22][CH3:23])=[O:21])[CH2:10]1)=[N+:7]=[N-:8]
Reactant: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2cc(Br)ccc21
Reactant: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2cc(Br)cc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of sodium nitrate (30 mg, 0.40 mmol) in trifluoroacetic acid (5 mL) was added bromo azide 13 (100 mg, 0.32 mmol). The resulting solution was stirred at 25° C. for 30 min and then concentrated under reduced pressure. The crude product was then dissolved in EtOAc (50 mL) and the organic portion washed sequentially with saturated aqueous sodium hydrogen carbonate (10 mL), NaOH (1 M solution, 10 mL), and water (10 mL), dried with anhydrous Na2SO4, and then concentrated under reduced pressure. It was purified by column chromatography with petroleum ether/EtOAc (6:4 v/v) to give nitro compound 14 (108 mg) as a thick liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([I:11])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]([CH3:23])([CH3:22])[CH2:20]O.S(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][CH2:20][C:19]([CH3:23])([CH3:22])[N:18]=2)=[C:4]([I:11])[CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc(Cl)cc1I
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COC(c2ccc(Cl)cc2I)=N1
Temperature: 0 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a solution of 4-chloro-2-iodobenzoic acid (10 g, 35.4 mmol) in dry dichloromethane (100 mL) was added DMF (4 drops) followed by addition of oxalyl chloride (4.65 mL, 53.1 mmol) drop wise at room temperature. The reaction mixture was stirred for 4 h then the solvent and excess reagents were evaporated by rotovap. The residue was dissolved in dry dichloromethane (80 mL), added a solution of 2-amino-2-methyl-1-propanol (7.9 g, 8.5 mL, 88.5 mmol) in dichloromethane (20 mL), and stirred at room temperature over night. The solvent was removed, the resulting residue was dissolved in ethyl acetate (200 mL), washed with water (100 mL), 1N HCl (3×100 mL), and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was dissolved in dry toluene (200 mL) and cooled to 0° C. Thionyl chloride (7.75 mL, 106.2 mmol) was added drop wise, stirred at 0° C. for 30 min, then room temperature for 3 h. The reaction mixture was diluted with ethyl acetate (400 mL) and poured into a stirred solution of saturated aqueous NaHCO3 (400 mL) portion wise (vigorous gas evolution). The two layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (120 g column, 0% ethyl acetate in hexanes to 60% ethyl acetate in hexanes) to give product (10.5 g, 88%). NMR (CDCl3) δ 8.04 (d, J=2.0 Hz, 1H), 7.67 (brs, 1H), 7.39 (dd, J=9.7, 1.5 Hz, 1H), 4.25 (s, 2H), 1.48 (s, 6H); MS EI m/z 336 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:6][NH:7][C:8]([NH:10][C:11](=N)[NH:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])=O)[CH2:3][CH2:4][CH3:5].C[O:23][CH:24](OC)[N:25](C)C>CC#N>[CH3:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:20])[C:13]=1[N:12]1[CH:11]=[N:10][C:8]([NH:7][O:6][CH2:2][CH2:3][CH2:4][CH3:5])=[N:25][C:24]1=[O:23]
Reactant: COC(OC)N(C)C
Reactant: CCCCONC(=O)NC(=N)Nc1c(C)cccc1C
Agent: Cl
Solvent: CC#N
Product: CCCCONc1ncn(-c2c(C)cccc2C)c(=O)n1
Reaction time: 0.08 h

Procedure:
To a magnetically stirred suspension of 12.06 g (38 mmol) of 1-N-butoxy-3-(2,6-dimethylphenyl) amidinourea hydrochloride in 25 ml of CH3CN was added 9.11 g (76 mmol) of N,N-dimethyl-formamide dimethyl acetal and another 25 ml of CH3CN. All of the solid dissolved after the reaction was stirred for 5 minutes. The reaction solution was refluxed for two hours and allowed to come to ambient temperature, then concentrated in vacuo to yield the desired product as a white solid. This was combined with 200 ml of H2O to an insoluble, thin gummy solid which was transferred to a separatory funnel and extracted with CHCl3 (3×75 ml). The organic layers were combined, washed with H2O (2×75 ml) and saturated aqueous brine (1×75 ml). All aqueous washes were combined and back-extracted with (2×50 ml), dried (Mg2SO4), filtered and concentrated in vacuo to yield 1-(2,6-dimethylphenyl)-4-n-butoxyamino-1,2-dihydro-1,3,5-triazin-2-one, as a white solid containing some liquid. Tlc (3% NH4OH/iPA) shows four spots, one of same Rf as starting material. The product was triturated with iPA to yield a white solid: m.p. 144°-145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.O.F[B-](F)(F)F.[O:23]=[N+:24]=[O:25]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])=[C:6]([N+:24]([O-:25])=[O:23])[CH:7]=1
Reactant: O=[N+]=O
Reactant: O=C(NCCc1ccc(Br)cc1)C(F)(F)F
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(NCCc1ccc(Br)cc1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
To a stirred solution of 23.89 g of N-[2-(4-bromophenyl)ethyl]-2,2,2-trifluoroacetamide in 200 mL of acetonitrile was added in one portion 13.87 g of nitronium tetrafluoroborate under ice-cooling. After the mixture was stirred at room temperature for 15 minutes, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 11.03 g of N-[2-(4-bromo-2-nitrophenyl)ethyl]-2,2,2-trifluoroacetamide.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCCN=C1CCCCC2.ClC(Cl)(Cl)[C:36]([NH:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2)=[O:37]>C(#N)C.O>[O:16]=[C:9]1[N:10]2[CH2:15][CH2:14][N:13]([C:36]([NH:38][C:39]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][CH:43]=[N:44]4)=[O:37])[CH2:12][CH:11]2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:8]1
Reactant: O=C(Nc1cccc2ncccc12)C(Cl)(Cl)Cl
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Nc1cccc2ncccc12)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Yield: 32.9 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.15 g, 0.51 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 g, 1.3 mmol) in acetonitrile (6 mL) was added 2,2,2-trichloro-N-(5-quinolinyl)acetamide (0.16 g, 0.55 mmol), and the mixture was heated under reflux for 6 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic layer was washed twice with water, once with saturated brine, and dried over magnesium sulfate. The solid was filtered off, and the filtrate was concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate), and then recrystallized from hexane-ethyl acetate to obtain the title compound (78 mg, yield 33%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1O)=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=2)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1O
Product: O=[N+]([O-])c1cnc2ccc(-c3ccccc3)cc2c1Cl

Procedure:
The title compound is prepared in analogy to Example 19e, starting from 900 mg (3.38 mmol) 3-nitro-6-phenyl-quinolin-4-ol (Example 53c) in 10 ml POCl3. The compound is crystallized from ethylacetate-hexane. mp: 144-145° C.; MS: 284 (M++1); HPLC: tret=140.51 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N+:3]=1[O-].ClC1C([N+]([O-])=O)=C(C)C=CN=1.[C:24]([O:27]C(=O)C)(=[O:26])[CH3:25]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:11][O:27][C:24](=[O:26])[CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc[n+]([O-])c(Cl)c1[N+](=O)[O-]
Agent: Cc1ccnc(Cl)c1[N+](=O)[O-]
Product: CC(=O)OCc1ccnc(Cl)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A 4:1 mixture of 2--Chloro-3-nitro-4-picoline-N-oxide and 2-Chloro-3-nitro-4-picoline (7.2g, 0.031mol, based on the N-oxide) was dissolved in acetic anhydride (20 mL) and the solution was heated in a 80° C. oil bath for 70 minutes. The solvents were removed under vacuum and the dark residue was partitioned between methylene chloride (100 mL) and saturated aqueous potassium carbonate (200 mL). The aqueous layer was re-extracted with more methylene chloride (1×50 mL) and the combined methylene chloride layers were dried with magnesium sulfate, filtered and evaporated under vacuum. The crude solid was dissolved in methylene chloride (20 mL) and was loaded onto a silica gel column (E. Merck 60, 230-400 mesh, 4×36 cm). The column was eluted with methylene chloride collecting 25 mL fractions. Fractions 22-48 were combined and evaporated to give substantially pure 2-chloro-3-nitro-4-acetoxymethylpyridine (1.75 g) as a white solid.