Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[Cl:19].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:19][C:13]1[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Oc1ccc(-c2cccc(F)c2)c(Cl)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
3-Fluorobenzeneboronic acid (405 mg, 2.89 mmol) and 4-bromo-3-chlorophenol (500 mg, 2.41 mmol) were dissolved in dioxane (15 mL) and water (3 mL) and the solution degassed. Tetrakis(triphenylphosphine) palladium (0) (278 mg, 0.24 mmol) was added followed by caesium carbonate (2.36 g, 7.23 mmol) and the reaction was stirred at 80° C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (509 mg, 95%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][O:12][C@@H:13]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:14][N:15]3[CH:19]=[CH:18][NH:17][CH2:16]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[N+:29]([O-:32])([OH:31])=[O:30]>C(O)C>[N+:29]([O-:32])([OH:31])=[O:30].[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([CH2:11][O:12][C@@H:13]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H](CN2C=CNC2)OCc2csc3c(Cl)cccc23)c(Cl)c1
Solvent: CCO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Clc1ccc([C@@H](Cn2ccnc2)OCc2csc3c(Cl)cccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
2.35 mg (5.37 mmol) of (S)-(+)-1-[2-(7-chlorobenzo[b]thiophen-3-yl-methoxy)-2-(2,4-dichlorophenyl )-ethyl]-2H-imidazole are dissolved in 17 ml of 96% ethanol. 3 ml of water are added and heated at a temperature between 35 and 40° C. To the obtained solution, 0.61 ml of 60% nitric acid (8.06 mmol, 1.5 eq.) are added. Then 13 ml of water are added and cooled first at room temperature and thereafter at 10° C. for 1 hour. The formed solid is filtered, washed twice with 10 ml of water and dried at vacuum for 24 hours to give 2.65 g (R=98.5%) of (S)-(+)-1-[2-(7-chloro-benzo[b]thiophen-3-yl-methoxy)-2-(2,4-dichlorophenyl)-ethyl]imidazole mononitrate.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[NH2:19][C:20]1[C:25]([NH2:26])=[C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[C:30]([F:41])[CH:29]=2)[CH:23]=[CH:22][N:21]=1>C1COCC1>[O:4]=[C:2]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[C:30]([F:41])[CH:29]=3)=[C:25]2[NH:26]1
Reactant: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
Method E3 (with triphosgene and Pyridine). N-(4-(2,3-Diaminopyridin-4-yl-oxy)-2-fluorophenyl)-2,2,2-trifluoroacetamide (500 mg, 1.5 mmol) was dissolved in dry THF (20 mL), pyridine (1 mL) was added and the solution was cooled at 0° C. Triphosgene (445 mg, 1.5 mmol) in dry THF (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residue washed with water. The precipitate was recovered by filtration to afford the title compound (260 mg, 49%). 1H-NMR (δ, ppm, DMSO-d6): 6.57 (d, 1H, HPy,5), 6.98 (d, 1H, Harom,Ph), 7.36 (d, 1H, Harom,Ph), 7.50 (d, 1H, Harom,Ph), 7.75 (d, 1H, HPy,6), 11.26 (s, 1H, NHPy3), 11.30 (s, 1H, NHCOCF3), 11.48 (s, 1H, NHPy2). LC-MS (m/z): 356 (M, 100).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([N+:19]([O-])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([NH2:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccccc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: NC1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a stirred solution of rac-(3S,4R)-1-benzyl-3-nitro-4-phenyl-pyrrolidine (1.0 g, 3.54 mmol) in EtOAc (50 ml) was added in one portion SnCl2.2H2O (3.99 g, 17.70 mmol). The reaction mixture was then heated at reflux for 2 hours, cooled down to RT and a saturated aqueous solution of NaHCO3 (100 ml) was added. The salts were filtered off and the product extracted with EtOAc. The organic phases were then dried over Na2SO4, and concentration under vacuum gave 0.72 g (80%) of rac-(3S,4R)-1-benzyl-4-phenyl-pyrrolidin-3-ylamine as a light yellow oil. The product was then used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:14][CH2:13][O:12][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[OH:12][CH2:13][CH2:14][CH:3]1[CH2:2][O:1][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[O:5][CH2:4]1
Reactant: OCC1CCOC2(CCCCC2)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OCCC1COC2(CCCCC2)OC1

Procedure:
A solution of 9-hydroxymethyl-7, 12-dioxaspiro[5,6]dodecane of the formula V (4 g) of the drawings in benzene (15 ml) was stirred at 10° C. for 5 hr with anhydrous p-toluenesulphonic acid (0.2 g). The reaction mixture was made alkaline by adding TEA and water. The benzene layer was separated and the aqueous layer extracted with benzene. The combined benzene solution was dried over K2CO3 and evaporate to a residue (4 g). It was chromatograped on silicagel using chloroform-methanol mixture as eluent to give 9-(2-hydroxyethyl)-7, 11-dioxaspiro[5,5]undecane of formula VI (2.8 g) (70%) of the drawings as colorless viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:9]1[C:10]([Cl:29])=[C:11]([C:17]2(O)[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:45])CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:9]1[C:10]([Cl:29])=[C:11]([C:17]2([F:45])[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]2)[CH:12]=[C:13]([C:15]#[N:16])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(C3(O)CN(C(=O)OC(C)(C)C)C3)c2Cl)cc1
Solvent: ClCCl
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(C3(F)CN(C(=O)OC(C)(C)C)C3)c2Cl)cc1
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To a solution of tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-hydroxyazetidine-1-carboxylate (408 mg, 0.75 mmol) in dry CH2Cl2 (12 mL) at −78° C. under nitrogen was added diethylaminosulfur trifluoride (153 μL, 0.90 mmol). The mixture was allowed to warm to 0° C. over 4 h and quenched by adding 1M aqueous NaOH at −5° C. The reaction mixture was diluted with EtOAc, washed with water, brine, and dried over sodium sulfate. Solvent was removed. The residue was purified by ISCO column (12 g) chromatography, eluting with hexane containing 0 to 40% EtOAc to afford tert-butyl 3-(3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)-3-fluoroazetidine-1-carboxylate (321 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:36])([F:35])[CH:30]([OH:34])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[CH:30]([OH:34])[C:29]([F:36])([F:35])[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=C(O)C(O)C(F)(F)F
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(O)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and rac-3,3,3-trifluoro-2-hydroxy-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=405.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(F)(F)F)=[C:4]([CH3:15])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH2:39]([O:41][C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([O:58]COC)[C:56]=1I)[CH2:45][C:46]1[C:47]([NH2:53])=[N:48][C:49]([NH2:52])=[N:50][CH:51]=1)[CH3:40].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+].Cl>O1CCOCC1.C(O)C.CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(COC)OC>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:56]2[C:55]([OH:58])=[CH:54][C:44]([CH2:45][C:46]3[C:47]([NH2:53])=[N:48][C:49]([NH2:52])=[N:50][CH:51]=3)=[CH:43][C:42]=2[O:41][CH2:39][CH3:40])=[CH:3][C:4]=1[CH3:15]
Reactant: Cc1cc(Br)ccc1NC(=O)C(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCOC)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: CCO
Solvent: CO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1ccc(N)c(C)c1
Temperature: 85 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
N-(4-Bromo-2-methyl-phenyl)-2,2,2-trifluoro-acetamide (described in example 4f) (4.9 g; 17.5 mmol), bis(pinacolato)diboron (6.66 g; 26.25 mmol), potassium acetate (5.15 g; 52.5 mmol) and bis(triphenylphosphine)palladium(II) dichloride (PdCl2(PPh3)2) (737 mg; 1.05 mmol) are suspended in dioxane (175 ml; dried over a molecular sieve), and four times the suspension is evacuated and ventilated with argon, with vigorous stirring. The mixture is then stirred at a bath temperature of 85° C. for 4 hours. After cooling to room temperature, the reaction mixture is concentrated and dimethoxyethane (10 ml), tetrakis-triphenylphosphine-palladium (1.21 g; 1.05 mmol), 5-(3-ethoxy-4-iodo-5-methoxymethoxy-benzyl)-pyrimidine-2,4-diamine (4.51 g; 10.5 mmol) and a 2 M aqueous sodium carbonate solution (70 ml) are added. The reaction mixture is stirred for approx. 25 hours under argon at 85° C. (bath temperature), cooled to room temperature and filtered with suction and the filtrate is concentrated. The residue obtained is dissolved in ethanol (210 ml), a 1 N aqueous sodium hydroxide solution is added and the mixture stirred is for 4½ hours in an oil bath of 50° C. The mixture is poured on to ice-water and extracted twice with ethyl acetate. The organic phases are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered with suction and concentrated. The residue is chromatographed over silica gel (810 g) with methylene chloride/methanol/NH4OH 19/1/0.05. The red powder obtained (2.6 g) is suspended in methanol (100 ml), a 4.5 N aqueous hydrochloric acid (30 ml; 137 mmol) is added and the mixture is stirred for 45 minutes in an oil bath at 60° C. The methanol is evaporated, the residue is dissolved in water (200 ml) and the pH is adjusted to approx. 10 with NH4OH conc., while stirring. After stirring for 30 minutes at room temperature, the suspension is filtered with suction and the residue is washed with water and dried under a high vacuum. 2.20 g (33%) 4′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-3′-methyl-biphenyl-2-ol are obtained as a light-red powder.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29]CC)[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][OH:29])[N:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)NCCCCn1c(CO)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.5 %

Procedure:
Boron tribromide (2.5 equivalents, 20 mL of 1 M solution in dichloromethane) was added dropwise to a cooled (ice bath) suspension of N-[4-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (3 g, 7.92 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to slowly warm to ambient temperature and then stirred for 4 hours. Additional boron tribromide (2 mL) was added and the mixture was stirred for 3 hours. The reaction was quenched slowly with methanol (20 mL) and then concentrated under reduced pressure. The residue was combined with 6 M hydrochloric acid (50 mL), heated to 50° C., and stirred for 2 hours. The resulting solution was concentrated under reduced pressure to a slurry that cooled (ice bath) and then free-based with the addition of 7 M ammonia in methanol (40 mL). The mixture was concentrated under reduced pressure and the addition of 7 M ammonia in methanol (40 mL) was repeated 2 more times. The concentrated brown sludge like material was purified by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of methanol in dichloromethane with 1% ammonium hydroxide) to provide a light brown solid. The solid was triturated with hot acetonitrile, allowed to cool, isolated by filtration, washed with ether, and dried under vacuum to provide N-[4-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide (0.1 g) as a fine beige solid, mp 216-219° C.; MS (ESI) m/z 364 (M+H)+; Anal. Calcd for C16H21N5O3S: C, 52.88; H, 5.82; N, 19.27. Found C, 52.62; H, 5.71; N, 19.02.
Reaction SMILES: CS([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)=O.[CH3:28][CH:29]([OH:31])[CH3:30].[H-].[Na+].Cl>O1CCCC1>[CH3:28][CH:29]([O:31][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:30]
Reactant: CC(C)O
Reactant: CS(=O)c1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
2-(Methylsulfinyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (100 mg) was suspended in tetrahydrofuran (4 ml), 2-propanol (77 μl) was added thereto, and then sodium hydride (25.0 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 min, and then at room temperature for 15 min. To the reaction mixture was added 0.5M hydrochloric acid (3 ml), and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (35.4 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:8]=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2].Br[C:28]1[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=1>>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=3)[C:13]=2[CH3:23])[CH:8]=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2]
Reactant: CCCn1cc(Br)cn1
Reactant: CCOC(=O)c1cc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)ccc1OC
Product: CCCn1cc(-n2c(C)c(Sc3ccc(OC)c(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 5-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-methoxy-benzoic acid ethyl ester and 4-bromo-1-propyl-1H-pyrazole.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=1)[CH2:8][NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([O:23][CH3:24])=[C:7]([CH:22]=2)[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)[S:25]1
Reactant: O=C1CSC(=O)N1
Reactant: COc1ccc(C=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COc1ccc(C=C2SC(=O)NC2=O)cc1CNC(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
1.5 g of N1-(5-formyl-2-methoxybenzyl)-4-(trifluoromethyl)benzamide was dissolved in 15 ml toluene, and 0.52 g of 2,4-thiazolidine dione, 36 mg pyrrolidine and 30 mg acetic acid were added thereto, and the mixture was heated under reflux for 2 hours with a Dean-Stark apparatus. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with ethyl acetate and then dried, to give 1.4 g of N1-[5-[(2,4-dioxo-1,3-thiazolane-5-ylidene)methyl]-2-methoxybenzyl)-4-(trifluoromethyl)benzamide.
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(C)=O>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH:16]([CH2:22][CH2:23][CH2:24][CH3:25])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:3]=1
Reactant: Brc1n[nH]c(Br)c1Br
Reactant: CCCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC(C(=O)OCC)n1nc(Br)c(Br)c1Br
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A quantity (30.4 g., 0.1 mole) of 3,4,5-tribromopyrazole was dissolved in 500 ml. acetone and 27.6 g. (0.2 mole) solid anhydrous potassium carbonate was added. The mixture was heated at the reflux temperature with stirring for 10 minutes and after cooling 23.0 g. (0.11 mole) ethyl 2-bromohexanoate was added. This reaction mixture was heated at the reflux temperature for 11/2 hrs., cooled, and then filtered. The solids on the filter were washed with acetone and the combined acetone filtrate and acetone washes were evaporated to dryness under reduced pressure. Distillation of the residue yielded ethyl 3,4,5-tribromo-α-butylpyrazole-1-acetate, 41.0 g. (92% yield), having a boiling point at 138° to 140° C. at 0.15 mm. mercury pressure.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[F:18])C(OC)=O>Cl>[F:18][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:9]=1[CH2:4][C:3]([OH:19])=[O:2]
Reactant: COC(=O)C(C(=O)OC)c1c(F)cccc1[N+](=O)[O-]
Agent: Cl
Product: O=C(O)Cc1c(F)cccc1[N+](=O)[O-]
Yield: 69.1 %

Procedure:
2-(2-Fluoro-6-nitro-phenyl)-malonic acid dimethyl ester (6.5 g, 23.98 mmol) was refluxed in 200 mL 6N hydrochloric acid for 24 hours. The solid was collected by suction filtration, and dried to give 3.3 g, 54% yield of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>>[N+:1]([C:4]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:17]2[C:13](=[N:14][NH:15][CH:16]=2)[NH:12][C:5]=1[CH2:8][CH2:9][CH3:10])([O-:3])=[O:2]
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Product: CCCC1=C([N+](=O)[O-])C(c2ccccc2[N+](=O)[O-])c2c[nH]nc2N1

Procedure:
The title compound was prepared from n-butylaldehyde, 2-nitrobenzaldehyde and 3-aminopyrazole in the same manner as in Example 93.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[CH3:12][CH2:13][C:14](=O)[C:15](=[O:18])[CH2:16][CH3:17].C(O)C>S(=O)(=O)(O)O.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][N:11]=[C:14]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:13][CH3:12])([O-:3])=[O:2]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: CCC(=O)C(=O)CC
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCC(=O)C(CC)=NNc1ccccc1[N+](=O)[O-]
Yield: 96.1 %

Procedure:
A mixture of 2-nitrophenylhydrazine (2.00 g), hexane-3,4-dione (1.80 g), sulfuric acid (2 drops) and ethanol (20 mL) was heated under reflux for 1 hr. The reaction mixture was poured into water, and the resulting crystals were collected by filtration, washed with water and dried to give the title compound (3.13 g, 96%) as brown crystals. melting point 96-97° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1[CH:15]=[C:14]([N:16]([CH:23]=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([CH2:25][CH3:26])[C:11]=1[NH:27][C:28]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=S)[CH3:9].[I-].ClC1C=CC=C[N+]=1C>C(#N)C>[CH2:8]([C:10]1[CH:15]=[C:14]([N:16]([CH:23]=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[C:12]([CH2:25][CH3:26])[C:11]=1[N:27]=[C:28]=[N:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH3:9]
Reactant: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(N(C=O)c2ccccc2)cc(CC)c1N=C=NC(C)(C)C

Procedure:
With stirring, 3.2 g of triethylamine are added dropwise at room temperature to 6.0 g of N-[2,6-diethyl-4-(N-formylanilino)phenyl]-N'-tert-butylthiourea and 4.8 g of 2-chloro-1-methylpyridinium iodide in 30 ml of acetonitrile. The reaction mixture is stirred for 1 hour at 70° C. and then concentrated by evaporation at 50° C. on a rotary evaporator. The residue is taken up in 50 ml of hexane and 30 ml of cold water. The hexane phase is separated, washed with water, dried over sodium sulfate and concentrated by evaporation, to give the title compound of formula ##STR21## as a yellowish oil with refractive index nD25 : 1.5840.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C1COCC1>[N:10]1([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCOCC1
Yield: 99.9 %

Procedure:
To a stirred solution of tert-butyl bromoacetate (1.61 mL, 10.0 mmol) in THF (25 mL) was added morpholine (1.74 mL, 20.0 mmol); the resultant suspension was stirred for 1.5 h and then concentrated. The residue was dissolved in CH2Cl2 (50 mL)/saturated Na2CO3 (75 mL), the layers were separated, and the aqueous layer was extracted with additional CH2Cl2 (2×25 mL). The combined organics were washed with saturated Na2CO3 (20 mL) and brine (30 mL), dried and concentrated to give crude title compound. Tituration with EtOAc (15 mL), filtration, and concentration of the filtrate gave the title compound (2.01 g, 100%) as a colorless oil. TLC: Rf 0.45 (EtOAc). 1H NMR: δ3.79-3.73 (m, 4H, CH2OCH2), 3.11 (s, 2H, CH2), 2.61-2.55 (m, 4H, CH2NCH2), 1.46 (s, 9H, t-Bu). MS (DCI/CH4): m/z (rel intensity) 202 (MH+, 15), 201 (8), 200 (13), 174 (20), 146 (100), 100 (23). HRMS (C10H19NO3) (MH+): calcd, 201.1365; obsd, 201.1371.