Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28](=[O:33])[NH:29][CH2:30][CH2:31]Br)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>C1COCC1>[C:23]([O:27][C:28](=[O:33])[NH:29][CH2:30][CH2:31][N:8]1[CH2:9][CH2:10][C:11]2[C:16](=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH:7]1[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)NCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(Cc1ccc(F)cc1)N(CCNC(=O)OC(C)(C)C)CC2
Temperature: 70 °C
Reaction time: 120 h

Procedure:
To a solution of 1-(4-fluorobenzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (example A31, 1.05 g, 3.5 mmol) in THF (40 mL) is added (2-bromo-ethyl)-carbamic acid tert-butyl ester (example B1, 0.94 g, 4.2 mmol) and DIPEA. The reaction mixture is stirred at 70° C. in a sealed flask for 5 days. After cooling to rt, the reaction mixture is evaporated to dryness, and the residue is purified by preparative HPLC to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:15][CH2:12][CH2:13][CH3:14])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: CCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and propylamine according to general procedure 1 providing the amino compound (247 mg, 100%) as a yellow solid: Rf=0.88 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J=9.6 Hz, 1H), 7.49 (s, 1H), 6.41 (d, J=9.6 Hz, 1H), 4.47 (br, 1H), 3.41-3.37 (m, 2H), 1.70 (sext, J=7.3 Hz, 2H), 1.03 (t, J=7.5 Hz, 3H); ES-MS: (M+H)=255, 257 m/z.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].[OH-].[K+].Br[C:9]([CH3:23])([CH3:22])[C:10]([NH:12][C:13]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[O:15][N:14]=1)=[O:11]>C(O)C>[C:18]([C:16]1[O:15][N:14]=[C:13]([NH:12][C:10](=[O:11])[C:9]([S:4][CH2:3][CH:2]([CH3:5])[CH3:1])([CH3:22])[CH3:23])[CH:17]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)CS
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CSC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a stirred solution of 82 μL (1.31 mmol) of 2-methyl-1-propanethiol in ethanol (2 mL) were added 37 mg (0.65 mmol) of KOH pellets, followed by 190 mg (0.65 mmol) 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (prepared as described in step 2, method B). The reaction mixture was heated to reflux for 18 h. The reaction was cooled to room temperature. The solid (KBr) was separated by filtration and rinsed with ethanol (15 mL). The filtrate was concentrated under reduced pressure to yield 160 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-isobutylsulfanyl-2-methyl-propionamide.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5]C=CC=1.[OH2:8]>>[CH3:5][CH2:6][CH2:1][CH2:7][O:8][C@H:6]([CH2:5][OH:8])[CH2:1][CH3:7]
Reactant: O
Reactant: Cc1ccccc1
Product: CCCCO[C@@H](CC)CO
Reaction time: 1.5 h

Procedure:
200 ml of an acidic ion-exchange resin (Bio-Rad 50W-X2) was added to the mixture and it was stirred for 1.5 hours. 200 ml of toluene was added to the mixture and water was removed by azeotropic distillation. The product was filtered to remove the resin, and the solvent was removed under reduced pressure. The resulting diol (482 g) had a hydroxyl number of 67 mg KOH/g.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](O)[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[C:5]1=[O:28])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:30]>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:30])[C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[C:16]([N+:24]([O-:26])=[O:25])[CH:15]=2)[C:5]1=[O:28])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Nc1ccc(C(O)=C2C(=O)N(C(C)=O)c3ccccc32)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A suspension of 11.4 g of 1-acetyl-3-(1-hydroxy-1-(4-acetylamino-3-nitrophenyl)-methylene)-2-indolinone and 9.37 g phosphorus pentachloride in 200 ml dioxane is stirred for 4 hours at 100° C. After the addition of another 2.0 g of phosphorus pentachloride the mixture is stirred for a further 3 hours at 10° C. Then the solvent is distilled off, the residue is stirred with 100 ml of ethyl acetate, suction filtered, washed with ethyl acetate and dried at 60° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:16][CH3:17])=[O:10]
Reactant: CCO
Reactant: O=C(O)Cc1ccccc1Br
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1ccccc1Br

Procedure:
43.0 g (0.2 mol) of DL-2-bromo-phenylacetic acid are dissolved in 400 ml of ethanol at ambient temperature with stirring. At 5°-10° C. 11.8 g (0.2 mol) of thionylchloride are slowly added dropwise whilst cooling with ice. After 12 hours at ambient temperature the solvent is distilled off and the residue is taken up in ethyl acetate. After extraction with saturated sodium bicarbonate solution and saturated saline solution the product is dried over sodium sulphate and evaporated down.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C=O.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])OCC.C([O-])([O-])=O.[K+].[K+]>C(O)C.Cl>[CH2:16]([O:15][CH:8]([O:12][CH2:13][CH3:14])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH3:17]
Reactant: O=Cc1cccs1
Reactant: CCOC(OCC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(OCC)c1cccs1
Yield: 89.9 %

Procedure:
A solution of 22.4 g (200 mmol) of 2-thiophene carboxaldehyde and 44.4 g (300 mmol) of triethyl orthoformate in ethanol (200 mL) with 3-5 drops of concentrated HCl was heated at reflux for 4 hrs. The reaction mixture was then neutralized with K2CO3. After filtered and concentrated, 33.5 g (90% yield) of 2-(diethoxymethyl)-thiophene was distilled under reduced pressure (bp 156° C./1 torr).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.[Br:11]N1C(=O)CCC1=O>CN(C)C=O>[Br:11][C:6]1[C:2]([OH:1])=[N:3][O:4][C:5]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)Cc1cc(O)no1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C(O)Cc1onc(O)c1Br
Reaction time: 1 h
Yield: 57.9 %

Procedure:
To a solution of 6.0 g (35 mmoles) of 3-hydroxyisoxazol-5-ylacetic acid in 10 ml of N,N-dimethylformamide were added 6.5 g (42 mmoles) of N-bromosuccinimide, with ice-cooling and stirring. The mixture was stirred under ice-cooling for 2 hours and then at room temperature for 1 hour. The N,N-dimethylformamide was then distilled off under reduced pressure. The residue was dissolved in ethyl acetate and extracted with an aqueous solution of sodium hydrogen carbonate. The pH of the extract was adjusted to a value below 1.0 by the addition of concentrated hydrochloric acid, and then the solution was extracted with ethyl acetate. After drying the ethyl acetate extract, the solvent was distilled off. The crystals which formed the residue were recrystallized from a 1:5 by volume mixture of ethyl acetate and cyclohexane, giving 4.5 g (58%) of the title compound in the form of colourless plate crystals, melting point 167° C. with decomposition.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:12][CH2:13][C:14]2=[O:17])[CH2:9]1)C1C=CC=CC=1.Cl[C:33]([O:35][CH:36]=[CH2:37])=[O:34]>ClCCCl.C(OC(C)C)(C)C>[Cl:31][C:27]1[CH:26]=[C:25]([C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH:10]3[CH:15]([CH2:16][N:8]([C:33]([O:35][CH:36]=[CH2:37])=[O:34])[CH2:9]3)[C:14](=[O:17])[CH2:13][CH2:12]2)[CH:30]=[CH:29][CH:28]=1
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(Cc3ccccc3)CC12
Solvent: ClCCCl
Solvent: CC(C)OC(C)C
Product: C=COC(=O)N1CC2C(=O)CCC(c3cccc(Cl)c3)(c3cccc(Cl)c3)C2C1

Procedure:
A solution of (3aRS,7aRS)-2-benzyl-7,7-bis(3-chlorophenyl)perhydro-4-isoindolone (11.5 g) in 1,2-dichloroethane (250 cc) is treated with vinyl chloroformate (2.8 cc) and heated to reflux for 16 hours, then concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 6 cm, height 32 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (80:20) and collecting 25-cc fractions. Fractions 19 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The meringue-like product obtained is solidified in isopropyl ether and the precipitate is drained, washed with isopropyl ether and dried to give (3aRS,7aRS)-7,7-bis(3-chlorophenyl)-2-vinyloxycarbonylperhydro-4-isoindolone (6.7 g) in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([CH3:12])[C:10]#[N:11].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([C:10]1[NH:15][CH2:14][CH2:13][N:11]=1)[CH3:12]
Reactant: CC(C#N)c1c(F)cccc1F
Reactant: NCCN
Product: CC(C1=NCCN1)c1c(F)cccc1F

Procedure:
rac-2-[1-(2,6-Difluoro-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,6-difluoro-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): white solid; MS (ISP): 211.1 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10](Cl)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].N12CCCN=C1CCCCC2.[CH3:24][O:25][C:26](=[O:30])[CH2:27][N+:28]#[C-:29]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][C:10]1[O:11][CH:29]=[N:28][C:27]=1[C:26]([O:25][CH3:24])=[O:30]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)Cc1ccc(F)c(F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1Cc1ccc(F)c(F)c1
Reaction time: 0.08 h
Yield: 3.4 %

Procedure:
3,4-Difluorophenylacetic acid (3.61 g, 20.9 mmol) in oxalyl chloride (7.31 ml, 83.8 mmol) was refluxed for 4 hours. The solution was cooled to room temperature, concentrated under reduced pressure to give 3,4-difluorophenylacetyl chloride which was used without purification. To a well stirred solution of 3,4-difluorophenylacetyl chloride (2.21 g, 11.59 mmol) in THF (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (3.47 mL, 23.18 mmol) at room temperature and the solution was stirred for five minutes. Then methylisocyanoacetate (1.55 mL, 11.59 mmol) was added over a three minute period to the reaction mixture. After stirring for 18 hours at room temperature, the reaction mixture was partitioned between ether (100 mL) and water (50 mL). The organic layer was washed with 1N HCl (10 mL), water (15 mL) and saturated solution of sodium bicarbonate (15 mL), and dried over sodium sulfate. The solution was then filtered and concentrated. The residue was chromatographed (hexanes:EtOAc, 3:2) to yield 100 mg (3.4%) of the product; 1H-NMR (CDCl3) δ3.89 (s, 3H), 6.98 (s, 2H), 7.00-7.09 (m, 3H), 7.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[C:9]#[N:10].B.C1COCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:11])[CH2:9][NH2:10]
Reactant: CC(C#N)c1ccccc1Cl
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(CN)c1ccccc1Cl
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a solution of 2-(2-chlorophenyl)propanenitrile (14 g, 84.8 mmol) in toluene at 0° C. was added BH3.THF (127, 255 mmol) and the reaction was warmed to room temperature and heated at reflux for 4 h. The reaction mixture was cooled; quenched with water, concentrated and the residue was purified by column chromatography (silica, ethyl acetate/hexanes gradient) to obtain the desired product (13.9 g, 97%) as a reddish oil: ESI MS m/z 170 [C9H12ClN+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([CH:12]=O)=[CH:5][CH:4]=1.[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:8]([C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:10])=[O:9]
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C=C2SC(=S)NC2=O)c(C(=O)O)c1

Procedure:
To a hot stirred solution of 0.90 g. (5.0 mM) of 5-methoxyphthalaldehydic acid and 0.67 g. (5.0 mM) of rhodanine in 4 ml. of acetic acid is added 1.35 g. (16.4 mM) of anhydrous sodium acetate. After refluxing 0.5 hour, the solid yellow mass is cooled, poured into water, and filtered to separate 5-(2-carboxy-4-methoxybenzylidene)rhodanine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([NH:14][NH:15][C:16](=O)[C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[C:3]([C:12]2[S:34][C:16]([C:17]([OH:23])([CH3:22])[C:18]([F:21])([F:20])[F:19])=[N:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(O)(C(=O)NNC(=O)c1ncc(C(F)(F)F)cc1N)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)(c1nnc(-c2ncc(C(F)(F)F)cc2N)s1)C(F)(F)F

Procedure:
A mixture comprising 3-amino-N′-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)-5-(trifluoromethyl) picolinohydrazide (184 mg, 0.511 mmol) in toluene (5.108 ml) was treated with Lawesson reagent (310 mg, 0.766 mmol) and heated at reflux for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed saturated sodium bicarbonate solution, brine, dried (phase separator) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded an orange gum. Further purification was carried out by preparative reverse phase HPLC eluting with 30-70% MeCN in water (0.1% TFA) to afford the title compound; 1H NMR (400 MHz, DMSO-d6) δ 8.2 (1H, s), 8.0 (1H, s), 7.6 (1H, s), 7.4 (2H, s), 1.9 (3H, s). LC-MS Rt=4.03 min [M+H]+ 359.4 Method 10minLC_v003.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=O.C(O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(N)=O)cc1Br
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(CN)cc1Br
Temperature: 50 °C
Reaction time: 120 h

Procedure:
To 3-bromo-4-methylbenzamide (2.14 g, 10 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (2 mL, 20 mmol) at 0° C. The mixture was then heated to 50° C. for 16 h. Additional borane dimethyl sulfide complex (1 mL, 10 mmol) was added and heating continued at 60° C. for an additional 5 days. The reaction mixture was cooled to room temperature and ethanol was cautiously added. When bubbling ceased, 1N HCl was added until the pH was ˜2. This mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous was washed 3× with EtOAc. The aqueous was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound. LC-MS m/z 199.8 (M+H)+, 1.01 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:39]=[CH:38][C:21]([O:22][CH2:23][C:24]([N:26]5[CH2:31][CH2:30][N:29]([C:32]6[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=6)[CH2:28][CH2:27]5)=O)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:39]=[CH:38][C:21]([O:22][CH2:23][CH2:24][N:26]5[CH2:27][CH2:28][N:29]([C:32]6[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=6)[CH2:30][CH2:31]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:40][CH:41]([CH3:42])[CH3:43])=[CH:9][CH:8]=2)=[CH:44][CH:45]=1
Reactant: CC(C)Cc1nc(-c2ccc(OCC(=O)N3CCN(c4ccncc4)CC3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: B
Solvent: C1CCOC1
Product: CC(C)Cc1nc(-c2ccc(OCCN3CCN(c4ccncc4)CC3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
The product of Example 522 was taken in 4 ml of THF to which was added 5 eq. of BH3-THF solution and the reaction was heated to reflux until the reaction was complete. The crude product was purified by silica gel chromatography to afford Example 527.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.Cl.[F:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C>[F:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[N:10]=[C:4]3[N:3]=2)[CH2:19][CH2:18]1
Reactant: FC1CCNCC1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC1CCN(c2ccn3c(n2)nc2ccccc23)CC1
Temperature: 25 °C

Procedure:
To a microwave vial equipped with a magnetic stir bar, containing DMF (1 mL) was placed 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.02 g, 0.089 mmol, 1.0 equiv), 4-fluoropiperidine hydrochloride (0.019 g, 0.133 mmol, 1.5 equiv) and triethylamine (0.037 ml, 0.266 mmol, 3.0 equiv). The suspension was irradiated in a Biotage Initiator microwave reactor (250 W) at 100° C. for 15 min. After cooling to room temperature, the crude product was purified by HPLC to afford 0.015 g (63%) of T777 as an off-white solid. MS (ESI, Pos.) m/z: 271.1 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH2:11]([O:10][C:8](=[O:9])[NH:7][C:1]1[CH:6]=[CH:5][C:4]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:3][CH:2]=1)[CH3:12]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)Nc1ccccc1
Product: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Temperature: 60 °C

Procedure:
To a stirred solution of chlorosulfonic acid (20 ml) at 0° C., was added N-phenylurethane (9.90 g) at such a rate that the temperature did not exceed 20° C. The reaction was then heated at 60° C. for 3 hours, cooled to ambient temperature and poured carefully onto ice. The resultant precipitate was collected by filtration and dried in vacuo to give (4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (140.50 g) as an off-white solid. LC-MS (METHOD B): RT=3.11 minutes, 284.23 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 63 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 5-chlorosalicylaldehyde (4.00 g) in N,N-dimethylformamide (40 mL) under nitrogen was added sodium hydride in portions (0.64 g). To the resulting reddish solution was added a solution of 1-fluoro-2-nitrobenzene (3.50 g) in N,N-dimethylformamide (10 mL) in one lot. The reaction was then stirred at 63° C. under nitrogen for 24 hours. The reaction was evaporated under vacuum, and the residue was partitioned between chloroform and 1 N NaOH. The layers were separated, and the aqueous layer was extracted once more with chloroform. The combined chloroform extracts were washed with 1 N NaOH, water, 1 N HCl, water, and brine, dried over magnesium sulfate, and evaporated under vacuum. The residue was crystallized from cyclohexane to yield the title compound as a light yellow solid. Mp: 103°-105° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38]Br)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>CN(C=O)C.O>[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][N:7]2[C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3][C:2]2([CH3:13])[CH3:1])=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: CC1(C)NC(=O)c2ccccc2O1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCN2C(=O)c3ccccc3OC2(C)C)cc1)OCC
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirred solution of 2,2-dimethyl-4-oxo-3,4-dihydro-1,3-benzoxazine (0.3 g, 1.69 mmol) in DMF (3 mL) was added potassium carbonate (0.47 g, 3.39 mmol) and stirred for 30 min. To this reaction mixture was added a solution of ethyl 2-ethoxy-3-[4-(2-bromoethoxy) phenyl]propanoate (0.70 g, 2.03 mmol) (disclosed in U.S. patent application Ser. No. 09/012,585) in DMF (1 mL) and stirred for 24 h at 60-70° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel using a gradient of 5-15% of ethyl acetate in pet ether as eluent to afford the title compound (0.34 g, 45%) as a liquid.
Reaction SMILES: C[O-].[Na+].C(OCC)(=O)[CH2:5][C:6]([CH3:8])=[O:7].[Cl:13][C:14]1[C:24]([Cl:25])=[C:23]([C:26](=O)[C:27](=[CH2:33])[CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]>C(O)C>[Cl:13][C:14]1[C:24]([Cl:25])=[C:23]([C:26]2[CH:27]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:33][CH2:8][C:6](=[O:7])[CH:5]=2)[CH:22]=[CH:21][C:15]=1[O:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: C=C(C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl)C1CCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)COc1ccc(C2=CC(=O)CCC2C2CCCC2)c(Cl)c1Cl
Yield: 35.7 %

Procedure:
To a stirred solution of sodium methoxide (2.3 g, 0.043 mole) in ethanol (50 ml) and ethyl acetoacetate (5.56 g, 0.043 mole) was added [2,3-dichloro-4-(2-methylene-2-cyclopentyl-1-oxoethyl)phenoxy]acetic acid (6.5 g, 0.019 mole). The reaction mixture was heated at reflux for 2 hours, then the solvent was distilled at reduced pressure. The residue was dissolved in water, acidified, extracted into ether, washed with water, extracted into sodium bicarbonate, acidified, extracted into ether, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 2.6 g of [2,3-dichloro-4-(6-cyclopentyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid which melted at 206°-207° C. after recrystallization from 300 ml of toluene.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[K+].[K+].[K+]>O>[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4]
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reaction time: 0.03 h

Procedure:
Potassium citrate ##STR95## The resulting product is added to 16 ounces of boiling water and stirred for a period of 1.5 minutes. The resulting material is poured into a mold and is permitted to cool. The resulting jell has an excellent "true fruit" flavor with intense blueberry and blackcurrant nuances. Note: CARMEL KOSHER® vegetable jell is produced by Carmel Kosher Food Products, Inc. of Chicago, Ill. 60632.