Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30](=[NH:33])SC)=[O:28])=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:30]([NH:29][C:27](=[O:28])[CH2:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[NH:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Reactant: CSC(=N)NC(=O)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NC(=O)Cc1ccc(F)cc1)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To a test tube containing 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (20 mg, 0.082 mmol) and 1-(2-(4-fluorophenyl)acetyl)-2-methylisothiourea (20 mg, 0.086 mmol) was added 0.3 mL of toluene followed by diisopropylethylamine (15 μL, 0.086 mmol). The reaction was stirred at 110° C. for 6 h. Additional portions of 1-(2-(4-fluorophenyl)-acetyl)-2-methylisothiourea (20 mg, 0.086 mmol) and diisopropylethylamine (15 μL, 0.086 mmol) were added. After stirring at 110° C. overnight, the reaction was cooled to room temperature and purified directly by flash chromatography on silica gel (SiO2, EtOAc/Hexane 1:1) to give the title compound as a white solid. The solid was treated with 4 N HCl in dioxane at 0° C. for 30 min. The solution was concentrated in vacuo to give the HCl salt of the title compound (15 mg, 40%) as a white powder. 1H NMR (CDCl3) δ 13.8 (br s, 1H), 11.5 (br s, 1H), 9.48 (br s, 1H), 7.85 (s, 1H), 7.78 (dd, 1H, J=2.5, 1.4 Hz), 7.30 (m, 5H), 7.01 (m, 3H), 6.85 (m, 1H); MS(ESI+) m/z 423.1 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>N1C=CC=CC=1>[C:32]([O:1][N:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4]1)(=[O:34])[CH3:33]
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=NO)c3ccccc32)cc1)c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ON=C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2)c2ccccc21

Procedure:
A solution of 5-hydroxyimino-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.06 g) in acetic anhydride (10 ml) and pyridine (10 ml) is stirred at room temperature overnight. After completion of the reaction, the reaction solution is concentrated. To the resulting residue is added water and the mixture is extracted with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=80:1), and recrystallized from ethanol/petroleum ether to give 5-acetyloxyimino-1-[4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.75 g) as colorless prisms, m.p. 142°-144° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([NH:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Cl:16])=[CH:9][CH:8]=3.[OH-].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>CO>[F:27][C:26]([F:29])([F:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([NH:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Cl:16])=[CH:9][CH:8]=3
Reactant: FC(F)(F)CCCCCBr
Reactant: O=c1c2ccc(O)cc2[nH]c2cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1c2ccc(Cl)cc2[nH]c2cc(OCCCCCC(F)(F)F)ccc12
Temperature: 70 °C

Procedure:
3-hydroxy-6-chloroacridone (594 mg) was stirred in 10 ml of methanol, and 5 ml of methanolic KOH (30 mg/ml) was added (1 equiv. base), whereupon complete dissolution occurred. 1-Bromo-5-trifluoromethylpentane (2.03 g, 3 equiv.) was added and the solution heated at 70° C. overnight, forming a fine solid precipitate; after cooling, 0.35 g of pale yellow powder was collected by filtration. When the filtrate is heated another 2 days, the same quantity of product may be isolated in addition. The crude product was crystallized from methanol. Analogous procedures can be applied for preparation of compounds with the O(CH2)3CF3, O(CH2)4CF3, O(CH2)7CF3, and O(CH2)10CF3— side chains and including aromatic ketone derivatives bearing O(CH2)C2F5 and O(CH2)C3F7 side chains.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:2]2[C:3]3[N:4]([N:8]=[C:9]([Cl:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Product: CC(C)(C)OC(=O)N1CCC(CNc2cccn3nc(Cl)nc23)C1

Procedure:
3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (475.0 mg, 2.372 mmol) in a manner analogous to Example 2d. Product isolated as pale yellow viscous oil (0.544 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.88 (d, J=6.6 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 4.98 (br s, 1H), 3.65-3.08 (m, 6H), 2.64-2.51 (m, 1H), 2.15-2.05 (m, 1H), 1.80-1.65 (m, 1H), 1.47 (s, 9H). 163 b) 3-({2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.421 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (300.0 mg, 1.568 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (78.0 mg, 0.143 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.284 g, 39%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.5 Hz, 1H), 7.46 (d, J=8.9 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.71 (t, J=7.3 Hz, 1H), 6.59 (s, 1H), 6.35 (d, J=7.7 Hz, 1H), 4.75 (br s, 1H), 3.66-3.05 (m, 10H), 2.63-2.52 (m, 5H), 2.36 (s, 3H), 2.15-2.04 (m, 1H), 1.80-1.65 (m, 1H), 1.46 (s, 9H). MS=507 (MH)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.C(N(CC)CC)C.O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:10][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:9]
Reactant: O=C(O)C1CC2C=CC1C2
Reactant: OCCN1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(OCCN1CCOCC1)C1CC2C=CC1C2
Yield: 75 %

Procedure:
Cyclopentadiene, which was obtained by thermolysis of dicyclopentadiene, was dissolved in a conventional organic solvent, and the solution was cooled to about −30° C. About 1 equiv. of cooled acryl acid was slowly added to the solution. The reaction mixture was stirred for about 10 hours, after which the reaction mixture was allowed to reach room temperature and stirred for additional 10 hours. The solvent was removed using a rotary evaporator, and 5-norbornene-2-carboxylic acid was obtained by vacuum distillation. About 1 mole of 5-norbornene-2-carboxylic acid and about 1 mole of thionyl chloride were slowly combined and agitated in a bath. The remaining or unreacted thionyl chloride was removed and about 1 mole of triethylamine and 4-(2-hydroxyethyl)morpholine were added to the mixture. The reaction mixture was extracted with ethyl acetate. And the organic layer was separated, dried over anhydrous MgSO4, and concentrated to provide the title compound represented by formula 1a in 75% yield.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1>ClCCl.N1C=CC=CC=1>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:42])[CH2:35][CH2:36][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:17][N:16]=1
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCCC4)cnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCCC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Methyl-1H-indole-2-carbonyl chloride (109 mg, 0.6 mmol) in dichloromethane (2 mL) was added to N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-pyrrolidin-1-ylpropanamide (0.5 mmol) in pyridine (3 mL) at about 0° C. The ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. The solvent was removed and residue was purified by reverse phase preparative HPLC to give the title compound as the acetate salt (116 mg, 37%). 1H NMR (DMSO, d6) δ 1.75 (m, 4H), 1.90 (s, 3H), 2.55 (m, 6H), 2.77 (t, 2H), 3.91 (s, 3H), 4.04 (s, 3H), 5.44 (s, 2H), 7.08 (d, 1H), 7.15 (t, 1H), 7.20 (s, 1H), 7.33(t, 1H), 7.35 (s, 1H), 7.55 (s, 1H), 7.59 (d, 1H), 7.71 (d, 1H), 7.91 (s, 1H), 7.99 (d, 1H), 9.51 (s, 1H), 10.14 (s, 1H). LCMS: MH+=567.3, Rt =2.579 min. (a).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][NH2:11].[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:11][CH3:10])[N:7]=1
Reactant: CN
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CNc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (184 mg, 1.00 mmol, 1.00 equiv) in CH3CN/H2O (1/1, 33 ml) was cooled to 0° C. Methylamine (40 w % in H2O) (0.252 ml, 3.25 mmol, 1.00 equiv) was added. The reaction mixture was adjusted to a pH of about 9-10 using 1 N NaOH. After being stirred at 0° for 10 min, the reaction was complete. The resulting suspension was used in the next step without workup or purification.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].O=C[C@H]([C@H]([C@@H]([C@H](CO)O)O)O)O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
The present invention provides a method for producing L-sugars, including L-idose and L-gulose from D-glucose. The method comprises the steps of hydrogenating D-glucose to provide D-sorbitol, oxidizing the D-sorbitol to provide L-sorbose, racemizing the L-sorbose to a mixture of L-sorbose, L-idose and L-gulose, and precipitating the remaining L-sorbose with lime under cooling from a dilute solution. L-idose and L-gulose are recovered from the filtrate by crystallization. L-sorbose is recovered from the filtered solids by carbonation of the aqueous suspension and recycled.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.Cl.[NH2:31][N:32]1[CH2:39][CH:38]2[CH:34]([CH2:35][CH2:36][CH2:37]2)[CH2:33]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][N:32]3[CH2:39][CH:38]4[CH2:37][CH2:36][CH2:35][CH:34]4[CH2:33]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: NN1CC2CCCC2C1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NN3CC4CCCC4C3)n2)cc1
Yield: 67 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (34 mg, 67% yield.) MS/ES+: m/z=440.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[CH2:18][C:19]([C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:8]([O:16][CH2:18][C:19]([C:21]1[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C=O)c1ccccc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C=O)c1ccccc1C(=O)COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (362.8 ml) was added to a stirred mixture of benzoic acid (239.1 g) and dichloromethane (1120 ml) at 0° and the resultant solution was added dropwise over a period of 1 hour to the solution of 2'-(2-chloroacetyl)-N-methylformanilide under nitrogen whilst maintaining the temperature below 5°. The resulting solution was stirred overnight at ambient temperature, washed with water (2×1250 ml), dried over magnesium sulphate and the solvent removed by distillation at 50° to give a solid residue. Trituration with petroleum ether (b.p. 60°-80°, 1 1) gave the novel compound 2-[2-(N-methylformamido)phenyl]-2-oxoethyl benzoate, m.p. 100°-102°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: OCCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.2 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (1 g, 5 mmol) in THF (15 ml) was added sodium hydride (60% in parafin liquid) (220 mg, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 15 minutes. To the mixture was added ethyl 2-bromoisobutyrate (1.08 g, 5.5 mmol), and the mixture was stirred at room temperature for 12 hours. To this reaction solution were added ethyl acetate and a saturated aqueous ammonium chloride solution, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the extracts were combined with the organic layer. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resultant was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (240 mg, 15%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21].C1(C)C=CC=CC=1>CO>[CH3:19][N:20]([CH3:22])[CH:21]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9](=[O:16])[C:10](=[CH:19][N:20]([CH3:22])[CH3:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)C(=CN(C)C)C(=O)C(=CN(C)C)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixed solution of ethyl 4-(4-fluorophenyl)-3-oxobutanoate (0.95 g), N,N-dimethylformamide dimethylacetal (1.59 g) and toluene (7 ml) was stirred at 100° C. to 105° C. for 14 hours while methanol was distilled off. After cooling to room temperature, the residue was concentrated under reduced pressure. Further, 7 ml of toluene was added and the residue was concentrated to one-third of its volume under reduced pressure. Toluene (3.5 ml) was added to give a solution of ethyl 5-(dimethylamino)-2-[(dimethylamino)methylene]-4-(4-fluorophenyl)-3-oxopent-4-enoate. This solution was cooled to 0° C. to 5° C., trifluoroethyl amine (0.43 ml) and a 4.3 M solution of hydrogen chloride in ethyl acetate (1.57 ml) were added, and the mixture was stirred at 100° C. to 105° C. for three hours. After cooling to room temperature, the layers were separated by adding water, and the organic layer was concentrated to 3.5 ml. Toluene (1.4 ml) was added, followed by stirring at room temperature. The resulting solid was collected by filtration to give 1.07 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl[C:5]1[C:6]2[N:7]([C:15]([CH2:18][CH3:19])=[N:16][N:17]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2>CN(C)C=O>[CH2:18]([C:15]1[N:7]2[C:8]3[C:13]([N:14]=[C:5]([NH:3][CH2:1][CH3:2])[C:6]2=[N:17][N:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH3:19]
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CCN
Solvent: CN(C)C=O
Product: CCNc1nc2ccccc2n2c(CC)nnc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
Monoethylamine was bubbled through a solution of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g., 0.005 mole), the product of Example 4, in N,N-dimethylformamide (50 ml.) at 0° C. for about 2 minutes. The clear solution was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. The reaction mixture was next poured over ice and the precipitate was separated by filtration, washed with water and air dried. Recrystallization from ethanol then afforded 1.0 g. (83% yield) of pure 1-ethyl-4-ethylamino-[1,2,4]triazolo[4,3-a]quinoxaline as white solid (m.p. 235°-238° C.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=2)=[C:15]([CH:19]=1)[C:16]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)=[O:17]
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Neat 1-(bromomethyl)-4-fluorobenzene (1533 mg, 8.11 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmol) in acetone (60 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After filtering, the filtrate was evaporated to give a solid, which was dried in vacuo to yield the title compound as a white solid. 1.56 g.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C@@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][C@@H:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:23]I.O>CN(C=O)C>[CH3:23][O:3][C@H:4]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C@@H:5]1[N:9]([CH3:10])[C:8](=[O:11])[CH2:7][C@@H:6]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1cccs1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H](c1cccs1)[C@H]1[C@@H](c2ccccc2)CC(=O)N1C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a slurry of NaH (60%, 32 mg, 1.0 mmol) in DMF (15 mL) was added (±)-(4R*,5R*)-5-((1S)-hydroxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (Example 5 step 1, 250 mg, 0.9 mmol). The resulting mixture was stirred for 30 min, then methyl iodide (0.08 mL, 1.3 mmol) was added. After 2 h water was added and the resulting mixture was extracted with EtOAc, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc) to give (±)-(4R*,5R*)-5-((1S*)-methoxy-2-thienylmethyl)-1-methyl-4-phenylpyrrolidin-2-one (125 mg, 46%) as a white solid: mp 101-102° C.; TLC (EtOAc/hex) Rf 0.50.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17](I)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=3)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(cis-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (100 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (70.6 mg), tetrakis(triphenylphosphine)palladium(0) (23.8 mg) and potassium carbonate (56.8 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (22.7 mg).
Reaction SMILES: O.O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Na+].[C:14](#[N:17])[CH:15]=[CH2:16].C(O)(=O)C>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:16][CH2:15][C:14]#[N:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: C=CC#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a suspension of sodium 4-bromophenylsulfinate dihydrate (130 g, 0.53 mol) in water (600 mL) was added acrylonitrile (70 mL, 1.07 mol) and acetic acid (62 mL, 1.07 mol). The reaction was stirred for 1.5 h at 100° C. then cooled to room temperature. The solid was filtered off, washed thoroughly with water and dried over P2O5 to give 3-[(4-bromophenyl)sulfonyl]propanenitrile (125 g). δH (400 MHz, CDCl3): 7.27–7.22 (4H, m), 2.85 (2H, t, J 7.6), 2.30 (2H, t, J 7.6).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCO>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:24]1[CH2:23][CH2:22][CH:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:20][CH2:19]2)[CH2:26][CH2:25]1)=[O:4])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: C=CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)CCN1CCC(C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h

Procedure:
4.4 mL (40.6 mmol) ethyl acrylate were added to a solution of 10.0 g (37.3 mmol) tert-butyl[4,4′]bipiperidinyl-l-carboxylate in 100 mL EtOH and the reaction mixture was refluxed for 2 h. To complete the reaction a further 1 mL (9.2 mmol) of ethyl acrylate were added, the mixture was refluxed for 1 h and left overnight at RT. The solvent was eliminated i. vac. and the crude product was further reacted without being purified.