Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])C[CH2:18][CH2:17]2)(=[O:10])[CH3:9].[Cl-].[Na+]>C(COC)OC.C(O)C>[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:23])=[C:16]2[C:21]=1[C:20](=[O:22])[C:7](=[CH:6][OH:5])[CH2:18][CH2:17]2)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCC2
Reactant: CCOC=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)C(=CO)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
960 mg of 60% aqueous solution of sodium hydride was added to 8 ml of ethyl formate under ice-cooling, and 5 minutes after the mixture was cooled to room temperature, a solution of 1.43 gm of 8-acetylamino-5-chloro-1-tetralone dissolved in 30 ml of dimethoxyethane was slowly added. After the addition of 0.06 ml of ethanol, the mixture was stirred for 30 minutes. The reaction mixture was poured into 300 ml of 14% aqueous solution of sodium chloride, extracted with ethyl acetate, washed with 10% aqueous solution of citric acid and saturated brine, and dried over anhydrous sodium sulfate. After concentration, ether was added to the residue to collect the precipitate of 1.30 gm of the title compound the by filtration.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[CH:15]=[N:14][CH:13]=[CH:12][C:9]=2[C:10]#[N:11])[CH:7]=1.C([Sn](CCCC)(CCCC)[C:22]1[N:26]2[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:33])[F:32])=[N:30][C:25]2=[N:24][CH:23]=1)CCC>>[F:16][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[N:26]3[CH:27]=[CH:28][C:29]([C:31]([F:32])([F:33])[F:34])=[N:30][C:25]3=[N:24][CH:23]=2)=[CH:7][C:6]=1[C:8]1[CH:15]=[N:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: N#Cc1ccncc1-c1cc(Br)ccc1F
Product: N#Cc1ccncc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-(5-Bromo-2-fluorophenyl)isonicotinonitrile (40 mg, 0.14 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (0.18 mmol) by the method of Example 32. Purification by chromatography on silica gel eluting with dichloromethane containing 3% methanol, then recrystallisation from toluene/isohexane, gave 3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)phenyl]isonicotinonitrile as a yellow solid: δH (400 MHz, CDCl3) 7.30 (1H, d, J 7), 7.51 (1H, t, J 9), 7.67-7.73 (3H, m), 8.13 (1H, s), 8.87 (1H, d, J 5), 8.96-8.98 (2H, m); m/z (ES+) 384 (M++H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH:12](=[N:19][N+:20]1[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]=1SC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS.C(OCC)C>CN(C)C=O>[F:7][B-:8]([F:11])([F:10])[F:9].[CH:12](=[N:19][N+:20]1[CH:24]=[CH:23][N:22]([N:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C1COCCN1
Reactant: CSc1n(N=Cc2ccccc2)cc[n+]1N=Cc1ccccc1
Agent: CS
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C(=Nn1cc[n+](N=Cc2ccccc2)c1N1CCOCC1)c1ccccc1

Procedure:
1.45 g of absolute morpholine are added under an argon atmosphere to 4.1 g of 1,3-bis-(benzylideneamino)-2-(methylthio)imidazolium tetrafluoroborate in 15 ml of absolute dimethylformamide, whereby the evolution of methyl mercaptan occurs immediately and a yellow-orange solution results. The solution is stirred at room temperature until the cleavage of methyl mercaptan is complete (about 12 hours). Then the solution is treated with 120 ml of diethyl ether and the resulting, slightly yellowish precipitate is removed by filtration under suction. The precipitate is washed five times with diethyl ether, and twice with a small amount of cold ethanol and re-precipitated from acetonitrile/diethyl ether. There is obtained colorless 1,3-bis(benzylideneamino)-2-morpholinoimidazolium tetrafluoroborate of melting point 242°-245° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][CH2:32][CH:33](O)[CH2:34][CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH:33]([CH2:34][CH3:35])[CH2:32][CH3:31])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CCC(O)CC
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Product: CCC(CC)OC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1CCCC1

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and pentan-3-ol according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 0.97 (t, J=7.38 Hz, 6H), 1.18-1.63 (m, 7H), 1.64-1.81 (m, 4H), 1.96 (ddd, J=26.11, 12.96, 4.16 Hz, 1H), 2.06-2.18 (m, 1H), 2.23-2.40 (m, 1H), 2.83-3.01 (m, 1H), 3.07-3.18 (m, 1H), 3.49 (ddd, J=13.76, 9.33, 4.83 Hz, 1H), 4.64 (dd, J=9.67, 5.37 Hz, 1H), 5.04 (dt, J=12.35, 6.18 Hz, 1H), 7.03 (dd, J=8.86, 2.15 Hz, 1H), 7.30 (d, J=2.15 Hz, 1H), 7.46 (d, J=8.86 Hz, 2H), 7.84-7.99 (m, 2H), 8.15 (d, J=8.06 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([OH:13])(=O)[CH:10]=[CH2:11].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5]3=[C:4]([C:9](=[O:13])[CH:10]=[CH:11][N:6]3[C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]2=3)[CH:3]=1
Reactant: C=CC(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccn2c3ccc(Cl)cc3c3cc(Cl)cc1c32
Yield: 87 %

Procedure:
p-chloroaniline (200 g) was suspended in water (100 ml) and acrylic acid (54.1 ml) was added to the suspension. The mixture was heated under reflux for 2 hours in a nitrogen atmosphere. After allowing to cool, 2 N aqueous solution of sodium hydroxide (500 ml) was added, and the mixture was extracted with ether. The aqueous layer was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (137.3g, 87%) was obtained without further purification.
Reaction SMILES: [Cl-].[NH4+:2].[CH:3]1[CH:8]=[C:7]([C:9](O)=O)[C:6]([Cl:12])=[CH:5][CH:4]=1>>[CH:3]1[CH:8]=[C:7]([C:9]#[N:2])[C:6]([Cl:12])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: [NH4+]
Agent: [Cl-]
Product: N#Cc1ccccc1Cl
Temperature: 225 °C
Yield: 880.8 %

Procedure:
OCBTC (230 g, 1.0 mol), ammonium chloride (59 g, 1.10 eq), and OCBA (15.7 g) were added to a 500 mL reactor equipped with thermocouple, overhead stirrer, and reflux condenser. The reaction mixture was stirred, heated upto 225° C., and maintained at that temperature while the reaction was periodically followed by gas chromatography (GC). After a reaction time of about 8 h, OCBN (121.5 g, 88.4%) was obtained by distillation (melting point: 45°-46° C.).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2cc(Cl)ccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-chloro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. MS (ESI) 491 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26]>O1CCOCC1.[Ag-]=O>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=[Ag-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 43.8 %

Procedure:
Silver (1) oxide (7.15 g.) was added to a solution of 5-nitroindole (5 g.) and methyl 4-bromomethyl-3-methoxybenzoate (B) (7.99 g.) in dioxane (30 ml.), under a nitrogen atmosphere. The mixture was stirred at 60° C. for 20 hours, dioxane removed by evaporation and ethyl acetate (50 ml.) added to the residue. The resulting suspension was separated by filtration through diatomaceous earth. The filtrate was evaporated to give a dark viscous oil, which was purified by flash chromatography on silica gel (600 ml.), eluting with 3:7 v/v ethyl acetate:hexane. The viscous yellow oil obtained was crystallized from a mixture of dichloromethane and hexane to give methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (C) (4.6 g., 45%) as yellow needles, m.p. 153°-155° C. NMR: 3.83(s,3H, COOCH3), 3.93(s,3H, OCH3), 4.12(s,2H, CH2.Ar), 7.25(d,1H), 7.43(d,1H), 7.49(m,3H), 7.95(dd, 1H, H6-indole), 8.47(d,1H, H4-indole), 11.65(broad s,1H, H1 -indole)
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.CO>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([N:7]2[C:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]=3[CH:10]=[N:9][C:8]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1NCc2cnc3[nH]ccc3c2N1C1CCCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=c1ncc2cnc3[nH]ccc3c2n1C1CCCCC1
Yield: 3.3 %

Procedure:
1-Cyclohexyl-3,4-dihydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2(7H)-one (18 mg, 0.066 mmol) in chloroform (2 mL) was stirred with manganese dioxide (100 mg, 1.15 mmol) at 50° C. for 5 hours. The reaction mixture was filtered, and the filtrate was purified by silica gel column chromatography (Hi Flash column amino type manufactured by Yamazen Corporation: chloroform/methanol=10/1 (v/v)) to give the title compound as a colorless solid (0.58 mg, yield 3.2%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([CH:8]([C:19](=O)[CH3:20])[C:9]([O:11]CC2C=CC=CC=2)=O)[N:3]=1.[NH2:22][NH2:23]>CCO>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:19]([CH3:20])=[N:23][NH:22][C:9]=2[OH:11])[N:3]=1
Reactant: CC(=O)C(C(=O)OCc1ccccc1)n1nc(C)nc1C
Reactant: NN
Solvent: CCO
Product: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Temperature: 25 °C

Procedure:
A mixture comprising benzyl 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-oxobutanoate (step 2) (7.1 g, 24.71 mmol) and hydrazine (2.327 ml, 74.1 mmol) in EtOH (124 ml) were stirred at 50° C. for 3 hours. The reaction was allowed to cool to RT overnight. The resultant solid was then collected by filtration and washed with a small amount of cold EtOH to afford the title compound as a pale yellow solid; LC-MS Rt 0.61 mins; MS m/z 193.9 [M+H]+; Method=Method LowpH_v001.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[CH:35]=[C:36]([CH:39]=[O:40])[O:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[CH:35]=[C:36]([CH:39]=[O:40])[O:37][CH:38]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: O=Cc1cc(Br)co1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)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: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(C=O)c4)cc23)CC1
Temperature: 150 °C
Yield: 122.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in dioxane (3.0 mL) and H2O (1.0 mL) was added 4-bromo-2-furancarbaldehyde (58 mg, 0.33 mmol), potassium carbonate (89.8 mg, 0.66 mmol), and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol). The reaction was heated in the microwave for 20 min at 150° C. to give 58 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-furanyl)-1H-indole-7-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][NH:17][CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:20]5[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Clc1ccc2c(c1)ncc1c3c([nH]c12)CCNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Yield: 4.3 %

Procedure:
A solution of 1.00 g (3.88 mmol) of 3-chloro-8,9,10,11-tetrahydro-7H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline, 0.47 g (3.88 mmol) of p-fluorobenzonitrile, 0.54 g (3.88 mmol) of K2CO3 and 8 ml of dimethylsulfoxide are stirred at 80° C. for 3 days. The reaction mixture is allowed to cool and is diluted with water producing a brown precipitate which is collected by filtration and dried. The crude product is purified by flash column chromatography (5% methanol in chloroform) to yield 0.06 g (4%) of the title compound as a pink solid: m.p.>275° C.; m/e 358.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:11])[CH:9]=O)=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15]([NH:18][CH:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:17])[CH3:16].C[O-].[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[CH2:23]([O:22][C:20]([C:19]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:12]([O-:14])=[O:13])=[CH:11][N:18]1[C:15](=[O:17])[CH3:16])=[O:21])[CH3:24]
Reactant: C=C(C=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CC(c2ccc(Cl)cc2[N+](=O)[O-])=CN1C(C)=O
Reaction time: 0.5 h

Procedure:
A solution of 143.0 g (0.676 mol) of 2-(4-chloro-2-nitrophenyl) acrolein in 600 ml. of benzene was added over 1.5 hour to a stirred suspension of 148.5 g (0.684 mol) of diethyl acetamidomalonate and 0.80 g of sodium methoxide in 600 ml. of benzene. The Michael addition was complete after 30 minutes. 3.8 g of p-toluenesulfonic acid monohydrate was added and the mixture was heated at reflux for 40 minutes with constant removal of the water formed. The reaction mixture was washed with saturated sodium bicarbonate and brine. After drying with anhydrous NaSO4, the orange solution was concentrated to yield 278.5 g, m.p. 90-95°. Crystallization from ethanol (500 ml) gave 264.6 g (95%) of deep yellow crystals, m.p. 96-98°. A sample was recrystallized again from ethanol: m.p. 96.5-98°.
Reaction SMILES: [C:1]1(=[CH:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1([CH3:22])[C:14]([CH3:16])([CH3:15])[O:13][B:12]([C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[O:11]1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:9][C:10]1([CH3:22])[C:14]([CH3:15])([CH3:16])[O:13][B:12]([C:17]2[CH:21]=[N:20][N:19]([C:1]3([CH2:6][C:7]#[N:8])[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:18]=2)[O:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=C1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3(CC#N)CCCC3)c2)OC1(C)C
Temperature: 25 °C
Yield: 17.2 %

Procedure:
A mixture of cyclopentylideneacetonitrile (0.65 g, 0.0061 mol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.60 g, 0.0031 mol, Aldrich, Cat. 525057), and 1,8-diazabicyclo[5.4.0]undec-7-ene (47 mg, 0.00031 mol, Aldrich, Cat. No. 139009) in acetonitrile (7 mL) was stirred at 60° C. overnight. After cooling to r.t., the reaction mixture was concentrated. The crude residue was purified by flash column chromatography on a silica gel column using 40% ethyl acetate in hexane as eluent to afford the desired compound (161 mg, 17.29%). LCMS (M+H)+: m/z=302.4.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][S-:16].[Na+].O>CN1CCN(C)C1=O>[CH3:15][S:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: COC(=O)c1ccc(SC)c([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 22.2 %

Procedure:
Methyl 4-fluoro-3-nitrobenzoate (13.6 g) was added over 10 minutes to a stirred solution of sodium thiomethoxide (4.8 g) in 1,3-dimethyl-2-imidazolidinone (100 ml). The dark brown solution was stirred for 2 hours and was then heated on a steam bath for 2.5 hours. After cooling, the solution was poured into water (1.0 liter) and was extracted with diethyl ether (300 ml and then 2×200 ml). The ether solution was washed with water (2×250 ml), was dried over magnesium sulphate and was then concentrated in vacuo to leave an orange slurry. Crystallization from methanol provided methyl 4-methylthio-3-nitrobenzoate (3.45 g), m.p. 118°-120° C. [Elemental analysis: C,47.8; H,3.9; N,6.2; S,13.7%; calculated: C,47.58; H,3.96; N,6.17; S,14.1%].
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[N:8][C:9]=2[N:10]=1.CN1CCCC1=O.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>O>[F:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[O:41][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[N:8][C:9]=2[N:10]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCCn1c(Oc2cccc(F)c2)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Temperature: 87.5 °C
Yield: 74.3 %

Procedure:
The first two steps were carried out as described earlier. A mixture of 2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.1 g, 0.34 mmol), N-methyl pyrrolidone (2 ml), potassium carbonate (0.093 g, 0.68 mmol) and 3-Fluoro phenol (0.036 ml, 0.4 mmol), were heated at 85-90° C. for 20 hours. The reaction mixture was cooled to 0° C. and then added water (10 ml). The solid obtained was filtered, washed with cold water, then washed with diethyl ether, dried to obtain -(3-Fluoro-phenoxy)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.093 g, 75%) as an off white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[C:11]([NH2:13])[CH:10]=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25](Cl)(=[O:27])=[O:26]>>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[S:25]([NH:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][O:5][CH2:4][CH2:3][C:2]([F:1])([F:14])[F:15])[N:12]=1)(=[O:27])=[O:26]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: Nc1cccc(COCCC(F)(F)F)n1
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCCC(F)(F)F)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(3,3,3-Trifluoro-propoxymethyl)-pyridin-2-ylamine (0.075 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.097 g) as a light yellow gum (0.08 g). MS (ESI−): 441.1 ([M−H]−).
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.C1([Mg]Cl)C=CC=CC=1.[CH3:23][C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1>[CH3:12][O:11][C:5]1[C:4]([O:13][CH3:14])=[CH:3][C:2]([CH:25]([OH:26])[C:24]([CH3:28])([CH3:27])[CH3:23])=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: COc1cc(I)c([N+](=O)[O-])cc1OC
Reactant: CC(C)(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(O)C(C)(C)C)c([N+](=O)[O-])cc1OC
Temperature: 40 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of 4-iodo-5-nitro-1,2-dimethoxybenzene (4.6 g, 15 mmol) in anhydrous THF (10 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 7.5 mL, 15 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for two hours, followed by addition of trimethyl acetaldehyde (2.0 mL, 18 mmol). The mixture was stirred at minus 40° C. for two hours and then at room temperature for another one hour. The reaction was quenched with brine (100 mL), and the mixture was extracted with CH2Cl2 (40 mL) three times. The combined organic phase was dried over Na2SO4 and concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield racemic (R/S)-1-(4,5-dimethoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (0.8 g, 20%). 1H NMR (400 MHz, CDCl3): δ 7.41 (1, 1H, Ph-H), 7.21 (s, 1H, Ph-H), 5.60 (s, 1H, PhCH), 3.95 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 0.90 (s, 9H, (CH3)3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of alcohol 92 (6.33 g, 30.0 mmol) in CH2Cl2 (60 mL) was treated with TEA (6.07 g, 8.36 mL, 60 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0–5° C. before MsCl (3.78 g, 2.55 mL, 33.0 mmol, 1.1 equiv) was dropwise introduced into the reaction mixture at 0–5° C. under N2. The resulting reaction mixture was subsequently stirred at 0–5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (40 mL) and CH2Cl2 (40 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with H2O (2×40 mL) and saturated aqueous NaCl (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5R)-methanesulfonic acid 3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester (mesylate 97, 7.69 g, 88.7% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H12FNO5S, LCMS (EI) m/e 290 (M++H).
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[C:27]1[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=1>O1CCCC1>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[C:27]1[CH:28]=[C:29]([NH:32][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:30][N:31]=1
Reactant: Cc1ccc(-c2cc(N)[nH]n2)c(C)c1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(NC=C3C(=O)Nc4ccccc43)[nH]n2)c(C)c1

Procedure:
The named compound is prepared by substituting 5-(2,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.250 gms. 5-(2,4-dimethyl-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) over the weekend.