Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:35](I)[CH3:36]>O>[CH2:35]([O:22][C:21]([C:19]1[O:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23])[CH3:36]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC)o1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 10.0 g (0.031 mole) of 5-tetradecyloxy-2-furoic acid, 4.3 g (0.034 mole) of potassium carbonate, and dimethyl formamide is stirred at room temperature after which 15.6 g (0.10 mole) of ethyl iodide is added. The mixture is heated to 50° C with stirring overnight then poured into water and extracted with ether. The ether layer is washed with water and salt water then dried over sodium sulfate, filtered, and the ether is distilled off and replaced by ethanol. Upon cooling the ethanol solution a solid is obtained which is 5-tetradecyloxy-2-furoic acid ethyl eseter, M.P. 39°-40° C.
Reaction SMILES: B.[C:2]1([C@H:8]2[CH2:12][CH2:11][NH:10][C@@H:9]2[C:13](O)=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1>[C:2]1([C@H:8]2[CH2:12][CH2:11][NH:10][C@@H:9]2[CH2:13][OH:14])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1NCC[C@@H]1c1ccccc1
Agent: B
Solvent: C1CCOC1
Product: OC[C@H]1NCC[C@@H]1c1ccccc1
Reaction time: 1 h

Procedure:
Borane in tetrahydrofuran (1.0 M, 1.0 mL) was added to (2S,3R)-3-phenylpyrrolidine-2-carboxylic acid (30.0 mg, 0.000157 mol) in tetrahydrofuran (1.0 mL, 0.012 mol) at rt. After stirring for 1 h the solvent was evaporated under reduced pressure and the residue was azeotroped with methanol (3×2 mL) to afford the desired product, which was directly used in next step reaction without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH2:13][CH2:12]1)=O>O1CCCC1>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][CH:14]1[CH2:13][CH2:12][CH:11]([CH2:9][OH:8])[CH2:16][CH2:15]1
Reactant: COC(=O)C1CCC(Cc2ccccc2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(Cc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
In a dry 50 mL 1 neck round bottom flask, lithium aluminium hydride (150 mg; 4.0 mmol) was suspended in dry tetrahydrofuran at 0° C. under nitrogen flow. Dissolved 4-(2-fluorobenzyl)cyclohexanecarboxylic acid methyl ester was added over 2 minutes and mixture was allowed to warm to room temperature. After 3 hours at room temperature, Reaction was quenched with at 0° C. with 0.15 mL of water. After 20 minutes, 0.15 mL of 15% NaOH was added. Finally, 0.45 mL of water was added and continued to stir at 0° C. for 20 minutes. White precipitate was filtered off and rinsed twice with 10 mL ethyl acetate each. Filtrate was concentrated to an oil. Oil was purified by flash chromatography (13:1) and eluted with 10-15% ethyl acetate in hexanes to give 161 mg of title compound. (73% yield).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[C:31]([O:35][C:36]([NH:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([NH:38][C:39]1[N:44]=[CH:43][C:42]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)=[CH:41][CH:40]=1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cn1
Product: CC(C)(C)OC(=O)Nc1ccc(C2=COCCN2C(=O)OC(C)(C)C)cn1
Yield: 26 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 6-(tert-butoxycarbonylamino)pyridin-3-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (26% yield); 1H-NMR (d6-DMSO) 1.10 (9H, s), 1.46 (9H, s), 3.69 (2H, t), 4.10 (2H, t), 6.43 (1H, s), 7.51-7.54 (1H, m), 7.73 (1H, m), 8.06 (1H, s), 9.75 (1H, s); 13C-NMR (d6-DMSO) 27.9, 28.3, 41.7, 66.8, 111.3, 132.3, 133.1, 135.0, 143.9; MS ES(+) 378.0 M++1); HRMS m/z calcd for C19H27N3O5+H+ 378.2029 [M+H+]. Found 378.2035. IR λmax=1699 cm−1.
Reaction SMILES: [Cl:1][Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([SH:7])[CH2:3]1.S(Cl)(Cl)(=O)=O>CCCCCCC>[Cl:1][Si:2]1([CH3:8])[CH2:6][CH2:5][CH:4]([S:7][S:7][CH:4]2[CH2:5][CH2:6][Si:2]([Cl:1])([CH3:8])[CH2:3]2)[CH2:3]1
Reactant: C[Si]1(Cl)CCC(S)C1
Solvent: CCCCCCC
Solvent: O=S(=O)(Cl)Cl
Product: C[Si]1(Cl)CCC(SSC2CC[Si](C)(Cl)C2)C1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a 0.5 liter 3-neck round bottom glass flask fitted with a magnetic stirrer, dropping funnel and a nitrogen source was added 33.4 grams (0.20 moles) of 1-chloro-1-methyl-3-mercaptosilacyclopentane and 0.025 liters of n-heptane. Sulfuryl chloride, 13.5 grams (0.10 moles) was rapidly added at 25 C. to the stirred mixture within 3 minutes. After an additional stirring for 42 hours at ambient room temperature, the solvent was removed at about 50 -75 C./20-50 mm and nitrogen bubbled through the viscous residue for 16-20 hours. GLC analysis of the residue (27 grams) indicated 90.2 wt.% of the desired disulfide and 9.8 wt.% of the mercaptan starting material. Based on the purity of the residue, a 74 mole % yield was obtained.
Reaction SMILES: CO.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:9]=[C:10]([C:13](OCC)=[O:14])[S:11][CH:12]=1.[BH4-].[Na+].Cl>O1CCCC1.O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:9]=[C:10]([CH2:13][OH:14])[S:11][CH:12]=1
Reactant: CCOC(=O)c1nc(-c2cccs2)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OCc1nc(-c2cccs2)cs1
Yield: 82.1 %

Procedure:
Methanol (1.5 ml) in tetrahydrofuran (2 ml) was added dropwise to a stirred and refluxed mixture of ethyl 4-(2-thienyl)-2-thiazolecarboxylate (1.36 g), sodium borohydride (0.35 g) and tetrahydrofuran (15 ml). After refluxing for 1 h, the reaction mixture was poured into water, acidified with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated to give 4-(2-thienyl)-2-thiazolylmethanol (0.92 g, 82%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 113-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([CH3:10])=[N:7][C:6]=3[CH:11]=2)[CH:14]=[CH:18][CH:17]=[CH:16]1
Reactant: COC1CCC(OC)O1
Reactant: Cc1nc2cc(N)ccc2s1
Solvent: CC(=O)O
Product: Cc1nc2cc(-n3cccc3)ccc2s1
Yield: 37.5 %

Procedure:
5-Amino-2-methylbenzothiazole (30.0 g, 0.203 mol) and 2,5-dimethoxytetrahydrofuran (27.0 g, 0.204 mol) were combined with 90 mL of acetic acid and the solution was heated at reflux for 1 hr. The mixture was evaporated to a dark slurry and purified by column chromatography. This afforded 16.3 g (39% yield) of product, m.p. 91-96° C.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])=S>C(#N)C.CN(C)C=O>[C:2]([NH:3][C:16]([NH:15][CH2:14][CH2:13][S:12][CH2:11][C:10]1[NH:9][CH:8]=[N:7][C:6]=1[CH3:5])=[N:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])#[N:1]
Reactant: N#CN
Reactant: Cc1nc[nH]c1CSCCNC(=S)NCCSCc1[nH]cnc1C
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCSCc1[nH]cnc1C
Reaction time: 24 h

Procedure:
Lead cyanamide (8.7 g.) was added to a solution of N,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea in acetonitrile (100 ml.) and dimethyl formamide (20 ml.) and the resultant suspension was heated under reflux with stirring for 24 hours. Additional lead cyanamide (8.7 g.) was added and heating was continued for 24 hours. Following filtration and concentration, the residue was chromatographed on a column of silica gel, eluting with ethyl acetate-isopropyl alcohol (5:1). Recrystallisation from isopropyl alcohol-isopropyl acetate afforded N-cyano-N',N"-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (0.6 g.), m.p. 92°-95°.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([C:25]([OH:27])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O>[C:25]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([OH:27])=[O:26]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 135 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
A mixture of 2,6-dichloroquinoline-3-carboxylic acid (243 mg, 1 mmol), L-phenylalanine (330 mg, 2 mmol) and potassium carbonate (415 mg, 3 mmol) in water (3 mL) is stirred for 24 h at 135° C. in closed reaction vial. After cooling, the reaction mixture is acidified by addition of 2N HCl, and the precipitated solid is collected on filter, washed with water and recrystallized from DMF-water to give the title compound (211 mg, 57%) as yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21]O)=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:19])[CH3:20]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2OCC(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(CN3C(=O)c4ccccc4C3=O)nc2OCC(C)C)c1
Yield: 90.5 %

Procedure:
To a solution of (5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanol (177 mg) in THF (5.0 mL) was added phthalimide (102 mg), triphenylphosphine (181 mg) and a 40% solution of diethyl azodicarboxylate in toluene (320 μL), and the mixture was stirred at room temperature for 15 hr. Water was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (228 mg) as a colorless oil.
Reaction SMILES: Cl.Cl.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[C:21]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:36])[CH2:26][CH2:25]3)[N:20]=[N:19][C:18]=2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OCc2ccccc2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A stirred suspension of 4-(4-Benzyloxy-phenyl)-3-butyl-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.34 mmol, 170 mg) and paraformaldehyde (6.1 mmol, 550 mg) in DCM was stirred for 20 min then sodiumtriacetoxyborohydride (6.1 mmol, 1.2 g) was added. Stirring was continued overnight. The solvent was evaporated and saturated NaHCO3 solution was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant product was purified by flash silica gel column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to provide 4-(4-benzyloxy-phenyl)-3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine.
Reaction SMILES: C(C=C)=O.O1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1>>[CH3:6][CH:7]=[CH:8][CH2:9][CH2:10][CH2:13][CH2:12][CH2:11][CH2:16][CH3:15]
Reactant: C1CCOCC1
Reactant: c1ccccc1
Agent: C=CC=O
Product: CC=CCCCCCCC

Procedure:
In this example, inverse electron demand D-A reaction of acrolein with 3,4-tetrahydropyran is described. The procedure involves refluxing of 0.056 g of acrolein, 1.68 g of tetrahydropyran and 0.30 g of the catalyst prepared according to example 1 above in 10 ml of benzene at 60 (C 20 h. The catalyst was filtered off. After evaporation of solvent, the residue was chromatographed over silica gel column by eluting with 5% acetone/petroleum ether to give 0.12 g of endo adduct, 1,9-dioxabicyclo[4.4.05,10 ]dec-2-ene
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](F)[CH:7]=1.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[Na+]>C(O)(C)(C)C.C(OCC)(=O)C>[C:12]([O:14][C:6]1[CH:7]=[C:2]([F:1])[C:3]([C:9]#[N:10])=[N:4][CH:5]=1)([CH3:15])([CH3:13])[CH3:11]
Reactant: N#Cc1ncc(F)cc1F
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1cnc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A solution (30 mL) of 3,5-difluoropyridine-2-carbonitrile (1.51 g, 10.8 mmol) in tert-butanol was added dropwise to a solution (40 mL) of sodium tert-butoxide (1.04 g, 10.8 mmol) in tert-butanol (40 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give a mixture (1.63 g) of 5-tert-butoxy-3-fluoropyridine-2-carbonitrile and 3-tert-butoxy-5-fluoropyridine-2-carbonitrile. To the obtained mixture (1.62 g, 8.34 mmol) was added 4N hydrogen chloride-dioxane (40 mL), and the mixture was stirred at 60° C. for 2 hr, and concentrated. To a solution of the obtained residue (1.46 g, 8.34 mmol) and potassium carbonate (2.31 g, 16.7 mmol) in DMF (20 mL) was added cyclopropylmethyl bromide (1.21 mL, 12.5 mmol), and the mixture was stirred at 60° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was purified by basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0 to 7:3) to give the title compound (365 mg, yield 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][O:12]C(=O)[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].O.[OH-].[K+]>C(O)C>[NH2:10][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH2:13][OH:12]
Reactant: O=C1NC(c2ccc(F)c(F)c2)CO1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(CO)c1ccc(F)c(F)c1
Yield: 87.2 %

Procedure:
To a solution of (+)-4-(3,4-difluorophenyl)-oxazolidin-2-one (1.39 mmol, 0.27 g) in 5.0 mL ethanol was added 5.0 mL of water and pellets of potassium hydroxide (5.0 mmol, 0.28 g). The resulting solution was then heated to reflux overnight. The solvent was removed in vacuo and the resulting residue was extracted with EtOAc (2×50 mL). The organic extracts were washed with brine and the organic layer was dried over Na2SO4. It was filtered and the solvent was removed in vacuo to obtain (+)-2-amino-2-(3,4-difluorophenyl)-ethanol as a white solid (0.21 g, 87% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)[CH3:2].[CH:8](C1NC=C(CC)C=1)=[O:9].OC1C=C(NC2C3=CC(C)=CN3N=CN=2)C=CC=1C>>[CH:8]([C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[CH2:1][CH3:2])=[O:9]
Reactant: CCc1cc[nH]c1
Reactant: CCc1c[nH]c(C=O)c1
Agent: Cc1cc2c(Nc3ccc(C)c(O)c3)ncnn2c1
Product: CCc1cc[nH]c1C=O

Procedure:
3-Ethylpyrrole was converted to a mixture of Compound A and 2-formyl-4-ethylpyrrole as described in the preparation of Compound A of Example 5. [M+H]+=124.1
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23]>ClCCl>[Br:20][CH2:21][C:22]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:23]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(NC(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a solution of isopropyl-(4-methoxy-phenyl)-amine (25.11 g) in dichloromethane (250 mL) was added triethylamine (15.38 g) with stirring at ambient temperature. The solution was cooled in an ice bath (<3° C.) and bromoacetyl bromide (30.68 g) dissolved in dichloromethane (100 mL) was added dropwise over a 45 minute period with stirring and cooling in an ice bath. The reaction mix was stirred overnight at ambient temperature, washed with 0.3N HCl (300 mL) and brine (300 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give a dark brown oil. The oil was filtered through a pad of silica gel (150 g) which was eluted with ethyl acetate/hexane (1:1, 900 mL) and the filtrate evaporated under reduced pressure to afford the title compound (41.05 g) as a brown oil which crystallized on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20](Cl)=[O:21])=[N:9]2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[N:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:11][C:10]([C:20]([NH:23][C:24]3[CH:29]=[N:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[O:21])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)nc1)C1=NN(c2ccc(Cl)cc2)C(c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A solution of 0.9 g of 1-(4-chlorophenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride in 10 mL of THF was added to a solution of 0.4 g of 5-amino-2-chloropyridine, 2.0 mL Of triethylamine and 10 mL of THF. The resulting suspension was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was triturated with 10 mL of methanol to afford 0.66 g of the title compound, mp 191°-193° C.
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[C:18]1([NH:17][C:2]2[C:7]3=[N:8][CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11](=[O:12])[N:6]3[CH:5]([CH3:16])[CH2:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Reactant: Nc1ccccc1
Solvent: CO
Product: CC1CC=C(Nc2ccccc2)c2ncc(C(=O)O)c(=O)n21
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To 800 ml of methanol 100.0 g. (0.348 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 100 cm3 of aniline are added. The mixture is heated under stirring until a solution is obtained. The solution is cooled to room temperature and stirred for 2-3 days. The precipitated crystals are filtered and washed with methanol. 64.0 g. (61.4%) of 9-(phenyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is obtained which melts at 172°-173° C. after recrystallization from methanol.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9].[Cl:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>CO.C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>[Cl:12][CH2:13][C:14]([NH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:11])[C:8]([CH3:10])=[CH2:9])=[O:15]
Reactant: O=C(Cl)CCl
Reactant: C=C(C)C(=O)NCCCN
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: C=C(C)C(=O)NCCCNC(=O)CCl
Temperature: 0 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
In a 3-liter 4-neck flask fitted with condenser, stirrer, and 2-dropping funnels were placed N-(3-aminopropyl)methacrylamide hydrochloride 157 g 0.88 moles) in methanol (1.2 L) and 2,6-ditert-butyl-p-cresol (1.0 g). In one funnel was placed chloroacetyl chloride (100 g, 0.89 mole), and in funnel two was placed triethylamine (178 g, 1.76 mole). The solution was cooled to 0°-5° C. (ice-methanol), and triethylamine was added in a slow stream over 30 minutes, and the chloroacetyl chloride was added over 1 hour. After the addition, the temperature was maintained at 0° C. for 2 hours, the ice bath was removed, and stirring was continued at room temperature overnight. The solvent was removed, and to the residue was added hot ethyl acetate (500 mL). The mixture was filtered to remove triethylamine hydrochloride, then the solid was washed with hot ethyl acetate (500 mL), filtered again, the filtrate combined, and the solvent was removed on a rotory evaporator. The residue was crystallized from ethyl acetate (400 mL) by heating to dissolve, filtering to remove any solid present, and cooling to 0° C. to crystallize. The crude monomer was purified by chromatography on a silica gel packed column. The product was eluted from the column using a 1:1 mixture of ethyl acetate and dichloromethane (4 L). The collected solvent was evaporated, and the residue crystallized from ethyl acetate (300 mL) with 2,6-di-tert-butyl-p-cresol (500 mg) to give a white crystalline compound, mp 85°-90° C., 83 g (43% yield).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1)#N.N1[C:19]2[C:14](=C[CH:16]=[CH:17][CH:18]=2)C=C1>>[CH2:16]1[C:17]2[CH:18]([N:9]=[C:6]3[C:5]=2[CH:4]=[CH:3][CH:8]=[CH:7]3)[CH2:19][CH2:14]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: N#Cc1ccc(NN)cc1
Product: c1ccc2c(c1)=NC1CCCC=21

Procedure:
In Step B, (R,S)-2-(3-oxo-cyclopentyl)-isoindole-1,3-dione (1) is reacted with 4-cyano-phenylhydrazine in a typical Fischer indole synthesis to give a tetrahydrocyclopenta[b]indole of formula (2). The skilled artisan will recognize that there are a variety of acidic conditions to effect a Fischer indole synthesis, including both proton and Lewis acids. The preferred conditions use a mixture of glacial acetic acid with 4 N HCl in dioxane, at a temperature of about 50° C. to the reflux temperature of the solvent, for about 4 to 24 hours. The product is isolated by addition of water followed by filtration of the resulting solid. The solid is sonicated in methanol to give material of sufficient purity. Alternatively, the reaction is effected using a Lewis acid, such as zinc chloride, in an amount of about 2 to 4 equivalents. Other preferred conditions for Step B use ethanol at reflux temperature for about 4 to 24 hours. The product is isolated and may be purified by filtration of the reaction mixture, followed by silica gel chromatography of the filtrate.