Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]34[CH2:24][CH2:23][C:20]([O:25]C)([CH2:21][CH2:22]3)[CH2:19][CH2:18]4)=[N:15][N:16]=2)[N:13]=1.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>Br>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:10][C:11]2[N:12]([C:14]([C:17]34[CH2:24][CH2:23][C:20]([OH:25])([CH2:19][CH2:18]3)[CH2:21][CH2:22]4)=[N:15][N:16]=2)[N:13]=1
Reactant: COC12CCC(c3nnc4cc(-c5ccc(Cl)cc5)c(-c5ccccc5Cl)nn34)(CC1)CC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: OC12CCC(c3nnc4cc(-c5ccc(Cl)cc5)c(-c5ccccc5Cl)nn34)(CC1)CC2
Temperature: 120 °C
Yield: 75.2 %

Procedure:
To a suspension of 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(4-methoxybicyclo[2.2.2]octan-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (Example 18) (48 mg, 0.1 mmol) in aqueous (48%) hydrobromic acid solution (0.37 mL) was added dropwise acetic anhydride (0.33 mL). After addition, the reaction tube was sealed, and heated at 120° C. for 16 h. After cooling to room temperature, the reaction mixture was adjusted to pH 7-8 by careful addition of saturated aqueous NaHCO3, then extracted with EtOAc (10 mL×2). The combined organic was washed with water, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5 μC18 21.2×100 mm; Eluted with 70% to 100% B, 18 min gradient, 100% B hold for 3 min, (A=90% H2O, 10% MeOH and B=10% H2O, 90% MeOH); Flow rate at 20 m/min, UV detection at 220 nm) to afford 35 mg (75%) of the title compound as a white solid. HPLC/MS (method A): retention time=3.61 min, (M+H)+=465.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].Cl.[Cl-].[Na+].N[CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3](=[N:4][N+:5]([O-:7])=[O:6])[NH:8][CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1
Reactant: NCc1cnc(Cl)s1
Reactant: COC(=N)N[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a mixture of O-methyl-N-nitroisourea (2.0 g, 0.0168 mol), 36% hydrochloric acid (1.5 ml), sodium chloride (8.0 g), and water (40 ml) was added 5-aminomethyl-2-chlorothiazole (2.5 g, 0.0168 mol) at 20° C. This mixture was adjusted to pH 7 with 30% aqueous solution of sodium hydroxide and stirred at room temperature for 8 hours, after which it was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated to provide 2.7 g (64.1% yield) of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:6]=2[C:7]=1[CH3:8])[CH3:2].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:13][C:9]1[C:6]2[C:7]([CH3:8])=[C:3]([CH2:1][CH3:2])[O:4][C:5]=2[CH:12]=[CH:11][CH:10]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: CCc1oc2cccc(O)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2oc(CC)c(C)c12
Yield: 118.3 %

Procedure:
A mixture of 2-ethyl 4 hydroxy 3 methylbenzofuran (760 mgs; 4.3mmoles), allyl bromide (1.0 g; 8.6 mmoles), anhydrous potassium carbonate (1.1 g; g; 8.6mmoles) 8.6mmoles) and acetone (50 ml) was refluxed for 4 hours. The mixture was filtered, concentrated, and chromatographed to obtain 1.1 g of the title compound as an oil which was used as such in the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:24])[CH2:16][CH:17]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccccc1)c1ccccc1OCc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccccc1OCc1ccccc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(2-benzyloxyphenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-(2-benzyloxyphenyl)-3-oxo-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:6])[CH3:3].[CH3:12][C:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])[CH:19]=1)([CH3:17])[C:14](O)=[O:15].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[CH2:2]([O:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:14](=[O:15])[C:13]([CH3:12])([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:29][C:30]=2[CH3:31])[CH:19]=1)[CH3:17])=[O:6])[CH3:3]
Reactant: CCOC(=O)[C@H]1CCCN1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(C(C)(C)C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN1C(=O)C(C)(C)c1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 48 h

Procedure:
To a stirred solution of (R)-pyrrolidine-2-carboxylic acid ethyl ester hydrochloride (1.7 g, 9.4 mmot), TEA (1.0 g, 10.3 mmol) and the title C compound, 2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid (3.0 g, 8.55 mmol) in DCM (50 mL) is added EDCl (2.0 g, 10.3 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt, 1.2 g, 8.55 mmol) at RT. The reaction mixture is stirred for 48 h. The reaction mixture is diluted with ethyl acetate, washed with 2 N aqueous HCl, water, 2 N aqueous sodium hydroxide, water and brine, dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified on a Biotage 40M column using 35% ethyl acetate in hexane to yield (R)-1-{2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionyl}-pyrrolidine-2-carboxylic acid ethyl ester as a clear oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([C:19]([OH:21])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1.[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[C:6]([C:19]([O:21][CH3:22])=[O:20])=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Yield: 70.8 %

Procedure:
To a solution of 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acid (298 mg, 1.1 mmol) in DMF (10 mL) was added potassium carbonate (316 mg, 2.3 mmol) followed by methyl iodide (0.15 mL, 2.3 mmol). The resultant suspension was stirred for 1.5 hours at which time water and ethyl acetate were added. The layers were separated and the organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulphate. Filtration and concentration followed by purification by silica gel chromatography provided methyl 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (234 mg, 77%) as a white crystalline solid upon standing. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=1.9 Hz, 1 H), 7.78 (br, 1 H), 7.24 (s, 1 H), 7.15 (dd, J=8.5, 5.4 Hz, 2 H), 7.00 (t, J=8.7 Hz, 2 H), 3.96 (s, 2 H), 3.93 (s, 3 H), 2.39 (m, 1 H), 0.77 (m, 2 H), 0.52 (m, 2 H); MS m/z 301 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:18]=1[CH3:27]>CS(C)=O>[CH3:27][C:18]1[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=[C:22]([CH3:23])[C:17]=1[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Reactant: COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1

Procedure:
A mixture of dimethylsulfoxide (875 ml), p-methoxyphenol (43.3g 0.3 48 mol), powdered potassium carbonate (69.9 g, 0.5 mol) and 4-chloro-3,5-dimethylnitrobenzene (see example 39, 64.6 g; 0.348 mol) is heated at a temperature of 125° for 18 hours. The suspension is cooled to 25° and pumped onto ice water (2620 ml) with stirring. The mixture is stirred for 2 hours, the product is filtered, washed with water (4×300 ml) and air dried. A solution of the product in tert-butylmethyl ether (3 L) is dried over magnesium sulfate and treated with charcoal (6.4 g) for 2.5 hours. The drying agent is filtered off and the filtrate concentrated in vacuo at 50°/3 mm Hg to give product which is recrystallized from toluene (212 ml) and petroleum ether (600 ml) to give 3,5-dimethyl-4-(4'-methoxyphenoxy)nitrobenzene, m.p. 120°-123°.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.C(N(C(C)C)CC)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][NH2:25])=[N+:20]=[N-:21]>CC(C)=O>[N:19]([CH2:22][CH2:23][CH2:24][NH:25][C:2]1[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=1)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=NCCCN
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: [N-]=[N+]=NCCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
To a solution of cyanuric chloride (18.42 g, 0.10 mol) in acetone (180 mL) in an ice-water bath was added diisopropylethylamine (DIPEA) (12.92 g, 0.10 mol). 1-azido-3-aminopropane (5.00 g, 0.050 mol) in acetone (50 mL) was added slowly over 2 hours. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, washed with water, dried (Na2SO4) and rotary evaporated. The resulting residue was purified by column chromatography on silica gel (eluent CH2Cl2) to give 1 as a white solid (5.62 g, 45%): ESI-MS m/z 248.1 (M+H+) calculated for C6H8Cl2N7 248.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:11].C(N(CC)CC)C.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>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.[Cu]I>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:6][C:5]=1[Cl:11]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1Cl
Temperature: 70 °C

Procedure:
To a degassed solution of 4-bromo-2-chloro-benzoic acid methyl ester (3.0 g, 12.0 mmol, 1.0 equiv; [CAS RN 185312-82-7]) in triethylamine (24.3 g, 33.5 mL, 240.5 mmol, 20.0 equiv; [CAS RN 121-44-8]) under Ar was added ethynyl-trimethyl-silane (1.24 g, 1.78 mL, 12.63 mmol, 1.05 equiv; [CAS RN 1066-54-2]), tetrakis(triphenylphosphine)palladium(0) (0.70 g, 0.60 mmol, 0.05 equiv; [CAS RN 14221-01-3]) and copper(I) iodide (0.23 g, 1.20 mmol, 0.1 equiv; [CAS RN 7681-65-4]) and the reaction mixture heated to 70° C. for 18 h. The crude reaction was filtered over Celite®, a sat. solution of NaCl (50 mL) added and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over Na2SO4 and the product used in the consecutive step without any further purification. Yield: 4.52 g (99%) of the title compound in ca. 70% purity as a slightly brown oil. MS (ISN): 267.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>CN(C)C=O>[CH2:27]([O:21][CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([O:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:22])[CH2:16]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1CCCC(OCc2nc(-c3ccc(F)cc3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of the 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy)cyclohexanol are dissolved in 15 ml of dimethylformamide, and 0.3 g of sodium hydride is added. After 30 minutes, 2.4 g of allyl bromide are added dropwise. The mixture is stirred at room temperature for 5 hours. 15 ml of 1N HCl are then added to the reaction mixture, and the mixture is washed three times with 15 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 2.4 g of 4-(3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole as a yellowish oil. C20H24FNO3 (345.42) MS (ESI): 346 (M+H+)
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([C:18]#[C:19][C:20]3[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=3)=[C:16]([CH3:27])[N:15]=[C:14]([NH2:28])[N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.O>[NH2:28][C:14]1[N:13]=[C:12]([N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[C:17]([C:18]#[C:19][C:20]2[CH:21]=[N:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[C:16]([CH3:27])[N:15]=1
Reactant: CCOC(=O)C1CCN(c2nc(N)nc(C)c2C#Cc2ccc(N)nc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(N2CCC(C(=O)O)CC2)c1C#Cc1ccc(N)nc1
Yield: 83.3 %

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 1.0 g (2.63 mmol) 1-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester and 126 mg (5.26 mmol) LiOH in 80 mL THF and 20 ml water. Yielding 772 mg (2.19 mmol) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH2:17]=O>CO>[CH2:17]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]1)=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: C=O
Solvent: CO
Product: COC(=O)C1Cc2c([nH]c3ccccc23)CN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of L-tryptophane methyl ester (25.4 g, 100 mmol) and 37% formaldehyde solution (12.5 mL) in aqueous methanol (170 mL; H2O:MeOH, v/v 10:1) was stirred at room temperature for 5 h. The reaction mixture was evaporated to dryness in vacuo. The residue was basified with sodium bicarbonate to give methyl 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate, 14.4 g (63%); mp 161-162° C. (lit.19 mp 164-165° C.). 1H NMR (DMSO-d6) δ 2.78 (1H, m, CH2), 2.98 (1H, m, CH2), 3.66 (3H, s, COOMe), 3.85 (1H, m, CH), 4.02 (2H, q, J=15.8 Hz, NCH2), 6.92-6.96 (1H, m, ArH), 7.00-7.04 (1H, m, ArH), 7.27-7.29 (1H, m, ArH), 7.37-7.39 (1H, m, ArH), 10.78 (1H, s, exchangeable NH).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC1(C)C(C)(C)OB([C:51]2[NH:59][C:58]3[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=3[CH:52]=2)O1.Br[C:63]1[CH:64]=[CH:65][CH:66]=[C:67]2[C:72]=1[N:71]=[C:70]([C:73]1[C:78]([CH3:79])=[CH:77][CH:76]=[CH:75][C:74]=1[CH3:80])[CH:69]=[N:68]2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:80][C:74]1[CH:75]=[CH:76][CH:77]=[C:78]([CH3:79])[C:73]=1[C:70]1[CH:69]=[N:68][C:67]2[C:72]([N:71]=1)=[C:63]([C:51]1[NH:59][C:58]3[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=3[CH:52]=1)[CH:64]=[CH:65][CH:66]=2
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Reactant: Cc1cccc(C)c1-c1cnc2cccc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(C)c1-c1cnc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
Argon was bubbled into a mixture of potassium phosphate tribasic (0.28 g, 1.02 mmol), Xphos (Strem, 0.012 g, 0.026 mmol), Pd2dba3 (Strem; 0.012 g, 0.013 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (0.201 g, 0.766 mmol), 8-bromo-2-(2,6-dimethylphenyl)quinoxaline (401a; 0.08 g, 0.255 mmol) in 2 mL dioxane and 0.4 mL water for 2 min. The reaction was sealed and heated to 80° C. After 3 h, the reaction was cooled and 1.6 g silica gel was added, and the material dried in vacuo. The material was purified by silica gel chromatography (24 g ISCO gold column) using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford 2-(3-(2,6-dimethylphenyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.055 g, 0.149 mmol, 58% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77 (1H, br. s.), 8.97 (1H, s), 8.14 (1H, dd, J=7.3, 1.3 Hz), 7.95-8.02 (1H, m), 7.86-7.94 (1H, m), 7.31-7.39 (1H, m), 7.21-7.31 (3H, m), 6.98 (1H, s), 3.40 (2H, td, J=6.8, 2.3 Hz), 2.85 (2H, t, J=6.8 Hz), 2.10 (6H, s). m/z (ESI, +ve) 369.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5]Cl.[CH2:8]([CH:17]1[S:21][CH:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[NH:19][C:18]1=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].[Cl-]>CN(C)C=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][N:19]1[C:18](=[O:28])[CH:17]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:21][CH:20]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCCCCCCC1SC(c2cccnc2)NC1=O
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCC1SC(c2cccnc2)N(CCN(C)C)C1=O
Reaction time: 10 h
Yield: 33.3 %

Procedure:
K2C03 (0 9 g, 6.52 mmol) and 2-dimethylamino-ethyl chloride hydrochloride (0.47 g, 3.26 mmol) were added to a solution of 5-(n-nonyl)-2-(3-pyridyl)-thiazolidin-4-one (1 g, 3.26 mmol) in dry dimethylform-amide (10 ml). The mixture was kept at 50° C. for 10 hours. The resulting mixture, after addition of aqueous NaCl, was extracted with ethyl acetate. The extract was washed with aqueous NaCl, dried, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel, giving 3-(2-dimethylaminoethyl)-5-(n-nonyl)-2-(3-pyridyl)thiazolidin-4-one (0.41 g, 33% yield).
Reaction SMILES: [H-].[Na+].CO.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12](Cl)[N:13]=1)[C:9]#[N:10].C[CH2:16][O:17]C(C)=O.CCCCCC>CN1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:17][CH3:16])[N:13]=1)[C:9]#[N:10]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: CCOC(C)=O
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1cc(C#N)cc(Cl)n1
Reaction time: 0.5 h

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with thermometer pocket fitted with an nitrogen inlet and a rubber septum, NaH (0.112 g, 1.0 eq.), methanol (0.11 mL, 1.0 eq.), suspended in N-methylpyrrolidine (5 mL). The reaction mixture was stir at 25-30 C for 30 minutes. To this reaction mixture 2,6-dichloroisonicotinonitrile was added at 0-5 C. The progress of the reaction was followed by TLC analysis on silica gel with 10% EtOAc-hexane as mobile phase which shows that starting material was consumed after 2 hours staring at 0-5 C. Reaction was quenched by water, precipitate was observed that was filter by filter paper and wash with hexane to give required compound (0.51 g, crude). Reaction was stirred for 20 min with water solid was separated and compound was collected by filtration on a Buchner funnel and washed with of hexane (30 mL); Yield: 0.51 g crude 2-chloro-6-methoxyisonicotinonitrile.
Reaction SMILES: C1CC1.[C:4]([OH:14])(=[O:13])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[O:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[C:4]([O-:14])(=[O:13])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[O:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]
Reactant: O=C(O)C=Cc1ccccc1
Agent: C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C1NCCO1
Product: O=C([O-])C=Cc1ccccc1

Procedure:
Cis and trans chiral cyclopropane intermediates of type XIV and XVII respectively, can also be prepared by the following two methods. The cinnamic acid XIII in presence of CDI is converted to the acyl-imidazole XIX, which under basic condition reacts with the optically pure oxazolidinone XX to afford the chiral cinnamate-oxazolidinone XXI. Cyclopropanation of XXI following previously described method gives rise to a separable (crystallization, SiO2) mixture (>5 to 1) of diastereoisomers XXII. Hydrolysis of the latter will afford the desired chiral cyclopropyl XIV. Similarly, a racemic mixture of cyclopropyl of type XIV (XVII) can be converted in two steps to the 1:1 diastereoisomeric mixture of the previously described cinnamate-oxazolidinone XXI.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=1)[CH2:24][CH2:23]2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1ccc2c(c1)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2cc(F)ccc21
Yield: 55 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 5-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 197 mg of 2-[2-(5-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][CH2:20][O:21][C:12]3=[CH:11][C:10]=2[N:9]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1ccccn1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCCO4)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccccn3)c3cc4c(cc3c2=O)OCCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 58 mg (0.17 mmol) of 8-(3,4-dimethyl-benzoyl)-2,3-dihydro-6H-[1,4]dioxino[2,3-g]quinolin-9-one, 18 mg of 60% sodium hydride, 57 mg of 2-bromomethylpyridine hydrobromide and 1.2 mL of N,N-dimethylformamide. Yield: 63 mg of a white solid: LC-MSD, m/z for C26H22N2O4 [M+H]+=427.5; HPLC retention time: 2.1 min.