Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.CCN(CC)CC.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][N:14]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(CNCc2ccc(-c3ccnc(Cl)n3)s2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(-c3ccnc(Cl)n3)s2)C(=O)c2ccccc2)cc1
Reaction time: 18 h

Procedure:
[5-(2-Chloro-pyrimidin-4-yl)-thiophen-2-ylmethyl]-(4-methoxybenzyl)-amine (22 mg, 0.063 mmol) was dissolved in CH2Cl2 (1 mL) and treated with pyridine (4.3 uL, 0.076 mmol) and Et3N (17.8 uL, 0.127 mmol), followed by benzoyl chloride (8.9 uL, 0.765 mmol). The mixture was allowed to stir for 18 h and was then washed with 1 N HCl, dried over Na2SO4 and concentrated. The material was used crude in the next step.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][CH:12]1[C:23](=[O:24])[N:14]2[CH:15]([C:20]([OH:22])=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12>CN(C)C=O>[CH:1]([NH:11][CH:12]1[C:23](=[O:24])[N:14]2[CH:15]([C:20]([OH:22])=[O:21])[C:16](=[CH2:19])[CH2:17][S:18][C@H:13]12)=[O:2]
Reactant: O=CO
Reactant: C=C1CS[C@@H]2C(N)C(=O)N2C1C(=O)O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: C=C1CS[C@@H]2C(NC=O)C(=O)N2C1C(=O)O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (1 () and acetic anhydride (2.5 l) was stirred at 50° C. for 1 hour and cooled at 40° C. To the mixture were added 7-amino-3-methylenecepham-4-carboxylic acid (1,070 g) and N,N-dimethylformamide (500 ml). The mixture was stirred for 1 hour at 55° C. and cooled in an ice-water bath. A resultant precipitate was collected by filtration and washed with a small amount of a mixture of ethyl acetate and diisopropyl ether (1:1) to give 7-formamido-3-methylenecepham-4-carboxylic acid (1.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH:12][S:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[CH:20][CH:19]=2)(=[O:15])=[O:14])[CH:3]=1.C([O-])(=O)C.[Na+].C1(C)C=CC(S(NN)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([NH:12][S:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:26])[F:27])=[CH:20][CH:19]=2)(=[O:14])=[O:15])[CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)/C=C/c1ccc(OC(F)F)cc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)CCc1ccc(OC(F)F)cc1
Temperature: 180 °C
Yield: 9.6 %

Procedure:
(E)-4-Chloro-2-(2-(4-(difluoromethoxy)phenyl)vinylsulfonamido)benzenesulfonamide (0.426 g, 0.97 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL). Sodium acetate (0.318 g, 3.88 mmol) and p-toluenesulfonic acid hydrazide (0.723 g, 3.88 mmol) were added and the reaction was heated in a microwave at 180° C. for 60 min. The mixture was filtered and the solvent was evaporated under vacuum. Purification by preparative HPLC, gave 41 mg (10% yield) of the title compound.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][NH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:19][C:20]1[C:24]([C:2]2[S:6][CH:5]=[C:4]([C:7]([N:9]3[CH:18]4[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]4)[CH2:12][CH2:11][CH2:10]3)=[O:8])[CH:3]=2)=[CH:23][NH:22][N:21]=1
Reactant: Cc1n[nH]cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1n[nH]cc1-c1cc(C(=O)N2CCCC3CCCCC32)cs1
Temperature: 140 °C
Yield: 30.4 %

Procedure:
cis-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.09 g, 0.27 mmol) was combined with 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (62 mg, 0.3 mmol), caesium carbonate (0.134 g, 0.41 mmol), and palladium tetrakis(triphenylphosphine) (0.031 g, 0.03 mmol) in DME (3 mL), IMS 0.6 mL) and water (0.3 mL). The reaction mixture was degassed then heated by microwave irradiation to 140° C. for 20 minutes then further quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g), caesium carbonate (0.067 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added. The mixture was heated by microwave irradiation to 140° C. for 20 minutes followed by addition of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g) and further heating at 140° C. for 20 minutes. Further quantities of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.062 g), caesium carbonate (0.097 g), and palladium tetrakis(triphenylphosphine) (0.031 g) were added and the mixture heated by microwave irradiation to 140° C. for a final 20 minutes before diluting with water and extraction with DCM (×3). The organic solution was dried over sodium sulfate, filtered and the solvent removed by evaporation. The residue was purified by chromatography on a silica II cartridge, eluting with 10-50% ethyl acetate in cyclohexane and then was further purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried to give the title compound as a white solid (0.027 g). LCMS m/z 330.30 [M+H]+ R.T.=9.62 min (Analytical Method 2).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]([O:14]C)=[O:13])[CH2:7]1.CC(C)=O>Cl>[ClH:2].[Cl:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]=[C:8]([C:12]([OH:14])=[O:13])[CH2:7]1
Reactant: COC(=O)C1=CCCN(Cc2ccccc2Cl)C1
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)C1=CCCN(Cc2ccccc2Cl)C1
Yield: 186.4 %

Procedure:
A solution of methyl 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (0.45 g.) in concentrated hydrochloric acid (10 ml.) was heated at 95°-100° C. for 2 hours, cooled and evaporated. The residue was evaporated several times with acetone and toluene to remove remaining traces of water. The solid obtained was stirred with acetone and then collected by filtration to give 1-(2-chlorobenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride (0.4 g.), m.p. 208°-210° C. (dec.).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH3:20]>C(C(C)=O)C(C)C>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([O:10][CH2:19][CH3:20])[CH:7]=[CH:8][CH:9]=1)[CH3:12]
Reactant: CCBr
Reactant: CCN(CC)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOc1cccc(N(CC)CC)c1
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A 1 liter reactor is charged with 300 ml of methyl isobutyl ketone, 73.1 g of 3-diethylaminophenol and 153.3 g of ground potassium carbonate and the mixture is stirred for 30 minutes. Then 72.7 g of ethyl bromide are introduced into the autoclave, which is then closed and heated for 3 hours to 115°-120° C. The temperature is then kept for a further 5 hours at 140°-142° C. (pressure: 5 bar). The contents of the autoclave are cooled to c. 25° C. and potassium bromide is removed by filtration. After washing with a small amount of methyl isobutyl ketone, the combined filtrates are concentrated by evaporation, to give 75.6 g (91.1% yield) of 3-diethylaminophenetol with a titre of 96.9%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[C:6]([CH3:11])[C:7]=1[N+:8]([O-:10])=[O:9].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.O>C(O)C>[CH3:11][C:6]1[CH:5]=[C:4]([NH:12][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:22][CH:21]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(N)cc(C)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: CCO
Solvent: O
Product: Cc1cc(NCc2ccc(C(F)(F)F)cc2)cc(C)c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 85 %

Procedure:
3,5-Dimethyl-4-nitro-phenylamine (3.95 g) and 4-trifluoromethyl-benzaldehyde (4.87 mL) were dissolved in ethanol (50 mL) and refluxed for 16 h. The reaction mixture was poured into water (75 mL) and the precipitate collected by filtration. Sodium cyanoborohydride (3.1 g) and acetic acid (7.0 mL) were added to the precipitate dispersed in methanol (130 mL) and stirred for 60 minutes. The reaction mixture was filtered, water (350 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (300 mL) to furnish 6.7 g (85% yield) of the title compound as a yellow solid. LC-MS (m/z) 325 (MH+); tR=2.00, (UV, ELSD) 92%, 93%. 1H NMR (500 MHz, CDCl3): 2.30 (s, 6H), 4.45 (broad, 3H), 6.25 (s, 2H), 7.45 (d, 2H), 7.60 (d, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[N:6]([CH2:13][CH2:14][CH3:15])[C:5]2=[O:16].C(Cl)([Cl:19])=O>C1(C)C(C)=CC=CC=1>[Cl:19][C:7]1[N:6]([CH2:13][CH2:14][CH3:15])[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCCn1c(Cl)nc2ccc(I)cc2c1=O
Temperature: 87.5 °C

Procedure:
2,3-Dihydro-6-iodo-3-propyl-2-thioxo4(1H)-quinazolinone (50 g, 0.144 mol) was slurried in xylene (283 g) and heated to 85-90° C. Phosgene (12.0 mL, 0.159 mol) was added. Heating was continued until the thioquinazolinedione was consumed by thin layer chromatography analysis (340 minutes). The excess phosgene was removed by codistillation with xylene at atmospheric pressure. The distillation was ceased when the distillate weight reached 37.9 g. The solution was cooled to room temperature and used directly in Step 3.
Reaction SMILES: [Li]CCCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[NH4+].[Cl-].C1[CH2:21][O:20][CH2:19]C1>>[Br:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:9]([CH:10]=[CH:19][O:20][CH3:21])[CH:8]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: COC=Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of (methoxymethyl)triphosphonium chloride (5.56 g, 16.21 mmol) in dry THF (13 mL) under inter atmosphere was added dropwise at 0° C. a solution of nBuLi in dry THF (22 mL, 21.62 mmol). The reaction mixture was stirred at room temperature for 1 h. Then, a solution of 3-bromobenzaldehyde (2.0 g; 10.81 mmol) in dry THF (20 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. A saturated solution of NH4Cl was added and the crude product was extracted with EtOAc (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated. The final product was purified by silica gel chromatography using 10 to 15% EtOAc/cyclohexane as eluent to give III-a as yellow oil in 66% yield. 1H NMR (300 MHz, CDCl3) δ 7.79 (s, J=1.5 Hz, 1H), 7.48-7.24 (m, 5H), 7.20-7.12 (m, 2H), 7.06 (d, J=13.0 Hz, 1H), 6.19 (d, J=7.0 Hz, 1H), 5.75 (d, J=13.0 Hz, 1H), 5.17 (d, J=7.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[N:9]1([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1>C(OCC)C.CS(C)=O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:15]1([CH2:14][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[CH2:4][O:16]1
Reactant: C[S+](C)(C)=O
Reactant: O=C(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
Sodium hydride (3.78 g, 0.079 mole as 50% dispersion in oil) was suspended, with stirring, in 20 ml of dry diethyl ether. The ether was then removed by decentation, and the sodium hydride was dried in a stream of dry nitrogen. Dry dimethyl sulphoxide (100 ml) was added followed by 17.34 g (0.079 mole) of dry powdered trimethylsulphoxonium iodide, in portions, over 15 minutes. The resulting mixture was stirred for 30 minutes at room temperature (20° C.). 2-(1H-1,2,4-Triazol-1-yl)-2',4'-dichloro acetophenone (18.33 g, 0.072 mole) as a solution in 50 ml of dry dimethyl sulphoxide was then added. The mixture was heated at 60° C. for 3 hours and allowed to stand at room temperature overnight. The reaction mixture was cooled and quenched in ice. The product was then extracted into ethyl acetate (600 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, and concentrated to give a red gum. Column chromatography of the gum on silica, eluting with ether, gave 6.62 g (34.4%) of the title compound as a gum.
Reaction SMILES: [ClH:1].[C:2]1([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[H-].[Na+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(Cl)Cl.C1COCC1>[ClH:1].[CH2:36]([O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:10]1([CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:24])[CH3:37]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1C(Cc2ccncc2)c2ccccc2N1c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)CCCC1(Cc2ccncc2)C(=O)N(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,3-dihydro-1-phenyl-3-(4-pyridinylmethyl)-2H-indol-2-one hydrochloride (33.7 g, 0.1 mol) in 200 ml CH2Cl2 was treated with 150 ml 1N NaOH. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to an oil which solidified on cooling. The "free base" was dissolved in 150 ml dry THF, cooled in an ice bath, treated with NaH (2.88 g, 0.12 mol), and stirred under dry nitrogen for 30 min. The mixture was treated with ethyl 4-bromobutyrate (19.5 g, 0.1 mol) in 25 ml dry THF. The mixture was stirred in the ice for 1 h and 16 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was partitioned between 300 ml Et2O and 200 ml water. The organic phase was washed with water and brine, dried over anhydrous MgSO4, filtered, treated with 150 ml 1N HCl-Et2O, and concentrated in vacuo. The residue was dissolved in 100 ml anhydrous EtOH with warming and stirred at room temperature for 24 h. The resulting crystals were collected by filtration, washed with a small portion of cold EtOH and Et2O, and dried in vacuo at 80° C. to give the desired product in 86% (38.6 g) yield; mp 182.5°-183.0° C.; IR(nujol): C=O @1722 and 1703 cm-1 ; NMR(DMSOd6TMS: δ1.15 (t, 3H, CH3), 1.2, 1.3 (2m, 2H, CH2CCCO), 2.1 (m, 2H, CH2CCO), 2.26 (t, 2H, CH2CO), [3.43 (d, 1H, J12), 3.64 (d, 1H, J12) CH2 -Pyr], 4.02 (q, 2H, OCH2), [6.54 (m, 1H), 7.2 (m, 2 H), 7.5 (m, 5H), 7.68 (m, 1H) Ar--N-Phe], [7.10 (d, 2H), 8.70 (d, 2H) 4-Pyr]; Anal calcd for C26H26N2O3HCl, MW 450.97: C, 69.25; H, 6.04; N, 6.21. Found: C, 69.02; H, 5.98; N, 6.52. Mass spec m/e 415(M+1-HCl).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)(C)C.C[O-].[Na+].Cl>CO>[C:6]([C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C#Cc1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of 5-(trimethylsilylethynyl)uracil (5.3g, 24.4mmol) in 0.2M solution of sodium methoxide in methanol (400 mL) was stirred at room temperature for 3 hours and neutralized to pH 7 with dilute hydrochloric acid. The precipitated product was filtered, washed with methanol and dried to give a first crop of the title compound. The filtrates and washings were combined, evaporated to dryness and the residue crystallised from methanol to give the second crop of product. Combination of both crops and a further recrystallisation from ethanol gave a pure product.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Fc1cccc(Br)c1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3cccc(F)c3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and 1-bromo-3-fluorobenzene.
Reaction SMILES: C[C:2]1([N:8]2[C:12]([C:13]3[S:25][C:16]4[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:15]=4[CH:14]=3)=[CH:11][N:10]=[CH:9]2)C=CC=CC1.[I:26]C1N=CN(C)C=1C1SC2N=CN=C(SC)C=2C=1>>[I:26][C:11]1[N:10]=[CH:9][N:8]([CH3:2])[C:12]=1[C:13]1[S:25][C:16]2[N:17]=[CH:18][N:19]=[C:20]([S:21]([CH3:24])(=[O:23])=[O:22])[C:15]=2[CH:14]=1
Reactant: CSc1ncnc2sc(-c3c(I)ncn3C)cc12
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Product: Cn1cnc(I)c1-c1cc2c(S(C)(=O)=O)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 17 but using 6-(4-iodo-1-methyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 93) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (example 7). Yellow solid (273 mg, 85%);
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1)(C(C)(C)C)(C)C.O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OC(=O)C)C>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: COc1ccc(C2(CCCO[Si](C)(C)C(C)(C)C)OCc3cc(C#N)ccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C2(CCCO)OCc3cc(C#N)ccc32)cc1
Reaction time: 2 h
Yield: 60 %

Procedure:
34.1 g (80.8 mmol) of the 1-(3-tert-butyldimethylsilyloxypropyl)-1-(4-methoxyphenyl)-1,3-dihydro-5-isobenzofurancarbonitrile prepared in step 4 was dissolved in 200 ml of tetrahydrofuran. 121.1 ml (121.1 mmol) of 1 M tetrabutylammonium fluoride tetrahydrofuran was added dropwise to the solution at room temperature, and the mixture was stirred for 2 hrs. The reaction mixture was diluted in ethylacetate, and washed with water and saturated NaCl solution. An organic layer was dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified using column chromatography to afford 15.0 g of the pale yellow target compound (yield: 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CCc2cccnc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
Methyl 4-[2-(2-benzyloxypyrid-3-yl)ethyl]benzoate was dissolved in EtOH (5 ml) and treated with NaOH (1N, 1.04 ml). The reaction was stirred at ambient temperature for 48 hours, 1N HCL (1.04 ml) was added and the precipitate was filtered and recrystllised from iso-propanol to give 4-[2-(2-benzyloxypyrid-3-yl)ethyl]benzoic acid as a white solid (0.054 g, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=O)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[S:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:13]=[C:19]3[S:15][C:16](=[O:21])[NH:17][C:18]3=[O:20])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COc1ncnc2ccc(C=O)cc12
Reactant: O=C1CSC(=O)N1
Product: COc1ncnc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example. 1, starting from 4-methoxy-quinazoline-6-carbaldehyde (intermediate 10) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: C[N:2]([CH3:14])[CH:3]=[C:4]([CH3:13])[C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[NH2:15][C:16]1[C:20](C#N)=[C:19]([CH3:23])[NH:18][N:17]=1>C(O)(=O)C>[CH3:23][C:19]1[C:20]([C:16]#[N:15])=[C:14]2[N:2]=[CH:3][C:4]([CH3:13])=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[N:17]2[N:18]=1
Reactant: CC(=CN(C)C)C(=O)c1cccnc1
Reactant: Cc1[nH]nc(N)c1C#N
Solvent: CC(=O)O
Product: Cc1cnc2c(C#N)c(C)nn2c1-c1cccnc1

Procedure:
A mixture of 1.90 g. of 3-dimethylamino-2-methyl-1-(3-pyridyl)-2-propen-1-one and 1.22 g. of 3-amino-5-methylpyrazole-4-carbonitrile in 25 ml. of glacial acetic acid is refluxed for 6 hours. The solvent is removed in vacuo and the residue partitioned between dichloromethane and saturated sodium bicarbonate solution. The dichloromethane layer is separated, dried over anhydrous sodium sulfate and passed through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 0.95 g. of the product of the example, m.p. 207°-209° C.