Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>CC(C)=O>[CH2:12]([O:11][C:9]([NH:8][C@@H:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:24][CH:25]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1

Procedure:
7.42 g (0.02 mol) of N-benzyloxycarbonyl-L-tyrosine tert-butyl ester were refluxed for 6 h together with 9.77 g(0.03 mol) of cesium carbonate and 3.9 g (0.02 mol) of ethyl 4-bromo-butyrate in about 60 ml of acetone. After cooling the reaction mixture, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water (1/1). After separation of the phases, the organic phase was washed two times each with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The oily crude product was purified by flash chromatography on silica gel (dichloromethane/acetonitrile 25/1). Yield: 9.4 g (97%) of viscous oil. Rf=0.36 (silica gel, dichloromethane/methanol 9911).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[CH2:21][CH2:20][N:10]3[C:11]4[N:19]=[CH:18][CH:17]=[CH:16][C:12]=4[NH:13][CH2:14][CH2:15][CH:9]3[CH2:8]2)=[CH:4][CH:3]=1.[CH:24]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25]1>ClCCl>[CH:24]1([C:28]([N:13]2[CH2:14][CH2:15][CH:9]3[CH2:8][N:7]([CH2:6][C:5]4[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:21][CH2:20][N:10]3[C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]2=3)=[O:29])[CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CCC1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Solvent: ClCCl
Product: O=C(C1CCC1)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the product of Example 64C (97 mg, 0.31 mmol) in dichloromethane (2 mL) was added to cyclobutanecarbonyl chloride (0.048 mL, 0.42 mmol). The resulting, turbid solution was stirred at room temperature for 12 hours, and then the reaction was quenched by the addition of 20% Na2CO3 (1 mL). After 30 minutes, the mixture was made basic (pH˜9) by addition of 1 M NaOH (˜0.2 mL), diluted with water (3 mL) and extracted with CHCl3 (3×2 mL). The combined organic phases were dried over K2CO3 and concentrated: 1H NMR (300 MHz, CD3OD) δ ppm 1.58-2.02 (m, 5H), 2.06-2.44 (m, 4H), 2.68-3.26 (m, 6H), 3.42-3.65 (m, 3H), 3.96-4.47 (m, 2H), 6.82-7.11 (m, 3H), 7.17-7.58 (m, 3H), 8.08-8.32 (m, 1H); MS (DCI) m/z 395 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]3[N:20]=[C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])[N:22]=[C:18]3[CH:17]=[C:16]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:27]([NH:26][C:24]([NH:23][C:21]1[N:22]=[C:18]2[CH:17]=[C:16]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:19]2[N:20]=1)=[O:25])[CH3:28]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)n2n1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N3CCNCC3)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product of Step 2, 4-[2-(3-ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.52 g, 1.1 mmol) was suspended in CH2Cl2 (10 mL) Trifluoroacetic acid (5 ml) was added and the resulting solution was stirred at rt for 30 minutes. The reaction mixture was diluted with toluene and solvent was evaporated. The residue was purified by column chromatography on silica gel (0-10% MeOH in CH2Cl2 containing 1% NEt3 as eluant) to afford the target compound as a solid. MS (APCI+) 366 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.[O:33]=[C:34]1[NH:38][CH:37]([CH2:39][CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]1>ClCCl.CN(C)C1C=CN=CC=1>[O:42]=[C:41]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([O:3][CH3:2])=[O:10])[CH2:40][CH2:39][CH:37]1[CH2:36][CH2:35][C:34](=[O:33])[NH:38]1
Reactant: O=C(O)CCC1CCC(=O)N1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CCC1CCC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 5.0 g (0.03 mol) L-proline methyl ester hydrochloride is dissolved in 30 ml of dichloromethane. The solution is cooled to 0° C. and 4.42 ml (0.032 mol) triethylamine is added dropwise over a ten minute period. The mixture is stirred 15 minutes and a mixture of the following is added in a single addition: 6.85 g (0.033 mol) of dicyclohexylcarbodiimide; 200 mg (0.0016 mol) of 4-dimethylaminopyridine; 4.71 g (0.03 mol) of 5-oxo-2-pyrrolidinepropanoic acid. The reaction is allowed to warm to room temperature and stirred for 24 hours. The solids are removed by filtration and are washed with 15 ml of 0° C. dichloromethane. The filtrate is concentrated at reduced pressure to an oil. The oil is chromatographed over silica gel using 12:1 dichloromethanemethanol for elution. Concentration at reduced pressure followed by heating at 0.1 mm pressure and 60° C. yields 1-[1-oxo-3-(5-oxo-2-pyrrolidinyl)propyl]-L-proline, methyl ester as an analytically pure oil (0.55 hydrate) with the following characteristic proton NMR spectrum: 1H-NMR (CDCL3) 1.6-2.5 (m, 14H), 3.4-3.85 (m, 2H), 3. (s, 3H), 4.5 (m, 1H), 6.37 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH:14][NH2:15])=[O:13])=[N:7]1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][CH:23]=1>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:13][C:26]([C:25]3[CH:29]=[CH:30][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=3)=[N:15][N:14]=2)=[N:7]1
Reactant: O=C(O)c1ccc(OC(F)(F)F)cc1
Reactant: Cc1nc(C(=O)NN)nn1Cc1cccc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2nnc(-c3ccc(OC(F)(F)F)cc3)o2)nn1Cc1cccc(Br)c1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
To a solution of 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carbohydrazide (682 mg, 2.19 mmol), dissolved in POCl3 (6 mL), 4-(trifluoromethoxy)benzoic acid (453 mg, 2.19 mmol) was added. The reaction was heated to 100° C. for 2.5 h. The solvent was removed under reduced pressure and the crude material was taken up in EtOAc. The organic layer was then washed with NaHCO3 (3×40 mL) and brine (1×40 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified on a Biotage pre-packed silica gel column (MeOH:DCM 2% to 40% MeOH) to afford 2-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(trifluoromethoxy)phenyl)-1,3,4-oxadiazole (443 mg, 42%). MS (ES+) C19H13BrF3N5O2 requires: 479, 481 found: 480, 482 [M+H]+(1:1).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-:28].[Na+]>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: [OH-]
Reactant: COC(=O)COc1ccc(CC(C)NCCc2csc(C(F)(F)F)n2)cc1
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared analogously to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in methanol with 1N sodium hydroxide solution. After neutralisation with 1N hydrochloric acid, the mixture is extracted by shaking with methylene chloride, the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: C[O-].[Na+].C([S:7][CH:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)(=O)C.C(O)(=O)C>CO>[SH:7][CH:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: CC(=O)SC1CN2CCC1CC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: SC1CN2CCC1CC2
Yield: 25 %

Procedure:
Sodium methylate (0.5 g) is added to a solution of 3-(acetylthio)quinuclidine (14.5 g) in methanol (150 cc). The reaction mixture is then heated under reflux for 1 hour. Sodium methylate (0.5 g) is added again and the mixture is then heated under reflux for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Distilled water (40 cc) is added to the residue obtained, followed by acetic acid (approximately 1 cc) to obtain a pH in the region of 8. The mixture obtained is extracted with methylene chloride (3×20 cc). The combined organic phases are dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30° C. The brown oil obtained is distilled under reduced pressure (920 Pa); the fraction distilling at about 94° C. is collected. 3-Mercaptoquinuclidine (2.8 g) is thereby obtained.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:8]=3)[CH:6]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:28])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
5-{1-[4-Trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.68) (0.73 g, 1.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.62 g, 1.8 mmol) according to the general procedure VI. Obtained as a light brown solid (0.43 g), which was subsequently deprotected.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14](Cl)=[N:15][CH:16]=1.[H-].[Na+].C(OCC)(=O)CO>O1CCOCC1>[Br:10][C:11]1[CH:12]=[C:13]([N+:18]([O-:20])=[O:19])[C:14]([O:5][CH2:4][C:3]([O:7][CH2:8][CH3:9])=[O:6])=[N:15][CH:16]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a suspension of sodium hydride (5.31 g, 133 mmol) in 1,4-dioxane (250 mL) was added drop wise ethyl glycolate (12.56 ml, 133 mmol) over a period of 30 minutes ensuring that the temperature was maintained below 30° C. The resulting thick suspension was stirred at room temperature for 15 minutes. In a separate 1 L round-bottomed flask was added 5-bromo-2-chloro-3-nitropyridine (21 g, 88 mmol) in 1,4-dioxane (150 mL) to give a brown solution. The sodium hydride/ethyl glycolate slurry was added drop wise over a period of 30 minutes. The resulting reaction mixture was heated to 80° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified via Biotage chromatography (silica 340 g column, gradient elution from 0% to 10% ethyl acetate in cyclohexane) to give a pale yellow solid (11.8 g, 43% yield). 1H NMR (500 MHz, CDCl3): 8.48 (1H, d), 8.42 (1H, d), 5.07 (2H, s), 4.25 (2H, q), 1.30 (3H, s).
Reaction SMILES: C([O:3][C:4](=[O:38])[C@@H:5]([NH:15][C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:23]([C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)C.C(=O)([O-])[O-:40].[K+].[K+]>CC(C)=O.O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([NH:15][C:16]([C:18]2[CH:37]=[CH:36][C:21]3[N:22]([CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[C:23]([C:25]4[CH:29]=[CH:28][O:27][CH:26]=4)=[N:24][C:20]=3[CH:19]=2)=[O:17])[C:4]([OH:3])=[O:38])=[CH:8][CH:9]=1)(=[O:40])[NH2:14]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)c1ccc(C[C@H](NC(=O)c2ccc3c(c2)nc(-c2ccoc2)n3C2CCCCC2)C(=O)O)cc1

Procedure:
(S)-3-(4-Cyanophenyl)-2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-propionic acid ethyl ester from example 10 (0.120 g, 0.235 mmol) was dissolved in a mixture of acetone (5 mL) and water (3 mL). Urea-hydrogen peroxide complex (1.0 mmol, 0.094 g) and potassium carbonate (10 mg) were added and the mixture stirred until completion (HPLC). The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DMSO (1.5 mL) and 5 N NaOH (0.2 mL) was added. After stirring for 30 min at room temperature, TFA (0.5 mL) was added and the product isolated by prep HPLC (18 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][OH:13])[CH:6]=1)=[O:4].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[CH:6][C:7]=1[CH2:12][OH:13]
Reactant: O=C(CBr)c1ccc(O)c(CO)c1
Reactant: c1ccc(CNCCCCCCOCCCCCCc2ccccn2)cc1
Solvent: C1CCOC1
Product: O=C(CN(CCCCCCOCCCCCCc1ccccn1)Cc1ccccc1)c1ccc(O)c(CO)c1
Reaction time: 24 h
Yield: 90.4 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)phenyl]ethanone (1.00 g), N-[6-[[6-(2-pyridinyl)hexy]oxy]hexyl]benzenemethanamine (1.5 g) and DEA (1.58 g) in THF (20 ml) was left to stand for 24 h. The reaction mixture was filtered and the filtrate was concentrated to give an oil which was purified by FCC eluting with System B (95:5:1), to give the title compound as a yellow oil (1.96 g), t.l.c. (System A 80:20:2)) Rf 0.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.Br[CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH2:33][CH:34]4[CH2:35][CH2:36]4)=[C:17]([NH:20][C:21](=[O:31])[CH:22]=[CH:23][CH2:24][N:25]4[CH2:30][CH2:29][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[O:47])[CH2:27][CH2:26]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C(C=CCN1CCNCC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(C=CCN1CCN(CC(=O)OCc2ccccc2)CC1)Nc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
500 mg of 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(piperazin-1-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline are dissolved in 5 ml of acetonitrile, and 0.35 ml of triethylamine followed by 0.17 ml of benzyl bromo-acetate are added dropwise at room temperature. The reaction mixture is stirred for approximately 45 minutes at room temperature and then concentrated in vacuo. The solid residue is triturated with water and filtered off. The crude product is purified by column chromatography on silica gel with methylene chloride/methanol (20:1) followed by recrystallization from ethyl acetate. Yield: 380 mg (59% of theory), Melting point: 174° C. Mass spectrum (ESI−): m/z=657, 659 [M−H]−
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl[CH2:14][C:15]1[NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(N(CC)CC)C>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:11][CH2:12]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a rapidly stirred solution of 1-(2-pyridyl)piperazine (5.9 g, 36 mmol) in DMF (15 mL) in a large round bottom flask in a water bath at 20° C. was added 2-chloromethylbenzimidazole powder (6 g, 36 mmol) over 2 minutes. Triethylamine (7.5 mL, 1.5 eq) was added, and the reaction was stirred for 16 hours, until TLC indicated complete consumption of starting material. The reaction was then treated with 5 mL of triethylamine followed by the slow dropwise addition of water (70 mL). After one hour, the precipitate was collected by suction filtration and washed with 400 mL of water and dried to give 9 grams of product. The solid was recrystallized twice from boiling n-butanol to give 7.6 grams (72% yield purified) of the title compound as a buff powder. mp 220-221° C. 1H NMR (d6-DMSO, 300 MHz) δ 2.55 (4H, J=4.5 Hz), 3.52 (4H, J=4.5 Hz), 3.77 (s, 2H), 6.62 (1H, J=6.6, 4.5 Hz), 6.81 (1H, J=8.7 Hz), 7.14 (2H, m), 7.41-7.58 (3H, m), 8.09 (1H, J=4.5, 1.8 Hz). MS (DCI/NH3) m/z 294 (M+H)+. Anal. Calcd for C17H19N5: C, 69.60; H, 6.53; N, 23.87. Found: C, 69.47; H, 6.58; N, 23.87.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH3:18])[C:14]=1[C:15]([NH2:17])=[O:16])(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[S:11][C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:13]([CH3:18])[C:14]=1[C:15](=[O:16])[NH2:17])(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1scc(C)c1C(N)=O
Product: CC(=O)Nc1sc(S(=O)(=O)Cl)c(C)c1C(N)=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Neat ClSO3H (6.7 mL, 100 mmol) is cooled to 0° C. 2-acetylamino-4-methyl-thiophene-3-carboxylic acid amide (1.98 g, 10 mmol) is added in portions over a period of 15 min, and the mixture is stirred at 40° C. for 3 h. The mixture is cooled down to room temperature and poured slowly onto ice cold water. The resulting suspension is washed twice with EtOAc, the combined organic fractions are dried over MgSO4, filtered and evaporated to yield the desired product which is used as such.
Reaction SMILES: Cl.[NH:2]([C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:7][N:8]=1)[NH2:3].O.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([NH:3][NH:2][C:4]1[S:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[N:7][N:8]=1)(=[O:19])[CH3:18]
Reactant: Cc1ccccc1-c1nnc(NN)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NNc1nnc(-c2ccccc2C)s1
Reaction time: 0.5 h

Procedure:
A solution of 2-hydrazino-5-(2-methylphenyl)-1,3,4-thiadiazole hydrochloride (1.0 g) in a mixture of acetic anhydride (0.5 ml) and pyridine (0.5 ml) was kept at room temperature under nitrogen for 0.5 hr. The solution was poured into water (100 ml) and extracted three times with methylene chloride. The organic layer was evaporated and the residue was fractionated on two 20 × 20 cm, 2 mm thick silica preparative t.l.c. plates by eluting with chloroform-methanol (4:1). The resultant product was crystallised from ethyl acetate (0.32 g; 31%) m.p. 165°-6°. C11H12N4OS requires C, 52.8; H, 5.6; N, 22.4; S, 12.8 Found C, 52.8; H, 5.1; N, 22.8; S, 13.2%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: Brc1ccccn1
Reactant: C#CCCn1ccc2ccccc2c1=O
Product: O=c1c2ccccc2ccn1CCC#Cc1ccccn1
Yield: 9841.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (100 mg, 0.63 mmol) and 2-but-3-ynyl-2H-isoquinolin-1-one (120 mg, 0.63 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 17 mg (62 mmol, 10%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoquinolin-1(2H)-one as a white solid (M.P.=85-90° C.).
Reaction SMILES: C(O[C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][CH2:16][C:17]2=[O:20])=[CH:12][CH:11]=1)=[O:5])C.C(N(CC)C(C)C)(C)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(Cl)Cl>[N:30]1([C:4](=[O:5])[CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH2:16][C:17]3=[O:20])=[CH:12][CH:11]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: CCOC(=O)CCCOc1ccc2c(c1)C(=O)CCC2
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCCc2ccc(OCCCC(=O)N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a suspension of 7-(3-ethoxycarbonylpropoxy)-1-tetralone (0.925 g, 3.7 mmol), HUBT (1.415 g, 3.7 mmol), N,N-diisopropylethyl amine (1.3 mL) in CH2Cl2 (20 mL) was added morpholine (0.330 mL, 3.7 mmol) at room temperature and under argon atmosphere. The reaction mixture was then stirred at room temperature for 24 h and then concentrated. The residue dissolved in ethyl acetate (50 mL) and the organic layer was washed with dil. HCl, water, brine, and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on the column of silica gel using ethyl acetate-hexane (8:2) as an eluent to give 7-(4-morpholin-4-yl-4-oxo-butoxy)-1-tetralone (1.010 g, 86%): mp 88-90° C., 1H NMR (500 MHz, CDCl3): δ 2.07-2.15 (m, 4H), 2.50 (t, J=7.5 Hz, 2H), 2.61 (T, J=7.5 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 3.46 (t, J=5.0 Hz, 2H), 3.59-3.66 (m, 6H), 4.04 (t, J=6.0 Hz, 2H), 7.01-7.03 (dd, J=3.0 and 8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.48 (d, J=3.0 Hz, 1H). HFABMS m/z 318.1706 (calc for C18H23NO4, MH+, 318.1705).