Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[C:7]([O:6][C:4]([C@H:3]([C@@H:11]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:12]([NH:14][N:15]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:2][NH:1][S:35]([C:31]1[S:30][CH:34]=[CH:33][CH:32]=1)(=[O:37])=[O:36])=[O:5])([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CN)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CNS(=O)(=O)c1cccs1)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
A solution of 0.504 g of 2(R)-[2-amino-1(R)-(tert-butoxycarbonyl)ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in 20 ml of dichloromethane was cooled to 0° C. while stirring and 0.242 g of 2-thiophenesulphonyl chloride was added. The mixture was left to come to room temperature and was stirred overnight. The solvent was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous citric acid solution. The ethyl acetate layer was washed with saturated sodium hydrogen carbonate solution and then with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue was triturated with ether and there was obtained 0.487 g of 2(R)-[1(R)-(tert-butoxycarbonyl)-2-[(2-thienyl)sulphonamido]ethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:8][C@@H:9]([OH:13])[CH2:10][CH:11]=[CH2:12].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2](/[CH:12]=[CH:11]/[CH2:10][C@H:9]([OH:13])[CH3:8])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C=CC[C@@H](C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: C[C@@H](O)C/C=C/c1cccnc1
Temperature: 140 °C
Yield: 65.1 %

Procedure:
A mixture of 3-bromopyridine (9.17 g, 58.04 mmol), (2R)-4-penten-2-ol (6.00 g, 69.65 mmol), palladium(II) acetate (130 mg, 0.58 mmol), tri-o-tolylphosphine (710 mg, 2.32 mmol), triethylamine (34.7 mL, 249.5 mmol), and acetonitrile (35 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give 6.17 g (65.2%) of a pale-yellow oil.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:10])[CH:8]=[CH2:9])[O:5][C:4](=[O:11])[C@@H:3]1[O:12][CH3:13].C([CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=C>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl.C(Cl)Cl>[CH:16]1(/[CH:9]=[CH:8]/[C@H:7]([C@@H:6]2[O:5][C:4](=[O:11])[C@H:3]([O:12][CH3:13])[C@@H:2]2[OH:1])[OH:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC1CCCC1
Reactant: C=C[C@@H](O)[C@@H]1OC(=O)[C@H](OC)[C@@H]1O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Product: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Temperature: 60 °C

Procedure:
100 mg (0.53 mmol) of 18, 4 ml of CH2Cl2, 726 μl (5.3 mmol) of vinylcyclopentane and then 90.2 mg (106 μmol) of second-generation Grubbs catalyst are introduced into a 5 ml vial. The solution is microwave-heated at 60° C. for 10 min. The solvent is subsequently evaporated to dryness under reduced pressure and the residue is then purified on a Biotage 12-M silica column (eluent: 40/60 Hept/EtOAc). The product 19 (76.3 mg, Rf=0.35 under the elution conditions used) is obtained in the form of a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH2:11].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH2:31][CH2:32][C:33]#[N:34])[CH:30]=2)O1.O>COCCOC.C(#N)C.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>[NH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][C:33]#[N:34])[CH:30]=3)[CH:3]=2)[NH:7][N:6]=1
Reactant: Nc1n[nH]c2ccc(Br)cc12
Reactant: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: COCCOC
Product: N#CCCn1cc(-c2ccc3[nH]nc(N)c3c2)cn1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a microwave vial was added 5-bromo-1H-indazol-3-amine (0.14 g, 0.66 mmol), tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol), and sodium carbonate (0.147 g, 1.39 mmol) followed by a solution of Example 267A (0.212 g, 0.858 mmol) in 1,2-dimethoxyethane (2.50 mL) and then water (1.25 mL). The mixture was heated in a CEM microwave at about 150° C. for about 20 minutes (275 psi maximum pressure, about 2 minutes ramp, 200 maximum watts) and then the mixture was concentrated under reduced pressure. Methanol (20 mL) was added and the resulting mixture was stirred for about 1 hour. The insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure onto silica gel and purified via silica gel chromatography eluting with a stepwise gradient of dichloromethane/methanol/ammonium hydroxide (990:9:1 to 985:13.5:1.5 to 980:18:2) to afford a solid. This solid was dissolved in a minimum amount of hot acetonitrile (˜2 mL), filtered to remove minor amount of insolubles, while washing with methanol (<0.5 mL), and left to sit at ambient temperature. The resulting solid that formed overnight was collected by filtration, while washing with additional acetonitrile, and dried in a vacuum oven at about 60° C. for about 2 hours to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.35 (s, 1H), 8.10 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.44 (dd, J=8.54, 1.26 Hz, 1H), 7.23 (d, J=8.62 Hz, 1H), 5.32 (s, 2H), 4.42 (t, J=6.36 Hz, 2H), 3.10 (t, J=6.43 Hz, 2H). MS (ESI+) m/z 253.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3O)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.[C:24]([O-:27])([O-])=O.[Cs+].[Cs+].BrC1[CH:32]=[N:33][CH:34]=[N:35][CH:36]=1.CN(C=O)C>O1CCOCC1.CO>[N:33]1[CH:32]=[C:24]([O:27][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:23])([F:22])[F:1])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[CH:36]=[N:35][CH:34]=1
Reactant: Brc1cncnc1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1-c1nnc(Nc2cccc(C(F)(F)F)c2)[nH]1
Agent: [Cs+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)[nH]2)c1
Yield: 28.1 %

Procedure:
4-(5-{[3-(trifluoromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl-phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (203.4 mg, 0.62 mmol) was added, followed by 5-bromo-pyrimidine (100 mg, 0.62 mmol). Then 1 mL of anhydrous DMF was added, the vial was capped and microwaved at 250° C. for 30 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water system with 0.01% of TFA. The fractions containing the product were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a light-brown foamy solid (34.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:29]4[N:28]=[CH:27][N:26](COCC[Si](C)(C)C)[C:25]=4[CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:21]2[C:29]4[N:28]=[CH:27][NH:26][C:25]=4[CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cnc2c(S(=O)(=O)c3ccc4cc(-c5ccc(F)cc5)ccc4c3)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1cccc2[nH]cnc12
Temperature: 25 °C
Yield: 43.1 %

Procedure:
To a stirring solution of 4-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (260 mg, 0.49 mmol) in THF (5 mL) was added tetrabutylammonium fluoride (0.60 mL of 1 M solution in THF; 0.6 mmol), and the resulting mixture was heated at reflux for 5 hours. The mixture was allowed to cool to room temperature, then was diluted with water (100 mL) and washed with ethyl acetate (2×50 mL), The combined organic layers were washed with water, then with saturated sodium chloride solution, were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel, eluting first with 1:1 ethyl acetate:isohexane, then with 100% ethyl acetate. The resulting material was purified further by flash chromatography on silica gel, eluting with 50% to 70% ethyl acetate in isohexane, and the resulting material was triturated using a 1:1 mixture of diethyl ether and isohexane, to afford the product as a white amorphous solid (85 mg, 43%). 1H NMR (500 MHz, d6-DMSO): δ 12.96 (1H, s), 8.89 (1H, s), 8.38 (1H, s), 8.30 (1H, s), 8.26 (1H, d, J=8.6 Hz), 8.14-8.08 (2H, m), 8.00 (1H, d, J=8.6 Hz), 7.95 (2H, t, J=6.8 Hz), 7.88 (2H, dd, J=5.4, 8.7 Hz), 7.45 (1H, t, J=7.9 Hz), 7.36 (2H, t, J=8.8 Hz); m/z (ES+) 403 [MH+].
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]([CH3:19])([CH3:18])[CH2:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([N:30]1[CH2:34][C@@H:33]([F:35])[CH2:32][C@H:31]1[C:36]#[N:37])=[O:29]>C1COCC1>[CH3:18][C:9]([NH:8][CH2:27][C:28]([N:30]1[CH2:34][C@@H:33]([F:35])[CH2:32][C@H:31]1[C:36]#[N:37])=[O:29])([CH3:19])[CH2:10][C:11](=[O:12])[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(N)CC(=O)N1CCCC1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CC(=O)N1CCCC1)NCC(=O)N1C[C@@H](F)C[C@H]1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a stirred solution of 3-amino-3-methyl-1-pyrrolidin-1-yl-butan-1-one trifluoroacetic acid (0.28 g, 1 mmol) in anhydrous THF (5 mL) was added potassium carbonate (0.55 g, 4 mmol). After stirred at room temperature for 1 h, the mixture was filtered through a Celite pad, and rinsed with ethyl acetate (5 mL). To the above filtrate was added (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.12 g, 0.5 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 12 h. Most of solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 (20 mL) and H2O (5 mL). The aqueous layer was further extracted with CH2Cl2 (10 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield a crude viscous oil. The crude oil was purified by chromatography (silica gel, 4 to 10% CH3OH/CH2Cl2 gradient) to give compound 1 (0.12 g, 74% overall yield) as a white solid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42]O)[CH:37]=2)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:28][CH2:27]1.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>[C:1]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[C:14]([O:16][CH2:42][C:38]3[CH:37]=[C:36]([CH:29]([CH:26]4[CH2:27][CH2:28]4)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:41]=[CH:40][CH:39]=3)[CH:13]=[CH:12][C:11]=2[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[F:25])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2-c2nnc(C(C)(C)C)s2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3nnc(C(C)(C)C)s3)c2)c1)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
To a solution of 2-(5-(tert-butyl)-1,3,4-thiadiazol-2-yl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (109 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (91 mg) and triphenylphosphine (319 mg) in THF (6.0 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (480 μL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (134 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:31]=1.C#C.C[SiH](C)C.C(N(CC)CC)C>CN(C)C=O.[Cu]I>[ClH:17].[CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15]([C:30]#[CH:31])[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(Cl)cc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Cu]I
Agent: C#C
Agent: C[SiH](C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1cc2c(C)c(C)n(Cc3ccccc3)c2c(N2CCc3ccccc3C2)n1
Product: Cl
Temperature: 25 °C
Yield: 31.3 %

Procedure:
A solution of 2-(1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.24 mmol) prepared in Example 658, bis(triphenylphosphine)palladium chloride(II) (9.4 mg, 0.013 mmol), triphenylphosphine (12.6 mg, 0.48 mmol), copper(I) iodide (2.5 mg, 0.013 mmol), trimethylsilane acetylene (42 μl, 0.3 mmol), and triethylamine (1 ml) in anhydrous N,N-dimethylformamide (2 ml) was refluxed for 8 hours at 120° C. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 32.1 mg of the titled compound as a white solid.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=O)(=[NH:4])[NH2:3].Cl.[NH2:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH2:22].CC1C=CC(S(O)(=O)=O)=CC=1.C=CC1C=CC=CC=1.C(C1C=CC=CC=1C=C)=C>O>[ClH:1].[ClH:1].[C:2]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH2:8][C:9]2=[N:16][N:17]1[CH2:21][CH2:20][N:19]=[C:18]1[NH2:22])(=[NH:4])[NH2:3]
Reactant: NC1=NCCN1N
Reactant: N=C(N)c1cccc2c1CCC2=O
Agent: C=Cc1ccccc1C=C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: O
Product: N=C(N)c1cccc2c1CCC2=NN1CCN=C1N
Reaction time: 18 h

Procedure:
A solution of 0.24 g (0.001 mol) of 4-amidino-2,3-dihydro-1H-inden-1-one hydrochloride and 0.136 g (0.001 mol) of 1,2-diamino-4,5-dihydro-imidazole hydrochloride [m.p. 245°-246° C., prepared from the corresponding p-toluenesulfonate salt, see EP 0 327 919, Example 12, by ion exchange on ®Amberlite IRA-400 (anion exchanger based on a styrene/divinylbenzene polymer with quaternary ammonium groups in the Cl- form; Fluka, Buchs, Switzerland)] in 3 ml of water is left to stand at room temperature for 18 hours. The product that has crystallized out is filtered off with suction and recrystallized from water, yielding the title compound (monohydrate), m.p. 280° C. (decomp.), 1 H-NMR (DMSO/D2O): δ=8.17 (d, 1H); 7.66 (d, 1H); 7.54 (t, 1H); 4.18 (t, 2H); 3.70 (t, 2H); 3.25 (m, 2H); 3.13 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20](F)=[C:21]([CH3:23])[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:25]1[CH2:29][CH2:28][NH:27][C:26]1=[O:30]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:27]4[CH2:28][CH2:29][O:25][C:26]4=[O:30])=[N:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCOC4=O)c(C)c3)CC2)c(C)c1
Yield: 38.5 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-5-methylpyridin-3-yl)methanone (529 mg) described in Preparation Example 148 and oxazolidin-2-one (281 mg), the title compound (245 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:35][C:36]([F:41])([F:40])[CH:37]1[O:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:38][CH:37]([OH:39])[C:36]([F:41])([F:40])[F:35])[C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:27])[F:28])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)NCc1ccccc1C(F)(F)F
Reactant: FC(F)(F)C1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)NCc1ccccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
100 mg (0.24 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[2-(trifluoromethyl)benzyl]-acetamide from Example 243A are placed with 119 mg (0.37 mmol) of caesium carbonate in 0.6 ml of DMSO and treated with 137 mg (1.22 mmol) of 1,1,1-trifluoro-2,3-epoxypropane. This is stirred for 3 hrs at 120° C. Next, 137 mg (1.22 mmol) of 1,1,1-trifluoro-2,3-epoxypropane are again added and the mixture stirred for a further hour at 120° C. The suspension is then cooled to RT, diluted with ethyl acetate and washed three times with saturated ammonium chloride solution. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 30.6 mg (24% of theory) of the target compound are thus obtained.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[N:8]=2)[CH2:6][CH2:5]1)=[O:29]
Reactant: O=C(O)c1ccco1
Reactant: c1ccc(-c2cc(N3CCNCC3)nc3c2CCCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccco1)N1CCN(c2cc(-c3ccccc3)c3c(n2)CCCC3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
A mixture of 2-(1-piperazinyl)-4-phenyl-5,6,7,8-tetrahydroquinoline (1.2 g), 2-furancarboxylic acid (0.46 g), chloroform (40 ml) and 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.79 g) is stirred at 25° C. for 2 hours. The reaction mixture is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene and subjected to silica gel column chromatography. The fractions eluted with toluene and toluene-ethyl acetate (9:1) are collected and recrystallized from ethanol to give the desired product (0.4 g), m.p. 128°-130° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[H][H].Br[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>CN(C)C=O.C(OCC)(=O)C.O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: [H][H]
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cc2ncc[nH]2)cc1
Reaction time: 1.5 h
Yield: 71.9 %

Procedure:
Under cooling, 23.15 g of imidazole in 250 ml of N,N-dimethylformamide is combined in portions with 14.8 g of sodium hydride, 60% in oil, and stirred for 1.5 hours at 25° up to the end of hydrogen release. In two portions, 50 g of 4-(bromomethyl)benzonitrile is added under ice cooling to this solution and the mixture is agitated for 1.5 hours at 25°. For processing, 100 ml of water is added under ice cooling, the mixture is agitated for 0.25 hour, poured into 1.5 1 of ethyl acetate, washed neutral with water, washed twice with sodium chloride and water, dried over sodium sulfate, concentrated to dryness under vacuum, and crystallized from acetone/diethyl ether, thus obtaining 33.6 g of 4-[1-(imidazolyl)methyl]benzonitrile as colorless crystals, mp 102°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[O-:13][CH2:14][CH3:15].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:13][CH2:14][CH3:15]
Reactant: Clc1ncnc2ccc(Br)cc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ncnc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
The suspension of 6-bromo-4-chloro-quinazoline (4.87 g, 20 mmol), sodium ethoxide (95%, 14.32 g, 200 mmol) in anhydrous ethyl alcohol (150 ml) was stirred at room temperature for 4 hr. After the reaction, solvent was evaporated. Then, ice water was added, followed by addition of 3 N HCL aq to adjust the pH to 9, and precipitate formed. The solid was collected and washed with H2O three times, then dried. Flash chromatography (Merck silica gel 60, 230-400 mesh, 10%-50% ethyl acetate in hexane for 30 min) afforded 6-Bromo-4-ethoxy-quinazoline (2.13 g, 55%) as a light yellow solid. LC-MS m/e 254 (MH+).