Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)#[CH:2].I[C:21]1[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=1[NH:23][S:24]([CH3:27])(=[O:26])=[O:25].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][S:24]([N:23]1[C:22]2[C:21](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:2]=[C:1]1[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)(=[O:26])=[O:25]
Reactant: C#Cc1ccc(OCCCN2CCN(C)CC2)cc1
Reactant: CS(=O)(=O)Nc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(CCCOc2ccc(-c3cc4ccccc4n3S(C)(=O)=O)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
The mixture of 1-ethynyl-4-(3-(4-methylpiperazino)propoxy)benzene (230 mg, 0.89 mmol), 2-iodo-N-(methanesulfonyl)aniline (0.89 mmol, 296 mg), Cul (17 mg, 0.089 mmol), Pd(PPh3)2Cl2 (32 mg, 0.045 mmol) and triethylamine (0.5 mL) in DMF (5 mL) was stirred at 80° C. for overnight. After concentration, water (20 mL) was added and extracted by methlene chloride (3×20 mL). The organics was concentrated and purified by column chromatography afforded the title compound (260 mg): 1H NMR (CDCl3, 400 MHz) δ 8.05 (d, 1H, J=8.8 Hz), 7.55 (d, 1H, J=2.1 Hz), 7.50 (td, 2H, J=8.8,2.1 Hz), 7.32 (d, 1H, J=2.1 Hz), 7.30 (d, 1H, J=2.1 Hz), 6.96 (td, 2H J=2.1, 8.8 Hz), 6.60 (d, 1H, J=0.5 Hz), 4.08 (t, 2H, J=6.3 Hz), 2.74 (s, H), 2.55 (m, 10H), 2.33 (s, 3H), 2.02 (quintet, 2H, J=6.3 Hz); EIMS m/z 462 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>C(Cl)Cl>[CH2:15]([O:14][C:3]1[C:2]([Br:1])=[CH:9][C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:7][C:4]=1[CH:5]=[O:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(OCc2ccccc2)c(C=O)c1

Procedure:
step 1—Benzylation of 3-bromo-5-tert-butyl-2-hydroxy benzaldehyde (36a) with benzyl bromide is accomplished treating 36a with benzyl bromide and tetrabutylammonium hydroxide in a biphasic system comprised of MeOH and DCM to afford 2-benzyloxy-3-bromo-5-tert-butyl-benzaldehyde (36b).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH3:27][Sn](C)(C)C>CN(C=O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:27])[C:9]2[N:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2-c1ccccc1
Reactant: C[Sn](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C)c2c(c1O)c1ccccc1n2-c1ccccc1
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
A mixture of 1-bromo-4-hydroxy-9-phenyl-9H-b-carboline-3-carboxylic acid ethyl ester (78 mg, 0.19 mmol), tetramethyltin (37 mg, 0.21 mmol), and Pd(PPh3)2Cl2 (6.7 mg, 0.0095 mmol) in DMF (1 mL) was stirred at 120° C. for 50 min. The mixture was then diluted with EtOAc, washed with water and saturated NaCl aqueous solution, respectively; the EtOAc phase was dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column to give a white solid, the desired title compound. The title compound, ESI MS (m/z): 347 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:7]([C:14]#[N:15])=[N:6][C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Br)c[n+]1[O-]
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Br)c(C#N)n1
Temperature: 100 °C

Procedure:
To the solution of 5-bromo-2-methylpyridine 1-oxide (8.935 g, 47.52 mmol) in acetonitrile (240 mL) was added trimethylsilyl cyanide (TMSCN) (25 mL, 190 mmol) and triethylamine (20 mL, 142.56 mmol). The reaction was heated at 100° C. for 16 h. The mixture was cooled to rt and concentrated in vacuo. The crude was purified by silica gel chromatography using 0-50% EtOAc in hexane to obtain the title compound.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]2[C:20]=1[CH:21]=[C:22]([C:29]([O:31][CH3:32])=[O:30])[NH:23]2>C(#N)C>[C:1]([C:21]1[C:20]2[C:24](=[C:25]([CH3:28])[CH:26]=[CH:27][C:19]=2[Cl:18])[NH:23][C:22]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc2c(Cl)ccc(C)c2[nH]1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1[nH]c2c(C)ccc(Cl)c2c1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
To 10 ml of anhydrous acetonitrile were added 0.74 ml (12.9 mmol) of acetic acid and 0.4 g of polyphosphoric acid. After the air in the reaction system was replaced with nitrogen, 1.86 ml (12.9 mmol) of trifluoroacetic anhydride was added and the reaction mixture was stirred at room temperature for 10 minutes. 10 ml of a solution of 1.0 g (4.3 mmol) of methyl 4-chloro-7-methylindole-2-carboxylate in acetonitrile was added dropwise over a period of 15 minutes and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into 100 ml of ice water and extracted with 15 ml of ethyl acetate three times. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude crystals were purified by silica gel column chromatography to provide 270 mg of white crystals. Yield: 25%
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2].[H-].[Na+].[CH:16]([Si:19](Cl)([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])([CH3:18])[CH3:17].O>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]2[C:12]([I:13])=[CH:11][N:10]([Si:19]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:16]([CH3:18])[CH3:17])[C:6]=2[N:7]=[CH:8][N:9]=1)[CH3:2]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CCOc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ncnc2c1c(I)cn2[Si](C(C)C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.7 %

Procedure:
To 4-ethoxy-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (12, 2.70 g, 9.34 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodium hydride (411.0 mg, 10.27 mmol) is added. The reaction is stirred at room temperature for 20 minutes, then triisopropylsilyl chloride (3, 2.177 mL, 10.27 mmol) is added. The reaction is stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 5-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (13, 3.90 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([O:1][C:2]1[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)[CH:17]=[CH2:16]
Reactant: CCC(=O)c1cc2c(cc1O)CCCC2
Reactant: C=CCBr
Product: C=CCOc1cc2c(cc1C(=O)CC)CCCC2
Yield: 108.4 %

Procedure:
The product of step (b) (14.5 g) was treated with allyl bromide (11.5 g) under the conditions of Example 1(a) to give the title compound (18.8 g) as a pale brown oil, whose structure was confirmed by MS and NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][O:34][C:35]1[CH:41]=[CH:40][CH:39]=[C:37]([OH:38])[CH:36]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([O:34][CH3:33])[CH:36]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OC(=O)c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.43 g (11.5 mmol) of resorcinol monomethyl ether and 20 ml of dry dimethylformamide is stirred at room temperature for 2 days, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel while eluting with ethyl acetate/n-hexane (3:1) and subsequently crystallized from ethyl acetate. There is obtained m-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 184°-185°.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[Na].Cl[CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl>C(O)C.O>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][CH2:9][CH2:8][S:1][CH2:2][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=1
Reactant: O=C(O)CS
Reactant: Oc1ccc(SCCCl)cc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)CSCCSc1ccc(O)cc1
Temperature: 25 °C

Procedure:
Mercaptoacetic acid (3.5 g, 0.039 mole) was added to ethyl alcohol (100 ml) containing sodium (1.8 g, 0.078 mole). The compound of Example 36 (7.3 g, 0.039 mole) in ethyl alcohol (20 ml) was added dropwise and the mixture refluxed 1 hour. The reaction mixture was cooled to room temperature, poured into water (250 ml) and acidified with 2N hydrochloric acid. The product was extracted into ethyl ether (2×150 ml) and the ethyl ether extracted with 1M sodium bicarbonate (3×80 ml). The combined basic washes were acidified with 2N hydrochloric acid and extracted with ethyl ether (3×150 ml). The combined ethyl ether extracts were washed with water (3×75 ml) and saturated sodium chloride (50 ml), dried over magnesium sulfate, filtered and concentrated to give yellow solid. Recrystallization from ethyl ether/pentane gave the title compound, m.p. ca. 105° C.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19](=[O:20])[CH:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[O:17][C:16]2=[O:28])C=CC=CC=1>O>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([CH:18]2[O:17][C:16](=[O:28])[NH:15][C:19]2=[O:20])=[CH:26][CH:25]=1
Reactant: O=C1OC(c2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(c2ccc(O)cc2)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 10 ml of trifluoroacetic acid was added 500 mg of 3-triphenylmethyl-5-p-hydroxyphenyl-2,4-oxazolidinedione and the reaction mixture stirred at room temperature for 10 minutes. The reaction was poured into 50 ml of water and extracted with ethyl acetate. The organic layer was separated, washed with water (2×40 ml) and dried over sodium sulfate. Removal of the solvent in vacuo gave a yellow solid which was recrystallized from ethyl acetate-cyclohexane, 226 mg.
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.[O-]CC.[Na+].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:30]([C:31](=O)[C:32]#[CH:33])=[C:29]3[N:24]([CH:25]=[N:26][CH:27]=[CH:28]3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1>C(O)C.O>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:30]([C:31]3[CH:32]=[CH:33][N:10]=[C:8]([NH:7][CH:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[N:9]=3)=[C:29]3[N:24]([CH:25]=[N:26][CH:27]=[CH:28]3)[N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C#CC(=O)c1c(-c2cccc(Cl)c2)nn2cnccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2nn3cnccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a mixture of cyclopentyl guanidine hydrochloride (1.05g, 6.43 mmol) in ethanol (60 mL) was added sodium ethoxide (2.15 mL, 3 M in ethanol, 6.43 mmol). The mixture was stirred at room temperature for 30 minutes then cooled to 0° C. A solution of 1-[2-(3-chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-2-propyn-1-one (1.4 g, 4.97 mmol) in ethanol (100 mL) was added and the reaction mixture was stirred at room temperature 16 hours. The reaction mixture was diluted with water (200 mL) then concentrated to about two thirds the original volume. The precipitated solids were collected on a filter to provide 4-[2-(3-Chlorophenyl)pyrazolo[1,5-c]pyrimidin-3-yl]-N-cyclopentylpyrimidin-2-amine (1.25 g, 64%) as a white solid. Rf 0.19 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ9.32 (s,1H), 8.22 (d,1H), 8.13 (d, 1H), 8.01 (d, 1H), 7.72 (s,1H), 7.55–7.39 (m, 3H), 6.38 (d,1H), 5.19 (d, 1H), 4.33 (m, 1H), 2.08 (m, 2H), 1.80–1.52 (m, 6H); MS m/z 391 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)=O)C.F[C:27]1C=CC(OC2C=CC(C3C=CN=C(C(O)=O)N=3)=CC=2)=CC=1.ICC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:10]3[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:3])[CH3:27])[N:11]=3)=[CH:13][CH:14]=2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reactant: CCOC(=O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CC(=O)c1nccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 62 %

Procedure:
4-[4-(4-Fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid ethyl ester: A mixture of 4-[4-(4-fluorophenoxy)phenyl]-pyrimidine-2-carboxylic acid (3.15 g, 10.2 mmol), iodoethane (2.0 mL, 25 mmol), and cesium carbonate (7.00 g, 21.5 mmol) in DMF (100 mL) was maintained at 70°-80° C. for 16 hours. The mixture was then partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed 3 times with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give an oil. Purification by column chromatography (1:1 hexane/ethyl acetate) afforded the desired product (2.14 g, 62%) as an oil which solidified upon standing at room temperature overnight, mp 61°-63° C. 1H NMR (CDCl3): δ 8.88 (d, J=5.4 Hz, 1H), 8.16 (d, J=8.7 Hz, 2H), 7.77 (d, J=5.4 Hz, 1H), 7.12-7.05 (m, 6H), 4.55 (q, J=7.5 Hz, 2H), 1.49 (t, J=7.5 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[Cl:22])=[O:4].[CH:24]([NH:27][CH3:28])([CH3:26])[CH3:25]>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:22])[CH:10]=1)[N:7]=[C:6]([N:27]([CH:24]([CH3:26])[CH3:25])[CH3:28])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNC(C)C
Reactant: COC(=O)c1c(Cl)nc2c(Cl)cc(Cl)cc2c1-c1ccccc1
Product: CC(C)N(C)c1nc2c(Cl)cc(Cl)cc2c(-c2ccccc2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 21 step D from 2,6,8-trichloro-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 21 step C) and isopropyl-methyl-amine. Light brown foam. MS (ESI): 389.2 (M+H)+.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[Mg+2].Cl([O-])(=O)(=O)=O.[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2.[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1>C(#N)C>[S:19]1[CH2:23][CH2:22][N:21]([C@H:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C@@H:12]2[OH:18])[CH2:20]1
Reactant: C1CCC2OC2C1
Reactant: C1CSCN1
Agent: [Mg+2]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: O[C@H]1CCCC[C@@H]1N1CCSC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46.9 %

Procedure:
To anhydrous magnesium perchlorate (12.93 g, 53.3 mmol) was added a solution of cyclohexene oxide (6.1 mL, 58.6 mmol) in anhydrous acetonitrile (25 mL) and the resulting mixture was stirred at room temperature for 20 min. Then a solution of thiazolidine (5.16 g, 55.0 mmol) in anhydrous acetonitrile was added and the reaction mixture was heated at 35° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between water (350 mL) and diethyl ether (350 mL). The aqueous layer was separated and extracted once more with diethyl ether (350 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to provide the crude product. The crude aminoalcohol was purified by dry-column chromatography with a mixture of ethyl acetate-hexanes (1:1, v/v) as eluent to yield 4.83 g (47% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH:16]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:22](=[O:23])[NH:21][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)NC1CCCC1
Temperature: 120 °C

Procedure:
[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol (0.120 g, 0.45 mmol) was mixed with cyclopentyl isocyanate (0.075 g, 0.68 mmol) in toluene and the reaction was heated to 120° C. overnight. After cooling, the crude material was submitted directly to silica gel purification to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=O)[CH:17]=[CH:18][C:4]1=2)[CH3:2].C(O)(=O)C.[CH3:25][C:26]1[N:27]=[CH:28][S:29][C:30]=1[CH2:31][NH:32][CH2:33][CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:32]([CH2:31][C:30]3[S:29][CH:28]=[N:27][C:26]=3[CH3:25])[CH2:33][CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: Cc1ncsc1CNCCc1cccnc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)Cc3scnc3C)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (0.423 g) and acetic acid (0.14 g) were added to a 1,2-dichloroethane solution (10 ml) of N-(4-methylthiazol-5-ylmethyl)-N-(2-pyridin-3-ylethyl)amine (0.36 g). The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.48 g) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→50:50). The purified product was condensed under reduced pressure. The residue was washed with diethyl ether, and dried to give the title compound (0.37 g) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:16]2[O:15][C:14]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[CH:10]=[CH:9][CH:8]=3)=[O:13])=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: O=C(O)Cc1cccc(NC(=O)c2ccc(-c3cccc(F)c3)o2)c1

Procedure:
The furyl bromide (16) (100 mg, 0.30 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the title compound.
Reaction SMILES: [BrH:1].C(O)(=O)C.[C:6]([C:8]1[CH:9]=[C:10]([C:14](=O)[CH2:15][S:16][C:17]#[N:18])[CH:11]=[CH:12][CH:13]=1)#[N:7].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]#[N:7])[N:18]=1
Reactant: N#CSCC(=O)c1cccc(C#N)c1
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2csc(Br)n2)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (10 ml) solution was added to a solution of 2-(3-cyanophenyl)-2-oxoethyl thiocyanate (1.0 g, 4.94 mmol) in acetic acid (10 ml), and the mixture was stirred at 130° C. for 2 hours and at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 990 mg (75.6%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:1]([O:8][N:9]1[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:10]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NCCN1OCc1ccccc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCN1CCN(OCc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of this imidazolidinone (4.0 g, 20.8 mmol) in DMF (50 ml) under nitrogen at 50° C. was added sodium hydride (1.0 g of a 60% dispersion in oil). A thick slurry formed at once. After 30 minutes, 1-bromopentane (2.84 ml) was added. After 15 minutes, the resulting clear solution was evaporated, and the residue was partitioned between ether and water. The organic extract was washed with water and brine, then dried (MgSO4), filtered, and evaporated. Purification by chromatography on silica provided 3-benzyloxy-1-pentyl-2-imidazolidinone as a colorless oil (4.15 g, 83% yield). Hydrogenolysis as in Example 2 above provided the title compound, after purification by chromatography on silica, as a white solid, mp 60°-61° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[CH3:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:22]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Oc1ccc2c(c1)CCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Oc1ccc2c(c1)CCC2
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 5-hydroxyindan (13.4 g), triethylamine (14.0 ml) and dichloromethane (150 ml) was added 2-methylbenzoyl chloride (15.4 ml) dropwise with constant stirring. The mixture was further stirred under ice-cooling for one hour, after which it was washed with water and dried (MgSO4). The solvent was then distilled off to give 5-(2-methylbenzoyloxy)indan as oil in quantitative yield.