Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[CH:26]12[CH2:34][CH2:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][NH:28][CH2:27]2.[I-].[K+].O>CC(=O)CC>[CH:26]12[CH2:34][CH2:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:28]5[CH2:29][CH:30]6[CH2:33][CH2:34][CH:26]([CH2:32][CH2:31]6)[CH2:27]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=1)=[O:6])[CH2:27]2
Reactant: C1CC2CCC1CNC2
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(CCCN1CC2CCC(CC2)C1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CC4CCC(CC4)C3)ccc1-2
Reaction time: 72 h

Procedure:
A mixture of 11.25g (0.03 mole) of 2,7-bis(4-chlorobutyryl)fluorene, 30.1g (0.24 mole) of 3-azabicyclo[3.2.2]nonane and 10.0g (0.06 mole) of potassium iodide in 200 ml butanone is heated at reflux with stirring for 3 days. The reaction mixture was poured into 1000 ml of water, and the resulting solid precipitate filtered and recrystallized from chloroform-acetone to yield the desired product.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:23])([CH3:22])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26]O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]([Cl:29])([Cl:28])[CH2:26][O:17][C:16](=[O:18])[CH:15]([O:19][CH2:20][CH3:21])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([CH3:22])([CH3:23])[O:6][SiH2:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:9][CH:10]=1
Reactant: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under nitrogene atmosphere 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-ethoxy-propionic acid (0.135 g, 0.4 mmol) and 2,2,2-trichloro ethanol (0.06 g, 0 4 mmol) were dissolved in dry DCM (5 mL) and DMAP (2 mg, 0.02 mmol) was added followed by EDCxHCl (0.092 g, 0.48 mmol) at 0° C. The mixture was stirred for 18 h at ambient temperature, then diluted with DCM and extracted with aq. HCl (2N) and water. The organic layer was separated, dried (MgSO4) and evaporated to afford the crude product which was used in the next step without further purification (0.176 g, 93.6%). 1H NMR (400 MHz, CDCl3): δ 7.12-7.19 (m, 4H), 4.62-4.71 (q, 2H), 4.63 (s, 2H), 4.05-4.08 (m, 1H), 3.55-3.59 (m, 1H), 3.27-3.31 (m, 1H), 2.92-3.03 (m, 2H), 1.08 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:16])[CH2:14][CH3:15])=[C:2]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Product: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 109.8 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)propan-1-one (250 mg, 0.98 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (430 mg, 1.5 mmol) to afford the desired product (550 mg, crude) as an dark brown solid: 1H NMR (500 MHz, CDCl3) δ 11.29 (s, 1H), 9.03 (s, 1H), 8.11 (d, J=9.0 Hz, 1H), 8.01 (d, J=3.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.31-7.29 (m, 1H), 6.72 (d, J=9.0 Hz, 1H), 4.79 (br s, 1H), 3.90-3.61 (m, 4H), 3.51-3.25 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 1.96-1.84 (m, 1H), 1.82-1.70 (m, 1H), 1.72-1.55 (m, 1H), 1.45 (s, 9H), 1.26 (t, J=7.0 Hz, 3H); ESI MS m/z 511 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36]>>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:52][CH2:51][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:55][CH2:54]2)([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1ccc(C2(CCOS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(OC)cc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.3 g, 1.0 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.52 g, 1.0 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.38 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][OH:23]>>[F:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:22][O:23][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C@@H:10]([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cccc(F)c1F
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3cccc(F)c3F)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (2,3-difluorophenyl)methanol.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][N:8]1[C:12](C=O)=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=[CH:9]1.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.O>[CH3:7][N:8]1[C:12]([C:1]([OH:2])=[O:4])=[C:11]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:10]=[CH:9]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cnc(-c2ccccc2)c1C=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cnc(-c2ccccc2)c1C(=O)O
Reaction time: 24 h
Yield: 68.8 %

Procedure:
Potassium carbonate (3.13 g) was added to 1-methyl-4-phenyl-1H-imidazole-5-carbaldehyde (intermediate 2) (2.33 g) dissolved in acetone (125 mL) and water (25 mL). Once dissolved, potassium permanganate (4.23 g) was added and the mixture stirred for 24 hours. The mixture was filtered through diatomaceous earth and the cake washed with water (2×20 mL). Acetone was evaporated from the filtrate which was extracted with EtOAc (50 mL). The aqueous layer was acidified with acetic acid to pH 5, reduced to half volume and a cream precipitate filtered and dried at 60° C. in vacuo to give the title compound as a cream solid (1.74 g, 69%);
Reaction SMILES: [C:1]1([C@H:7]([CH3:12])[CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12>ClCCl.N1C=CC=CC=1>[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH:32]3[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]3)[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:9](=[O:10])[CH2:8][C@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH3:12])=[C:25]([O:30][CH3:31])[CH:24]=3)[C:15]=12
Reactant: C[C@H](CC(=O)Cl)c1ccccc1
Reactant: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)ccc1NC(=O)C[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
(3R)-3-Phenylbutanoyl chloride (2.22 g, 12.18 mmol) in dichloromethane (10 mL) was added to a solution of 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (2.86 g, 8.12 mmol) in pyridine (50 mL) at −10° C. After 15 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature overnight. Sodium hydroxide (1.0N, 15 mL) was added and the organic solvent was evaporated. The aqueous residue was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichlromethane/methanol (95:5) as mobile phase to give N1-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-(3R)-3-phenylbutanamide (3.11 g, 77%). 1H NMR (CDCl3) δ 1.40 (d, J=6.97 Hz, 3H), 2.04 (m, 1H), 2.59-2.78 (m, 9H), 3.40 (m, 1H), 3.98 (s, 3H), 5.28 (m, 1H), 5.70 (bs, 2H), 7.15-7.35 (m, 7H), 7.66 (s, 1H), 8.38 (s, 1H), 8.51 (d, J=8.18, 1H). HPLC (Waters Alliance-Column: Waters SymmetryShield, RP18, 3.5 um, 2.1×50 mm. Eluents: 5% B/A to 95% B/A in 9.0 min.(B: acetonitrile, A: 100 mM ammonia acetate buffer, pH 4.5), 0.5 mL/min.): Rt=6.273 min.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12](I)[S:13][C:6]=12.Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=1.C[Sn](C)(C)[Sn](C)(C)C>O1CCOCC1>[F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][N:24]=3)[S:13][C:6]=12
Reactant: O=Cc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 100 °C
Yield: 50.2 %

Procedure:
To a solution of intermediate 24 (6 g, 14.42 mmol) in dioxane (40 mL) were added 6-bromopyridine-3-carbaldehyde (7) (3.22 g, 17.30 mmol), palladium tetrakistriphenylphosphine (0.500 g, 0.433 mmol), and hexamethyldistannane (3.29 mL, 15.86 mmol). The mixture was heated at 100° C. for 20 h, concentrated, adsorbed on silica gel, placed onto a silica gel column and subjected to flash chromatography purification (eluent DCM/MeOH: 100/0, 99/1, 98/2, 97/3), to afford intermediate 25 (2.864 g, 50% yield). MS (m/z): 396.1 (M+H).
Reaction SMILES: C(S[C:5]1[C:10]([F:11])=[CH:9][N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[C:7](=[O:17])[N:6]=1)C=C.[NH3:18]>CO>[NH2:18][C:5]1[C:10]([F:11])=[CH:9][N:8]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[C:7](=[O:17])[N:6]=1
Reactant: N
Reactant: C=CCSc1nc(=O)n(-c2ccsc2)cc1F
Solvent: CO
Product: Nc1nc(=O)n(-c2ccsc2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
This material was prepared by the procedure described in J. Org. Chem. 2006, 71, 9183-9190. 4-(Allylthio)-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (330 mg, 1.23 mmol) was dissolved in a methanol solution of ammonia (7 N, 5 mL). The reaction mixture was stirred overnight at 100° C. in a pressure vessel. After removal of solvent, the residue was purified by preparative thin layer chromatography to give 4-amino-5-fluoro-1-(thiophen-3-yl)pyrimidin-2(1H)-one (177 mg, 68%) as a yellow solid: mp 228-229° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=6.9 Hz, 1H), 7.89 (s, 1H), 7.65 (d, J=1.9 Hz, 2H), 7.56 (dd, J=5.1, 3.3 Hz, 1H), 7.29 (dd, J=5.1, 1.0 Hz, 1H); ESIMS m/z 212 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]3[CH2:14][N:15]([C:31](=[O:33])[CH3:32])[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:12]3=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncc3n2CNc2ccccc2-3)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ncc3n2CN(C(C)=O)c2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-(4-methoxyphenyl)-5,6-dihydroimidazo[1,5-c]quinazoline (100 mg) and diisopropylethylamine (50 ml) in THF (20 ml) is added acetyl chloride (50 ml) and the mixture stirred at RT for 5 hours. The reaction is extracted with ethyl acetate (200 ml), the solvent evaporated, and the residue is purified by preparative-plate chromatography (75% ethyl acetate/hexane) to afford 3-(4-methoxyphenyl)-5,6-dihydro-6-acetylimidazo[1,5-c]-quinazoline (Compound 49) as a light yellow solid. m.p. 80°-82° C.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]([O:19]CC)=[O:18])=[N:12][N:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[N:12][N:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(CSc2nnc(SCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
In 7.8 ml of 90% methanol was dissolved 0.98 g of ethyl [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]acetate obtained in Example 1 with heating at 60° C. Further 6.1 ml of a 1N aqueous sodium hydroxide solution was added to the solution followed by stirring at 60° C. for 30 minutes. A 1N aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with a 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with, in sequence, water, a saturated aqueous sodium chloride solution and water and then, dried over anhydrous magnesium sulfate. The solvent was then distilled off. Recrystallization of the thus obtained solid from isopropyl alcohol gave 0.75 g of [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]-acetic acid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([C:18]([OH:20])=O)=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:22]1([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:27][NH:28][C:18]([C:11]2[C:12]([C:14]([F:15])([F:16])[F:17])=[N:13][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][CH:10]=2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cnc(Nc2ccccc2)nc1C(F)(F)F
Reactant: NCC1CCCC1
Agent: Cl
Product: O=C(NCC1CCCC1)c1cnc(Nc2ccccc2)nc1C(F)(F)F
Yield: 82.9 %

Procedure:
In a manner similar to Reference Example 1 (c), 2-(Phenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (30 mg) and cyclopentylmethylamine hydrochloride (21 mg) afforded the title compound (32 mg) after purification by trituration with diethylether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>O1CCCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[C:14]([B:22]([OH:27])[OH:23])=[CH:13][C:12]([Cl:15])=[N:11][CH:10]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)nc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cnc(Cl)cc1B(O)O
Temperature: -78 °C
Yield: 100.3 %

Procedure:
Tert-butyl[(6-chloropyridin-3-yl)methyl]carbamate (1.00 g, 0.004 mol) was dissolved in anhydrous tetrahydrofuran (20 mL) in an oven-dried 50-mL round-bottomed flask. The solution was stirred under an atmosphere of nitrogen and cooled to at −78° C. Tert-butyllithium (1.7 M in pentane, 5.1 mL, 0.009 mol) was slowly added via syringe. The reaction solution turned yellow, then dark orange during the addition. The resulting solution was stirred at −77° C. for 10 min, then was slowly warmed to −20° C. Triisopropyl borate (3.79 mL, 0.017 mol) was added quickly via syringe and the mixture was allowed to warm to room temperature with stirring. The reaction was cooled to 0° C. and quenched by the slow addition of 1.00 M of hydrochloric acid in water (8.65 mL) with good stirring. The reaction mixture was then added to water (100 mL) in a separatory funnel and was extracted with ethyl acetate (3×75 mL). The extracts were combined, dried over sodium sulfate, filtered, concentrated and dried under vacuum to leave 1.15 g (97% yield) (5-{[(tert-butoxy-carbonyl)amino]methyl}-2-chloropyridin-4yl)boronic acid as an orange foam. The product structure was confirmed by NMR and MS and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22](=O)[CH2:23][CH2:24][C:25]([O:27]C)=O)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.O.[NH2:31][NH2:32]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:22]4[CH2:23][CH2:24][C:25](=[O:27])[NH:31][N:32]=4)[CH:19]=3)[CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NN
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(OC)cc1)C2
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)NC2Cc3ccc(C4=NNC(=O)CC4)cc3C2)cc1

Procedure:
5.0 g (12 mmol) of methyl 4-(2-p-methoxybenzenesulphonamido-indan-5-yl)-4-oxobutyrate and 3.0 g (60 mmol) of 99% hydrazine hydrate in 25 ml of glacial acetic acid are boiled for 30 minutes. The mixture is evaporated, water is added to the residue, and the reaction product is filtered off with suction and recrystallised from n-propanol.
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([C:27]3[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=3)[S:7][C:6]=2[CH:34]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1>C1COCC1>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:2]2[CH:3]=[CH:4][C:5]3[C:9]([C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[CH:16][CH:17]=4)=[O:11])=[C:8]([C:27]4[CH:28]=[CH:29][C:30]([C:43](=[O:44])[NH:42][C:39]5[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=5)=[CH:31][CH:32]=4)[S:7][C:6]=3[CH:34]=2)=[O:44])=[CH:38][CH:37]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(-c2sc3cc(C(=O)Nc4ccc(Cl)cc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.1 %

Procedure:
5.56 g (10.7 mmol) of [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 200 mL of dry THF and 5.45 g (35.2 mmol) of 4-chlorophenyl isocynate was added. The reaction mixture was stirred at room temperature under an atmosphere of nitrogen. After 18 hours, the solvent was removed by evaporation in vacuo, and redissolved in CHCl3. The CHCl3 solution was cooled to -20° C. for 24 hours and the precipitate formed was filtered off. The remaining solution was chromatographed (Waters Prep 500, HPLC) on a silica gel column, eluted with a linear gradient of CHCl3 ending with CHCl3 --MeOH (19:l)(v/v). The desired fractions were determined by TLC, combined and evaporated to dryness to afford 4.01 g of the title compound as a tan amorphous powder.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[CH3:31][C:32]1[CH:41]=[C:40]([OH:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.C[Si](Cl)(C)C.N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[OH:42][C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32](/[CH:31]=[CH:1]/[C:3]2[N:4]=[C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:9][CH:8]=[N:7][N:6]3[C:17]=2[C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])=[CH:20][CH:19]=2)[CH:41]=1
Reactant: Cc1cc(O)c2ccccc2n1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2c(/C=C/c3cc(O)c4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of compound 5f (150 mg, 0.367 mmol) and 2-methylquinolin-4-ol (292 mg, 1.84 mmol) in 4 mL of DMF was added TMSCl (469 μL, 3.67 mmol) dropwise. The resulting mixture was stirred at 90° C. for 16 h. After cooling to rt, the mixture was treated with 60 mL of EtOAc and washed with water (3×20 mL) and brine (15 mL). The solvent was removed in vacuo and the residue was treated with DCM (5 mL). To this mixture was added imidazole (50.0 mg, 0.734 mmol), and the resulting mixture turned clear and was purified by flash column chromatography on silica gel (0:1-1:19 MeOH/DCM) to afford compound 64a as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 11.97 (br. s., 1H), 8.26 (d, J=7.8 Hz, 1H), 7.88-8.03 (m, 3H), 7.43-7.83 (m, 6H), 7.22 (t, J=7.5 Hz, 1H), 6.49 (s, 1H), 6.03 (d, J=5.6 Hz, 1H), 3.94 (br. s., 4H), 3.82 (br. s., 4H), 1.55 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H31N5O4, 550.2 (M+H). found 550.5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: Oc1ccccc1
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2.33 h
Yield: 61.3 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (100 mg), phenol (109 mg), and triphenylphosphine (127 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (82 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 140 min and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate/hexane=1/10) and then with recrystallization from ethyl acetate-hexane to obtain the entitled compound (78 mg).