Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[H-].[Na+].[CH3:26][O:27][C:28]1[CH:53]=[CH:52][C:31]([CH2:32][NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:40]=3)[CH:35]=2)=[CH:30][CH:29]=1>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH:40]=3)[CH:35]=2)[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][C:7]([O:6][CH3:5])=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH:9]=2)=[CH:52][CH:53]=1
Reactant: COc1cccc(-c2cc(C(=O)O)ccc2OC)c1
Reactant: COc1ccc(CNc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Thionyl chloride (308 μl, 502 mg, 4.22 mmol) was added to 4-methoxy-3-(3-methoxyphenyl)-benzoic acid (365 mg, 1.41 mmol) in anhydrous THF (4.75 mL) at room temperature, and the resulting solution was heated at reflux for 4.5 hours. The solvent was removed and the resulting acid chloride was used without further purification. Sodium hydride (85 mg, 2.12 mmol) was added to 37 (378 mg, 1.02 mmol) in anhydrous THF (7.50 mL). After stirring for two hours at room temperature, a solution of the freshly-prepared acid chloride (1.41 mmol) in anhydrous THF (2.40 mL) was added and the reaction was heated to reflux for 18 hours. The reaction was cooled, partitioned between saturated aqueous NaHCO3 (50 mL) and CH2Cl2 (50 mL), then extracted with CH2Cl2 (3×100 mL). Combined organic extracts were washed with saturated aqueous NaCl solution (200 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 4:1:1 Hexanes:EtOAc:CH2Cl2) to give 38 as a brown-yellow amorphous solid (515 mg, 83%): 1H NMR (CDCl3, 500 MHz) δ 7.58 (d, J=9.0 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.50-7.45 (m, 3H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 2H), 7.29 (d, J=2.2 Hz, 1H), 7.25 (m, 2H), 7.21 (dd, J=8.9, 2.6 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.09 (m, 1H), 7.01 (dd, J=8.7, 2.1 Hz, 1H), 6.80 (m, 2H), 6.77 (ddd, J=8.2, 2.7, 0.9 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.59-6.56 (m, 2H), 5.16 (s, 2H), 5.14 (s, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.62 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.0, 159.3, 159.0, 157.6, 157.3, 139.9, 139.1, 136.8, 133.0, 132.4, 130.5, 130.1, 130.1 (2C), 129.6, 129.5, 129.1, 128.9, 128.9 (2C), 128.4, 128.2, 127.9, 127.7 (2C), 127.3, 125.8, 122.1, 120.0, 114.7, 114.0 (2C), 113.2, 110.4, 107.1, 70.3, 55.7, 55.4, 55.2, 53.9; IR (film) νmax 3059, 3032, 2999, 2934, 2835, 1636, 1601, 1506, 1456, 1389, 1248, 1209, 1026, 854, 818, 735, 698 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C40H35NO5, 610.2593; found, 610.2567.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18](=[O:21])[CH2:19][CH3:20])([CH3:16])([CH3:15])[CH3:14].C(O[C:25]([C:27]1[C:32]([F:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1)=[O:26])C>CCCCCC.O1CCCC1.COC(C)(C)C.C(O)(=O)C.O>[C:13]([O:17][C:18](=[O:21])[CH:19]([CH3:20])[C:25]([C:27]1[C:32]([F:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1)=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ncc(Cl)cc1F
Reactant: CCC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CCCCCC
Product: CC(C(=O)OC(C)(C)C)C(=O)c1ncc(Cl)cc1F
Reaction time: 0.75 h

Procedure:
32.3 g of diisopropylamine are introduced into 200 ml of tetrahydrofuran and, with cooling with a CO2/acetone cooling bath, 200 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise. 49.2 ml of propionic acid tert-butyl ester are then added dropwise at approximately −75° C. and the mixture is stirred at that temperature for 45 minutes. At approximately −75° C. a solution of 32.6 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid ethyl ester (Example P1) in 40 ml of tetrahydrofuran (THF) is then added dropwise and the mixture is stirred at that temperature for 1 hour, after which it is diluted with 250 ml of tert-butyl methyl ether. A mixture of 100 ml of water and 200 ml of glacial acetic acid is added, the phases are separated, the aqueous phase is extracted again, and the combined organic phases are washed with water. After drying over magnesium sulfate, filtration and concentration to dryness in vacuo are carried out. 51 g of the desired compound are obtained in the form of an oil (crude product).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(C1C=C[NH+]=CC=1)C1C=CC=CC=1.C(C1C=C[NH+]=CC=1)C1C=CC=CC=1.[C:36]1([C:42]2[CH:49]=[CH:48][C:45]([CH2:46][OH:47])=[CH:44][CH:43]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(OCC)C.CCCCCC>ClCCl>[C:36]1([C:42]2[CH:43]=[CH:44][C:45]([CH:46]=[O:47])=[CH:48][CH:49]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1ccc(Cc2cc[nH+]cc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
65 mmol of 4-benzylpyridinium dichromate are added to 54 mmol of 4-phenylbenzyl alcohol in 400 ml of dichloromethane. The reaction mixture is stirred for 2 hours at room temperature. 600 ml of a mixture of ethyl ether and hexane in a ratio of 1 to 1 are added. After stirring for 30 minutes, the mixture is filtered. The filtrate is washed once with 100 ml of a 1N hydrochloric acid solution. The organic phase is dried over magnesium sulphate and then concentrated to yield the expected compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[S:23](Cl)(=[O:25])=[O:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:23]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=2)(=[O:25])=[O:24])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=S(=O)(c1ccc2ccccc2c1)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, off-white solid, m.p. 166° C. and MS: m/e=355 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and naphthalene-2-sulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(OCC)C.O>O1CCCC1>[CH3:1][C:2]1[C:10]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1c(C(=O)O)cccc1-n1cccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1c(CO)cccc1-n1cccc1
Yield: 98.2 %

Procedure:
To a stirred solution of 7.5 grams (0.037 mole) of 2-methyl-3-(pyrrol-1-yl)benzoic acid in 125 ml of tetrahydrofuran was added dropwise 4.8 grams (0.056 mole) of a borane-tetrahydrofuran complex. The addition required 30 minutes. Upon complete addition the reaction mixture was heated under reflux for 2.5 hours then cooled slowly. To the cooled reaction mixture was carefully added 150 ml of diethyl ether previously saturated with water, followed by 50 ml of water. The mixture was poured into a separatory funnel and washed with 100 ml of aqueous 2 N sodium hydroxide. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 6.8 grams of 2-methyl-3-(pyrrol-1-yl)phenylmethanol as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:8]([CH3:9])=[CH:7][S:6][C:5]=1[C:10]1([C:15]2[N:16]([CH3:21])[C:17](=[S:20])[NH:18][N:19]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][S:20][C:17]1[N:16]([CH3:21])[C:15]([C:10]2([C:5]3[S:6][CH:7]=[C:8]([CH3:9])[C:4]=3[Cl:3])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:19][N:18]=1
Reactant: Clc1ccccc1CBr
Reactant: Cc1csc(C2(c3n[nH]c(=S)n3C)CCCC2)c1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1csc(C2(c3nnc(SCc4ccccc4Cl)n3C)CCCC2)c1Cl
Reaction time: 0.08 h

Procedure:
Sodium hydride (55%, 24 mg) was added to a THF (10 ml) solution of 5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-2,4-dihydro-3H-1,2,4-triazol-3-thione (154 mg) at 0° C. and the whole was stirred for 5 minutes. Then, 2-chlorobenzyl bromide (0.07 ml) was added thereto, followed by stirring at 0° C. for 3 hours. The reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution and then the organic layer was separated. Furthermore, the organic layer washed with brine, dried over anhydrous sodium sulfate, and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by column chromatography (hexane:ethyl acetate=1:1) to obtain 200 mg of 3-[(2-chlorobenzyl)thio]-5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-4H-1,2,4-triazole (pale yellow foam). It was converted into an ethyl acetate (5 ml) solution and 4M hydrogen chloride-ethyl acetate (0.23 ml) was added, followed by removal of the solvent by evaporation under reduced pressure. The resulting solid washed with ether to obtain 185 mg of 3-[(2-chlorobenzyl)thio]-5-[1-(3-chloro-4-methyl-2-thienyl)cyclopentyl]-4-methyl-4H-1,2,4-triazole hydrochloride (colorless solid).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12](=[N:14]O)[NH2:13]>C(Cl)Cl.O>[Cl:10][CH2:11][C:12]1[N:14]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][N:13]=1
Reactant: NC(CCl)=NO
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: ClCc1noc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
Benzoyl chloride (1.60 ml, 13.8 mmol) was added to a suspension of 2-chloro-N′-hydroxyacetimidamide (1.0 g, 9.21 mmol) in DCM (25 ml), with stirring at room temperature. After 30 minutes, TEA (1.41 ml, 10.1 mmol) was added to the white suspension and the mixture was stirred for 30 additional minutes (UPLC-MS: complete conversion). The solution was diluted with DCM (20 ml) and water (30 ml) was added. The aqueous phase was extracted three times with DCM (15 ml×3) and then the combined organic phases were dried (Na2SO4) and evaporated. The crude was suspended in toluene (25 ml) and the mixture was heated to reflux for 6 h (UPLC-MS: complete conversion). The solvent was evaporated and the crude was purified by flash chromatography (petroleum ether/EtOAc=95/5) to obtain 3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (803 mg, 44.8% yield) as an off-white solid.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:24]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C.O1CCOCC1>[C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[CH2:20][CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:24])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)[C@@H]1CCC(=O)O1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1COCCO1
Product: COc1ccc(C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CCC(=O)O2)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A suspension of 4.00 g (12.44 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-hydroxyphenyl)ethyl]dihydrofuran-2-(3H)-one (Example 11f)) in 240 ml of DMF/dioxane, 1:1, is reacted, under an N2 atmosphere, with 8.1 g (24.88 mmol) of Cs2CO3 and 0.77 ml (12.44 mmol) of methyl iodide. After 18 h, the reaction mixture is poured onto 190 ml of ice-water, and this mixture is extracted 3× with methylene chloride. The organic phases are washed with water and saline, dried with Na2SO4 and evaporated. Stirring with hexane in an ultrasonication bath affords the title compound: TLC Rf (C)=0.43; tRet (II)=13.5 min; FAB-MS (M+H)+ =336.
Reaction SMILES: [CH:1]1([N:4]([C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][CH:24]=3)[CH:13]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>ClCCl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[CH:1]1([NH:4][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[O:22])=[C:16]3[N:15]=[C:14]([C:23]3[CH:27]=[C:26]([CH2:28][OH:29])[S:25][CH:24]=3)[CH:13]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(c1cc(-c2csc(CO)c2)nc2c(C=O)cnn12)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CO)c3)nc12
Reaction time: 1 h
Yield: 23 %

Procedure:
Tert-butyl cyclopropyl(3-formyl-5-(5-(hydroxymethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-7-yl)carbamate (20 mg, 0.05 mmol) was dissolved in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL). After 1 h, the solution was concentrated under a stream of air. The residue was purified via preparative HPLC to furnish 7-(cyclopropylamino)-5-(5-(hydroxymethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 2,2,2-trifluoroacetate (4.8 mg, 23%).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1>>[CH3:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:17])=[CH:8][C:9]=3[F:16])=[O:13])[CH2:27][CH2:26]2)=[CH:23][CH:22]=[C:21]([CH3:31])[N:20]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)n1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)c(C)n1
Yield: 36 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (291 mg) described in Preparation Example 23 and 1-(2,6-dimethylpyridin-3-yl)piperazine (215 mg) described in Preparation Example 94 and by the reaction and treatment in the same manner as in Example 87, the title compound (175 mg) was obtained.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[O:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Mg]Br>C(OCC)C>[CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CCOCC
Product: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.17 h

Procedure:
1-Benzhydryl-azetidin-3-one (335 mg) in diethyl ether (6.0 mL) was treated with 3.0 M methylmagnesium bromide in diethyl ether (0.52 mL) at 0° C., stirred for 10 minutes and quenched with saturated aqueous sodium bicarbonate. The solution was then extracted with methylene chloride (×3), and the combined organics were dried over magnesium sulfate, and concentrated to provide 363 mg of the title compound as a clear, colorless oil. 1H NMR (CDCl3, 300 MHz) δ ppm 1.53 (s, 3H), 1.96 (s, 1H), 1.96 (d, 2H, J=8.42 Hz), 3.19 (d, 2H, J=8.42 Hz), 4.34 (s, 1H), 7.17 (m, 2H), 7.26 (m, 2H), 7.31 (m, 2H), 7.40 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2Cl)n1Cc1ccc(F)cc1
Temperature: 80 °C
Yield: 51.1 %

Procedure:
A mixture of (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 43; 150 mg, 0.47 mmol), tetrabutylammonium iodide (174 mg, 0.47 mmol) and 4-fluorobenzyl bromide (230 μL, 1.85 mmol) in dimethylformamide (3 mL) was heated at 80° C. overnight. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 50-60% ethyl acetate/petroleum ether, and dried under high vacuum for 2 days to give (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-1-(4-fluoro-benzyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (103 mg, 51%) as a light brown solid. APCI(+)-MS (M+H) 429.
Reaction SMILES: C(C1C=CC(N)=CC=1)#C.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.Cl[C:25]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([N:37]1[CH:41]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:39]=[N:38]1)[NH:31][C:30]2=[O:47])=[CH2:26]>>[C:25]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[C:32]([N:37]1[CH:41]=[C:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:39]=[N:38]1)[NH:31][C:30]2=[O:47])#[CH:26]
Reactant: C=C(Cl)c1ccc2nc(-n3cc(C(=O)OCC)cn3)[nH]c(=O)c2c1
Agent: C#Cc1ccc(N)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Product: C#Cc1ccc2nc(-n3cc(C(=O)OCC)cn3)[nH]c(=O)c2c1

Procedure:
The titled compound was prepared in a manner analogous to Example 27, steps C-D, using 4-ethynylaniline in step C, and with the addition of 4.0 equivalents of 2,6-di-tert-butylpyridine in step D. The crude product contained a 2.4:1 mixture of the titled product and 1-[6-(1-chloro-vinyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, ethyl ester. A portion of this mixture was purified by HPLC to afford 1-(6-ethynyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid, ethyl ester. MS (ESI): mass calcd. for C16H12N4O3, 308.1; m/z found, 309.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 12.98 (br s, 1H), 8.95 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.82 (dd, J=8.4, 1.9 Hz, 1H), 7.72-7.54 (m, 1H), 4.31 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][C@@H:14]([CH3:16])[CH2:13][C@H:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)[N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[CH:64]=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[C:62](Br)=[CH:61][C:60]=3[Cl:71])=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:51]2[CH:56]=[CH:55][C:54]([C:57](=[O:72])[NH:58][C:59]3[C:60]([Cl:71])=[CH:61][C:62]([C:25]4[CH:26]=[CH:27][C:22]([C:20]5[N:21]=[C:17]([C@@H:12]6[CH2:13][C@H:14]([CH3:16])[CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:37])[CH:6]([CH3:8])[CH3:7])[NH:18][CH:19]=5)=[CH:23][CH:24]=4)=[C:63]([O:65][C:66]([F:69])([F:68])[F:67])[CH:64]=3)=[CH:53][N:52]=2)[C@H:47]([CH3:73])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(=O)Nc2cc(OC(F)(F)F)c(Br)cc2Cl)cn1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1nc(-c2ccc(-c3cc(Cl)c(NC(=O)c4ccc(N5CCN(C(=O)OC(C)(C)C)C[C@H]5C)nc4)cc3OC(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 100 °C

Procedure:
To a solution of [(S)-2-methyl-1-((2S,4S)-4-methyl-2-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (155 mg, 0.30 mmol) and (R)-4-[5-(4-bromo-2-chloro-5-trifluoromethoxy-phenylcarbamoyl)-pyridin-2-yl]-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.30 mmol, Preparation 1) dissolved in toluene (1.9 mL) and water (0.33 mL) was added potassium carbonate (210 mg, 1.52 mmol). The reaction mixture was sparged under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.036 mmol) was added and the reaction mixture was sparged with nitrogen and heated at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to produce the title intermediate as a brownish solid. (m/z): [M+H]+ calcd for C44H52ClF3N8O, 897.36. found 897.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.C(#N)C.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>O.ClCCl>[C:14]1([S:20][C:2]2[C:7]([F:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1ncnc(Cl)c1F
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCc1ncnc(Sc2ccccc2)c1F
Temperature: 25 °C
Yield: 95 %

Procedure:
40 g of 4-chloro-6-ethyl-5-fluoropyrimidine was added to 400 ml of acetonitrile, and 28 ml of thiophenol was added thereto, followed by lowering the temperature to 10° C. 43.39 ml of diisopropylethylamine was added to the resulting solution, and reacted for 2 hours while maintaining the temperature at room temperature. 65 ml of dichloromethane and 200 ml of water were added to the resulting mixture to separate layer, and the resulting aqueous mixture was extracted with 200 ml of dichloromethane. The organic layer was dried over magnesium sulfate and concentrated under a reduced pressure to obtain the title compound as an oil (63.6 g, yield: 95%).
Reaction SMILES: C([N:4]1[C@H:13]([CH2:14][N:15]2[C:19]([CH2:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)=[CH:18][N:17]=[CH:16]2)[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl>[CH2:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:12][C@@H:13]([CH2:14][N:15]2[C:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=3)=[CH:18][N:17]=[CH:16]2)[NH:4]1
Reactant: C=CCN1Cc2ccccc2C[C@H]1Cn1cncc1Cc1ccc(C#N)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: N#Cc1ccc(Cc2cncn2C[C@@H]2Cc3ccccc3CN2)cc1
Temperature: 35 °C

Procedure:
A solution of 4-{3-[2-(allyl)-(S)-1,2,3,4-tetrahydro-isoquinolin-3-yl-methyl]-3H-imidazol-4-yl-methyl}-benzonitrile (0.56 g, 1.52 mmol) in 7 ml degassed methylene chloride was added to palladium tetrakistriphenylphosphine (0.045 g, 0.04 mmol) and 1,3-dimethylbarbituric acid (0.712 g, 4.56 mmol) under argon atmosphere. The resulting solution was heated at 35° C. for 3 hr. The mixture was partitioned with methylene chloride, saturated sodium carbonate and water. The methylene chloride layer was dried with saturated sodium chloride and magnesium sulfate. The methylene chloride was removed in vacuo to obtain the title compound as an oil which was used in the next step without further purification.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][C:3]=1C.[Na+:13].[C:14]1(=O)NC(=O)C2=CC=CC=C12>>[C:4]1([CH3:14])[C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:6][CH:7]=[CH:2][CH:3]=1.[Na+:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1C
Agent: [Na+]
Product: Cc1ccccc1S(=O)(=O)[O-]

Procedure:
The procedure of Example 2 was repeated using 30.6 grams Naxonate ST, a commercially available sodium toluene sulfonate from Ruetgers-Naese (0.15 mol sodium toluene sulfonate with a content of 93%) instead of phthalimide to yield a product in which toluene sulfonic acid methyl 6,13-dihydro quinacridone having a molecular weight of 500 was detected by MALDI.