Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]([O:15][CH3:16])=[O:14].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[N:18]1>CO.N1CCCCC1>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](/[CH:26]=[C:8]2\[O:9][C:5]3[C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:18]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COC(=O)c1c(OC)ccc2c1OCC2=O
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1c(OC)ccc2c1O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A solution of methyl 6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate (0.070 g, 0.32 mmol) in methanol (5.0 mL) was added with 1H-indazole-3-carboxaldehyde (0.046 g, 0.32 mmol). Then, the mixture was added with 7 drops of piperidine, then the mixture was stirred at room temperature for 2 hours, and the solid formed was collected by filtration to obtain the objective substance. Further, the filtrate was concentrated, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (97:3→90:10)) to obtain the objective substance. Two portions of the objective substance was combined to obtain 0.090 g (80%) of methyl (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([NH2:22])=[N:18][NH:19]2)=[CH:15][CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([NH:22][C:5](=[O:6])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[CH:8]=3)=[N:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2cc(Cl)ccc12)c1cc(Cl)cc(Cl)c1
Temperature: 3 °C
Reaction time: 0.17 h

Procedure:
0.83 cm3 of 3,5-dichlorobenzoyl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, after cooling in an ice bath to about 3° C., and the mixture is then stirred for 10 minutes at this temperature and is allowed to return to room temperature over 18 hours. The reaction medium is then concentrated to dryness under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 25 cm3 of ethyl acetate and 25 cm3 of water. The precipitate formed is filtered off and, after drying (90 Pa; 50° C.), 700 mg of N-[6-chloro-1H-indazol-3-yl]-3,5-dichlorobenzamide are obtained in the form of a white solid melting at about 240° C.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[S:9][C:10]([CH3:24])=[CH:11][C:12]=1[C:13](=O)[C:14]([C:16]1[CH:20]=[C:19]([CH3:21])[S:18][C:17]=1[CH3:22])=O.[CH:25]1[CH:30]=CC=[CH:27][CH:26]=1>>[CH3:7][C:8]1[S:9][C:10]([CH3:24])=[CH:11][C:12]=1[C:13]1[CH:30]=[CH:25][CH2:26][CH2:27][C:14]=1[C:16]1[CH:20]=[C:19]([CH3:21])[S:18][C:17]=1[CH3:22]
Reactant: c1ccccc1
Reactant: Cc1cc(C(=O)C(=O)c2cc(C)sc2C)c(C)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1cc(C2=C(c3cc(C)sc3C)CCC=C2)c(C)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
Potassium t-butoxide (163 mg, 1.45 mmol) was added to a suspension of 1,4-butanebis(triphenylphosphonium)dibromide (537 mg, 0.725 mmol) in benzene (50 mL). The reaction was stirred for 45 min at room temperature. The resulting orange solution was heated to reflux and treated drop-wise with a solution of 1,2-bis(2,5-dimethyl-3-thienyl)ethanedione 23 (202 mg, 0.72 mmol) in benzene (25 mL). The reaction mixture was stirred at reflux for 20 min, at which point the heating mantle was removed and the reaction was allowed to cool to room temperature. The reaction was quenched by the addition of water (50 mL) and extracted with Et2O (3×50 mL). The organic extracts were combined, washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography through silica (1:9 EtOAc:hexanes) to yield 55 mg (25%) of 25 as a white solid. Mp=55-57° C. 1H NMR (CDCl3): δ=6.13 (s, 2H), 5.88 (m, 2H), 2.26 (m, 10H), 2.14 (s, 6H); 13C NMR (CDCl3) δ=137.8, 134.4, 133.9, 131.6, 127.4, 126.7, 22.7, 15.1, 14.0. MS (EI): m/z=300 (M+).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2(C)CC2)=CC=1.[Li]CCCC.CN(C=O)C>>[CH3:13][C:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: CC1(c2ccc(Br)cc2)CC1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC1(c2ccc(C=O)cc2)CC1
Yield: 80 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 1-bromo-4-(1-methylcyclopropyl)-benzene (2.10 g, 9.95 mmol), nBuLi (9.33 ml, 1.6M solution in hexane, 14.92 mmol) and DMF (3.87 ml, 49.74 mmol). The isolated residue was purified by flash column chromatography (1:9 ether:pentane) to give 4-(1-methylcyclopropyl)-benzaldehyde (1.28 g, 80%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): 9.96 (s, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.5 Hz, 2H), 1.46 (s, 1H), 0.98-0.93 (m, 2H), 0.90-0.84 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][NH:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1.[Cl:30][CH2:31][C:32](Cl)=[O:33]>>[CH3:29][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([C:6]1[CH:28]=[CH:27][C:9]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:7]=1)[C:32](=[O:33])[CH2:31][Cl:30]
Reactant: O=C(Cl)CCl
Reactant: CN(C)CCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: CN(C)CCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 22, 1-[4-(2-dimethylaminoethylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 54b) is reacted with chloroacetyl chloride, yielding 1-{4-[N-(2-dimethylaminoethyl)-N-chloroacetylamino]benzoyl}-4-[2(4-chlorophenyl)ethyl]piperazine. The hydrochloride thereof melts at 215°-216° (decomposition).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH2:3][NH2:4].Cl.[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28](=[NH:31])OC)[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9].C(OCC)(=O)C>CO>[CH2:8]([N:10]([CH2:32][CH3:33])[CH2:11][CH:12]([N:14]1[C:27]2[CH:26]=[C:25]([C:28]([NH:4][CH2:3][CH:2]([CH3:1])[CH2:5][CH3:6])=[NH:31])[CH:24]=[CH:23][C:22]=2[S:21][C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH3:9]
Reactant: CCC(C)CN
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=N)OC)cc21
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)CNC(=N)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of (2RS)-2-methylbutylamine (3.18 cc) in methanol (5 cc) is added dropwise in the course of 5 minutes to a solution, cooled to 0°-5° C., of methyl 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarboximidate hydrochloride (3.49 g) in methanol (21 cc). The mixture is stirred for 2 hours at 5° C. and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give a residue which is taken up with ethyl acetate (50 cc). The solution is washed with distilled water (50 cc) alkalinized to pH 9 with N sodium hydroxide. The two phases are allowed to settle and the organic phase is separated and washed with half-saturated sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue is purified by chromatography on a column of neutral alumina (height: 23 cm; diameter: 2.1 cm), eluting with mixtures of ethyl acetate and cyclohexane in proportions (by volume) of 20:80 (850 cc) and 10:90 (500 cc), then with pure ethyl acetate (500 cc) and finally with mixtures of ethyl acetate and methanol in proportions (by volume) of 95:5 (500 cc), 90:10 (500 cc) and 80:20 (500 cc and collecting 50-cc fractions. The first litre is discarded and fractions 40 to 56 are then combined, concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-[ (2RS)-2-methylbutyl]-2-phenothiazinecarboxamidine (1.33 g) in the form of a yellow product of meringue-like consistency.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][C@H:10]1[N:31]1[CH:39]=[N:38][C:37]2[C:32]1=[N:33][C:34]([F:41])=[N:35][C:36]=2[NH2:40])C1C=CC=CC=1.C([O-])(O)=O.[Na+].C>C(Cl)Cl.CCO>[C@@H:10]1([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][C:34]([F:41])=[N:35][C:36]=3[NH2:40])[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@@H:9]1[OH:8]
Reactant: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: Nc1nc(F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reaction time: 8 h

Procedure:
BCl3 gas (72.9) was bubbled in CH2Cl2 (610 ml) at 0°in a 2-l., 3-necked flask equipped with a thermometer, magnetic stirrer, and addition funnel and the stirred solution then cooled to -72° (dry ice-acetone) before the dropwise addition (1 hr) of a cold solution of 9-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-2-fluoroadenine (II, 7.0 g, 12.5 mmol) in CH2Cl2 (70 ml). After a total reaction time of 23/4 hr, the cooling bath was removed and the solvent and gas removed in vacuo. The residue was dissolved in CH2Cl2 (40 ml) and the solution evaporated to dryness (six times), or until a solid white residue is obtained, before adding 450 ml of 5% NaHCO3 followed by solid NaHCO3 to adjust the pH to 6-7. The mixture was diluted with EtOH, heated to boiling, treated with charcoal, filtered through Celite, and then allowed to stand at room temperature overnight. It was then chilled and the solid collected by filtration, washed with cold H2O and then ether, and dried in vacuo; yield 3.23 g (91%); mp 259°-260°; homogeneous according to TLC (19:1) and HPLC (23 H2O:2 MeCN); pmr; 3.7 (m, H4' and 2H5'), 4.15 (m, H2' and H3'), 5.1 (t, 5'-OH), 5.55 and 5.65 (2d, 2'-OH and 3'-OH), 6.14 (d, J1'2' 3Hz, H1'), 7.8 (broad s, NH2), 8.2 (s, H8); uv: pH 1--262 (13.2); ph 7, 13--261 (15.3).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O-:5])=[O:4].[Ca+2].O[CH:12](CCSC)C([O-])=O.CO.OS(O)(=O)=O>C(Cl)Cl>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CSCCC(O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(O)CCSC
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Commercial calcium 2-hydroxy-4-(methylthio)butyrate (20 g, 0.12 mol) was suspended in 250 ml CH2Cl2. CH3OH (15 ml, 0.36 mol) was added and the mixture cooled to 10° C., at which point H2SO4 (3.7 ml, 0.07 mol) was added. An obvious physical change in the slurry was noted. The mixture was heated at reflux for 60 minutes, by which time tlc indicated reaction was nearly complete. As a matter of convenience, the reaction mixture was stirred 64 hours at room temperature, at which time insoluble byproducts were removed by filtration. The filtrate was washed with 150 ml each of saturated NaHCO3 and brine, dried (MgSO4) and stripped to yield title product as an oil; tlc Rf 0.8 (ethyl acetate)0.25 (3:1 hexane:ethyl acetate).
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:15]([CH2:16][CH2:17][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:14]([F:37])[C:13]([F:38])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:39]([O:43][C@@H:44]([C:50]1[C:51]([CH3:93])=[N:52][C:53]2[N:54]([N:88]=[C:89]([CH:91]=O)[CH:90]=2)[C:55]=1[N:56]1[CH2:61][CH2:60][C:59]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][C@H:68]([O:70][Si:71]([C:84]([CH3:87])([CH3:86])[CH3:85])([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[CH3:69])([CH3:62])[CH2:58][CH2:57]1)[C:45]([O:47][CH2:48][CH3:49])=[O:46])([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[CH2:2]([O:9][C:10]1[C:15]([CH2:16][CH:17]=[CH:91][C:89]2[CH:90]=[C:53]3[N:52]=[C:51]([CH3:93])[C:50]([C@H:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:55]([N:56]4[CH2:61][CH2:60][C:59]([O:63][CH2:64][CH2:65][CH2:66][CH2:67][C@H:68]([O:70][Si:71]([C:84]([CH3:85])([CH3:86])[CH3:87])([C:72]5[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=5)[C:78]5[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=5)[CH3:69])([CH3:62])[CH2:58][CH2:57]4)[N:54]3[N:88]=2)=[C:14]([F:37])[C:13]([F:38])=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=O)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Reactant: Fc1ccc(OCc2ccccc2)c(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(C=CCc3c(OCc4ccccc4)ccc(F)c3F)nn2c1N1CCC(C)(OCCCC[C@@H](C)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 50.2 %

Procedure:
To a suspension of (6-(benzyloxy)-2,3-difluorophenethyl)triphenylphosphonium, iodide salt (217 mg, 0.340 mmol) in THF (5 ml) at 0° C. was added n-Buli (0.213 ml, 0.340 mmol) and the resulting mixture was heated at 60° C. for 1 h. The mixture was then cooled to rt and (S)-ethyl 2-(tert-butoxy)-2-(7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-2-formyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (175 mg, 0.227 mmol) dissolved in THF (5 ml) was added dropwise and the mixture was stirred rt for 5 h. The reaction was quenched with water and the product was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage; 0%-30% EtOAc/hexane) to afford (S)-ethyl 2-(2-(3-(6-(benzyloxy)-2,3-difluorophenyl)prop-1-en-1-yl)-7-(4-(((R)-5-((tert-butyldiphenylsilyl)oxy)hexyl)oxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (114 mg, 0.114 mmol, 50% yield) as mixture of E and Z isomers. LCMS (M+H)=1001.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15].[C:16]1([CH:23]=CC(O)=[CH:19][CH:18]=1)O.C=CC=C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:19][CH:18]=[CH:16][CH2:23][C@H:10]2[N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[O:14][CH3:15]
Reactant: Oc1ccc(O)cc1
Reactant: COc1ccc(/C=C/[N+](=O)[O-])cc1OC
Agent: C=CC=C
Solvent: Cc1ccccc1
Product: COc1ccc([C@@H]2CC=CC[C@H]2[N+](=O)[O-])cc1OC
Temperature: 160 °C
Reaction time: 144 h

Procedure:
50.0 g of 3,4-dimethoxy-ω-nitrostyrene (compound G2), and 1.0 g (9.1 mmol) of hydroquinone are suspended in 200 ml of abs. Toluene and treated at −70° C. with 55.0 g (1.02 mol) of liquid 1,3-butadiene. The mixture is stirred at 160° C. for 6 days in an autoclave and then cooled. Some of the solvent is removed on a rotary evaporator, and the resulting precipitate is filtered off with suction and recrystallized in ethanol. M.p.: 113.5-115.5° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:11]1[C:24]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[C:35](F)=[N:36][CH:37]=[CH:38][CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]=2[CH:14]=[CH:13][CH:12]=1.C1OCCOCCOCCOCCOCCOC1>O1CCCC1>[CH:21]1[C:22]2[C:23]3([CH2:26][N:27]4[CH2:32][CH2:31][C:30]([C:34]5[C:35]([N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[N:36][CH:37]=[CH:38][CH:39]=5)([OH:33])[CH2:29][CH2:28]4)[CH2:25][CH:16]([C:15]4[C:24]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: OC1(c2cccnc2F)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: C1CCNC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccnc2N2CCCC2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled solution (0° C.) of pyrrolidine (0.417 mL, 5.00 mmol, 5 eq) in tetrahydrofuran (10 mL) under nitrogen was added n-butyllithium (2.5M in hexane, 1.92 mL, 4.80 mmol, 4.8 eq). This was followed by 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)-piperidin-4-ol (described in example 58) (0.400 g, 1.00 mmol) in tetrahydrofuran (10 mL). The bath was removed and the solution warmed to room temperature over 1.5 h. No reaction was evident after stirring for 18 h. To accelerate the reaction, 18-crown-6 (0.528 g, 2.00 mmol, 2.0 eq) was added and the solution was heated to 60° C. for 5 h. The reaction was quenched with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (35 mL, eluent: 50% ethyl acetate in hexane) to yield 0.450 g (quantitative) of the title compound. TLC analysis (Rf 0.23, 50% ethyl acetate in hexane). 1H NMR (CDCl3, 300 MHz) 8.35 (dd, J=1.7, 4.6 Hz, 1H), 7.63 (dd, J=1.8, 7.9 Hz, 1H), 7.22 (m, 4H), 7.12 (dd, J=7.9, 4.6 Hz, 1H), 6.93 (m, 4H), 4.27 (br s, 1H), 3.48 (s, 2H), 3.21 (m, 4H), 2.85 (m, 2H), 2.76 (m, 2H), 2.63 (d, J=1.3 Hz, 2H), 2.01 (m, 6H), 1.70 (m, 2H) MS (CI, CH4) m/z 452 (M+1,100), 480 (M+29,12), 434 (16). The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (60° C., 16 pascal, 18 h) to yield a white solid, mp 249°-253° C.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[CH:13]([CH2:12][C:11]2[CH:20]=[CH:21][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:3][CH2:4]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp >150° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.10 (m, 2H), 2.55-3.60 (m, 7H), 2.93 (s, 3H), 3.67 (brd, J=12.8 Hz, 2H), 4.56 (dd, J=9.6, 4.0 Hz, 1H), 4.64 (brd, J=6.5 Hz, 1H), 6.70-6.95 (m, 3H), 6.95-7.15 (m, 3H), 7.22 (d, J=2.1 Hz, 1H); MS (ES) m/z: 535.0 (MH+); HRMS Calcd. for C24H31N4O6S2 (MH+): 535.1685. Found: 535.1720.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)[C:11](=[O:12])[O:10]2)=[CH:5][CH:4]=1.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1.[OH-].[K+].Cl>O>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:30]=[CH:29][C:28]=1[CH:9]([C:18]1[CH:17]=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[CH:14][C:13]=1[C:11]([OH:10])=[O:12])[C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:22])[CH3:1])=[CH:4][CH:5]=1
Reactant: CN(C)c1ccc(C2OC(=O)c3cc(N(C)C)ccc32)cc1
Reactant: CN(C)c1cccc(N(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CN(C)c1ccc(C(c2ccc(N(C)C)cc2C(=O)O)c2ccc(N(C)C)cc2N(C)C)cc1
Temperature: 25 °C

Procedure:
A mixture of 6.0 g of 3-(4-dimethylaminophenyl)-6-dimethylaminophthalide prepared as described in part A above, 100 ml of water, 3.5 g of N,N,N',N'-tetramethyl-m-phenylenediamine and 1.8 g of flake potassium hydroxide was heated at reflux with stirring for a period of approximately eighteen hours and then allowed to cool to room temperature. The resultant solution was made slightly acidic by the addition of ten percent aqueous hydrochloric acid causing a cream-colored solid to precipitate. The solid was collected by filtration, washed with water and air dried at 40° C. to obtain 2-[2,4,4'-tris(dimethylamino)benzhydryl]-5-dimethylaminobenzoic acid (Formula III: R=CH3 ; X=H; Y=4-(CH3)2NC6H4 ; Z=2,4-[(CH3)2N]2C6H3) as a slightly sticky, cream-colored solid melting over the range 119°-121° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]2[CH2:12][N:13]([CH:16]([C:18]3[CH:19]=[N:20][C:21]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[C:22]([CH3:24])[CH:23]=3)[CH3:17])[C:14](=[O:15])[C:10]=2[CH:9]=[CH:8][N:7]=1)=[O:4].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CN(C=O)C>[CH3:24][C:22]1[CH:23]=[C:18]([CH:16]([N:13]2[C:14](=[O:15])[C:10]3[CH:9]=[CH:8][N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[C:11]=3[CH2:12]2)[CH3:17])[CH:19]=[N:20][C:21]=1[O:25][CH2:26][C:27]([F:28])([F:30])[F:29]
Reactant: C1COCCN1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CCl)C2=O)cnc1OCC(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CN3CCOCC3)C2=O)cnc1OCC(F)(F)F
Temperature: 60 °C
Yield: 38.4 %

Procedure:
A mixture of 2-chloro-N-(2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-1-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)acetamide (25 mg, 0.056 mmol, Step-1, single enantiomer), and morpholine (15 mg, 0.17 mmol) in DMF (1.0 mL) is heated at 60° C. for 3 hours. The reaction mixture is concentrated. The residue is purified by preparative LC-MS to give 10.6 mg (38% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:27])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Br)ccc3n2)ccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ccc3n2)ccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 16 h
Yield: 27.9 %

Procedure:
An 8 mL vial is charged with N-[5-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.044 g, 0.11 mol), (2-fluorophenyl)boronic acid (Combi-Blocks, 28 mg, 0.2 mmol), Na2CO3 (0.032 g, 0.3 mmol), bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) and isopropanol-water (1 mL, 3:1). The reaction mixture is stirred at 80° C. for 16 hr, then cooled, concentrated, taken into EtOAc and CH2Cl2 (1:1), filtered, concentrated onto celite and purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (25.4 mg, 55% yield). LCMS m/z=456.5 [M+H]+, tR=2.69 min. (compound same as Example 83)