Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@H:9]([OH:11])[CH3:10])(C)(C)C.[H-].[Na+].Br[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45]>>[CH2:12]([C@H:8]1[C@H:9]([CH3:10])[O:11][C:6](=[O:19])[N:7]1[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@@H](C)[C@@H]1Cc1ccccc1

Procedure:
tert-butyl[(1S,2R)-1-benzyl-2-hydroxypropyl]carbamate (Step B, 39 mg, 0.148 mmol) was treated with sodium hydride (60% in oil, 12 mg, 0.309 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 50 mg, 0.123 mmol) as described in Example 305 to afford (4S,5S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one as a clear glass. LCMS=516.4 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.68 (d, J=11.5 Hz, 1 H), 7.66-7.63 (m, 1 H), 7.39-7.36 (m, 1 H), 7.28-7.23 (m, 3 H), 7.07 (d, J=8.5 Hz, 1 H), 6.94 (d, J=6.9 Hz, 2 H), 6.73 (d, J=4.8 Hz, 1 H), 4.81 (d, J=16 Hz, 1 H) 4.38 (d, J=16.1 Hz, 1 H), 4.28-4.23 (m, 1 H), 3.78 (s, 3 H), 3.29-3.17 (m, 2 H), 2.81 (dd, J=13.3, 3.9 Hz, 1H), 2.38-2.28 (m, 1 H), 1.29-1.13 (m, 6 H), 0.98 (d, J=6.2 Hz, 3 H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[C:24]([C:28]2[NH:32][N:31]=[N:30][N:29]=2)[CH:25]=[CH:26][CH:27]=1>>[NH:32]1[C:28]([C:24]2[CH:23]=[C:22]([NH:21][S:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:19])[F:1])=[CH:4][CH:5]=4)[CH:10]=3)(=[O:17])=[O:16])[CH:27]=[CH:26][CH:25]=2)=[N:29][N:30]=[N:31]1
Reactant: O=S(=O)(Cl)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 64.2 %

Procedure:
The product was synthesized according to General Procedure 1, described in Example 1, starting with {3-[4-(trifluoromethyl)phenyl]phenyl}sulfonyl chloride (17.6 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8 mg, 0.05 mmol) yielding 14.3 mg (64%) of the title compound. MS (ESI+) calcd for C20H14F3N5O2S 445.082030, found 445.081660.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:4]=2[C:5]2[NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[C:19](O)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[CH3:18][N:15]1[CH2:16][CH2:17][C:3]2[C:2]([NH:1][C:19](=[O:21])[CH3:20])=[CH:11][C:10]3[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6][C:5]=3[C:4]=2[CH2:14]1
Reactant: CC(=O)O
Reactant: CN1CCc2c(N)cc3[nH]c(=O)c(=O)[nH]c3c2C1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2[nH]c(=O)c(=O)[nH]c2c2c1CCN(C)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product from Example 79 (0.27 g, 1.1 mmol) in 25 mL acetic acid and 10 mL acetic anhydride was stirred at room temperature for 18 hours. After removing the solvent, the residue was washed with ether, dissolved in water and then basified with saturated sodium bicarbonate. The flask was cooled in the freezer for 2 hours and the precipitate collected by filtration, washed consecutively with water and ether, and dried over P2O5 in vacuo to give the title compound (0.2 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[F:5][C:6]([F:20])([F:19])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1.C(OCC)C>O1CCCC1>[CH:16]1([C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:7][C:6]([F:19])([F:20])[F:5])=[CH:13][CH:12]=2)([OH:15])[CH:1]=[CH2:2])[CH2:18][CH2:17]1
Reactant: C=C[Mg]Br
Reactant: O=C(c1ccc(OC(F)(F)F)cc1)C1CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)(c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 550 ml (0.55 mole) of 1M vinylmagnesium bromide in tetrahydrofuran was cooled to 10°-15° C., and a solution of 115.0 grams (0.5 mole) of cyclopropyl 4-trifluoromethoxyphenyl ketone in 100 ml of tetrahydrofuran was added dropwise during a 30 minute period. Upon completion of addition the reaction mixture temperature was maintained at less than 20° C. where it was stirred for one hour. The reaction mixture was poured into a mixture of 2000 ml of pH5 buffer in 1000 ml of ice. To this was added 1000 ml of diethyl ether. The mixture was stirred until the ice melted. The aqueous layer was separated and was washed with two 500 ml portions of diethyl ether. The ether washes were combined with the original organic layer, and the combination was washed in turn with two 500 ml portions of the pH5 buffer solution, two 500 ml portions of water, and one 300 ml portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with ground sodium carbonate and filtered. The filtrate was concentrated under reduced pressure yielding 130.0 grams of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-2-propen-1-ol.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:42]=1)[C:37](O)=[O:38])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][N:44]2[CH2:45][CH2:46][CH2:47][CH2:48]2)[CH:42]=1)[C:37]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:38])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1cc(CN2CCCC2)cc(C(=O)O)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(CN3CCCC3)cc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
35 mg (0.12 mmol) of the compound of Example 6A and 47 mg (0.12 mmol) of the compound of Example 22A were reacted and worked up analogously to the procedure of Example 16. This gave 55 mg (95% pure, 81% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH:25][CH:26]1[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]1)[N:10]=[CH:9][N:8]=2
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 93.4 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (151 mg, 0.403 mmol, 1 eq.) in 4 mL of ethanol was added tert-butyl 4-aminopiperidine-1-carboxylate (96 mg, 0.483 mmol, 1.2 eq.) and triethylamine (0.08 mL, 0.6 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 203 mg (94%) of tert-butyl 4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38-1.55 (m, 11 H) 2.14 (d, J=12.34 Hz, 2 H) 2.98 (t, J=12.10 Hz, 2 H) 4.00-4.21 (m, 2 H) 4.28-4.52 (m, 1 H) 5.83 (d, J=7.63 Hz, 1 H) 7.17-7.27 (m, 2 H) 7.31-7.44 (m, 5 H) 7.50 (d, J=6.88 Hz, 1 H) 8.44 (s, 1 H), [M+H]+ 539.4.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][NH:27][CH3:28])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[CH3:39][CH2:40][O:41][C:42](Cl)=[O:43]>CN(C=O)C>[NH2:31][C:29]([C:16]1[CH:17]=[C:18]([C:21]2[CH:25]=[C:24]([CH2:26][N:27]([CH3:28])[C:42](=[O:43])[O:41][CH2:40][CH3:39])[S:23][CH:22]=2)[CH:19]=[C:20]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:9]1[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:30]
Reactant: CCOC(=O)Cl
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNC)c4)cc23)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 53.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMF (1.0 mL) at 0° C. was added triethylamine (0.06 mL, 0.44 mmol), and ethyl chloridocarbonate (0.021 mL, 0.22 mmol). The resultant mixture was reacted for 30 min followed by purification on Gilson Preparatory HLPC to afford 31.4 mg of the title compound (53.5%).
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([CH2:11][OH:12])[CH2:6]1)=[O:4].O[NH:14][C:15](=[NH:22])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[N:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:22]=[C:3]([C@@H:5]3[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][OH:12])[CH2:6]3)[O:4][N:14]=2)=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccncc1
Reactant: COC(=O)[C@H]1CCC[C@@H](CO)C1
Product: OC[C@H]1CCC[C@@H](c2nc(-c3ccncc3)no2)C1

Procedure:
cis-Methyl-3-hydroxymethylcyclohexane-1-carboxylate was reacted with N-hydroxy-isonicotinamidine, using the reaction conditions described in Preparation 5, to afford cis-[3-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexyl]methanol: RT=2.70 min, m/z (ES+)=246.1 [M+H]+. This was subsequently alkylated with 1-bromobutane, under similar conditions to those described in Example 106, to afford the title compound: RT=4.11 min, m/z (ES+)=316.3 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([F:18])=[C:10]([CH:17]=1)[NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])(=[O:4])=[O:3].[Cl:19]Cl>C(O)(=O)C.O>[Cl:19][C:7]1[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:17][C:10]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])=[C:9]([F:18])[CH:8]=1
Reactant: ClCl
Reactant: CCOC(=O)Nc1cc(NS(C)(=O)=O)ccc1F
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Nc1cc(NS(C)(=O)=O)c(Cl)cc1F
Yield: 90 %

Procedure:
80.6 g (292 mmol) of ethyl 5-methylsulfonylamino-2-fluorocarbanilate was dissolved in a mixture of 1075 ml of acetic acid and 100 ml of water, and chlorine gas was added to the resultant solution at a temperature of not higher than 25° C. until the starting material disappeared. After the reaction was completed, the surplus chlorine gas was removed by blowing nitrogen gas thereinto, and hexane was added. The precipitates crystals were filtered out to obtain 81.4 g of the objective product (yield: 90%) in the form of yellow crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]([O-:35])([O-:34])=[O:33].[Na+:36].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:32]([O-:35])(=[O:34])=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:36]
Reactant: BrCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])CCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 15.2 %

Procedure:
1,4,5-Triphenyl-2-(6-bromohexyloxy)imidazole (0.95 g) was dissolved in hot ethanol (5 ml) and a solution of sodium sulphite (0.25 g) in hot water (3 ml) was added. The white suspension was heated at reflux for 24 hours then evaporated to dryness. The residue was recrystallised from ethanol then methanol/ethanol to give sodium 6-(1,4,5-triphenylimidazol-2-yloxy)hexane-sulphonate (0.15 g, 15%) as a colourless solid, m.p. 265° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](O)(=O)[CH:11]([CH3:13])[OH:12].C(Cl)Cl>C1(C)C(C)=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([CH:11]([OH:12])[CH3:13])[O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(F)cc1O
Reactant: CC(O)C(=O)O
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: CC(O)c1nc2ccc(F)cc2o1
Yield: 61.2 %

Procedure:
A suspension of 2-amino-5-fluorophenol (5.50 g, 43.3 mmol) and 85-92% lactic acid (6 g) in xylene was refluxed overnight while removing off water by-produced as a result of the reaction. After replacing the solvent with methylene chloride, the resultant mixture was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, and then concentrated. The resulting residue was subjected to recrystallization from a mixture of diisopropyl ether and hexane to afford 6-fluoro-2-(1-hydroxyethyl)benzoxazole (4.80 g, yield: 61%).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(N(CC)CC)C.Cl[S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41]>C(Cl)Cl>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41])[CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Reactant: COC(=O)CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)OC)CC5)cc4s3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To a solution of 2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (150 mg, 0.344 mmol) and triethylamine (0.120 mL, 0.861 mmol) in CH2Cl2 (3 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (104 mg, 0.517 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt for 2 h. The reaction mixture was quenched with sat. aq. NaHCO3 (4 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 55% EtOAc) to afford methyl 4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate (84 mg, 0.14 mmol, 41% yield) as a white solid. LCMS (m/z)=600 (M+H)+.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](O)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(=O)C([Cl:14])=O>C1C=CC=CC=1.CN(C=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:14])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1C(=O)O
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Cl

Procedure:
Meanwhile, the 2-methylbenzoyl chloride acylating agent was prepared by suspending 4.750 g (42.2 mmol) of o-toluic acid in 100 ml benzene. To this solution was added 2.0 equiv. (7.37 ml) of oxalyl chloride, dropwise via a pressure-equalizing dropping funnel at 0° C. DMF (2-3 drops) was added to the reaction mixture catalytically and the ice bath was removed. The progress of the reaction was monitored via infrared spectroscopy. The solvent was removed by rotary vacuum evaporation and the residual oil was pumped down under high vacuum overnight.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[F:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.C(NCC)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[F:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[NH:6][CH2:5]3)[CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1cccc(F)c1
Reactant: O=C1NCc2cc(Br)ccc21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: O=C1NCc2cc(C#Cc3cccc(F)c3)ccc21
Temperature: 60 °C

Procedure:
To a solution of 5-bromoisoindolin-1-one III-3 (100 mg, 0.47 mmol) in DMF (2 mL) was added 3-fluorophenylacetylene III-4 (67 mg, 0.56 mmol), Pd(Ph3P)4 (27 mg, 0.02 mmol), CuI (9 mg, 0.04 mmol) and diethylamine (200 μL). The reaction vessel was sealed and heated at 60° C. for 1 h in a microwave reactor. The reaction was cooled to rt, diluted with EtOAc:hexanes (2:1, 8 mL) and washed with water (2×5 mL) and brine (5 mL). The organic phase was dried over MgSO4, filtered and concentrated under vacuum. The crude product was purified by mass directed preparative HPLC to afford 5-((3-fluorophenyl)ethynyl)isoindolin-1-one III-5 (42 mg, 35%) as a light brown solid; 1H-nmr (400 MHz, CDCl3) δ 7.92 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.40-7.31 (m, 2H), 7.28-7.22 (m, 1H), 7.14-7.07 (m, 1H), 5.36 (s, 2H); LC (214 nM) 3.38 min (>98%); MS (ESI) m/z=253.1.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31])([O-:26])=[O:25].C(=O)(O)[O-].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=1)=[O:31])([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CNC(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
A solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.0 g, 9 mmol) and triethylamine (1.3 mL, 9.5 mmol) in tetrahydrofuran (26 mL) at 0° C. was treated with a solution of 3-nitrobenzoyl chloride (1.8 g, 9.5 mmol) in tetrahydrofuran (7.3 mL) and stirred at 20° C. for 1 h. The reaction mixture was treated with saturated sodium bicarbonate and the aqueous layer was separated and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated to give the desired product (3.5 g, 105%) as a crude off-white solid that was used without further purification. LCMS for C15H14N3O5 ([M-(t-Bu)+H]+H)+: m/z=316.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][C:24]2[N:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:27]=[N:26][N:25]=2)[C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=2)[C:7]=1[CH2:19][CH2:20][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CCCCc1c(C(=O)OCC)cc(O)c2ccc(OC)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)OCC)cc(Oc2nnnn2-c2ccccc2)c2ccc(OC)cc12
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
As in Example 132, 1-butyl-4-hydroxy-7-methoxy-2-naphthalenecarboxylic acid ethyl ester (2.9 g) was reacted with 5-chloro-1-phenyl-1H-tetrazole (1.87 g) in dimethylformamide (25 mL) in the presence of potassium t-butoxide (1.25 g). After 0.5 hours at room temperature, the reaction was worked up in the described manner and the crude product was crystallized from diethyl ether-hexane to afford 2.9 g of 1-butyl-7-methoxy-4-[(1-phenyl-1H-tetrazole-5-yl)oxy]-2-naphthalenecarboxylic acid ethyl ester, mp 94°-96° C. A sample was recrystallized from the same solvents to provide the analytical specimen, mp 95.5°-96.5° C. Anal. Calcd for C25H26N4O4 : C, 67.25; H, 5.87; N, 12.55 Found: C, 67.16; H, 5.99; N, 12.66
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:4][CH2:3]1.[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42](O)=[O:43]>>[O:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]([N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[CH:12]=[C:11]([C:13]3[CH:36]=[CH:35][C:16]4[N:17]([C:20]5[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([F:33])([F:32])[F:34])=[O:28])[CH:23]=[CH:24][CH:25]=5)[CH:18]=[N:19][C:15]=4[CH:14]=3)[CH:10]=[N:9]2)[CH2:6][CH2:7]1)=[O:43]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: O=C(O)C1CCCO1
Agent: Cl
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCN(C(=O)C6CCCO6)CC5)c4)ccc32)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 (Step 6) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea HCl salt and 2-tetrahydro-furancarboxylic acid, (Aldrich, Cat. No. 341517), LCMS (M+H)+: m/z=582.2.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:19])[O:18][C:7]2=[CH:8][C:9]3[CH2:10][C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[CH2:5]1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23].Cl>C(Cl)Cl.C1C=CC=CC=1>[CH3:19][C:4]1([CH3:3])[O:18][C:7]2=[CH:8][C:9]3[CH:10]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[C:11](=[O:17])[N:12]([CH2:15][CH3:16])[C:13]=3[CH:14]=[C:6]2[CH2:5]1
Reactant: CCOC(=O)OCC
Reactant: CCN1C(=O)Cc2cc3c(cc21)CC(C)(C)O3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCOC(=O)C1C(=O)N(CC)c2cc3c(cc21)OC(C)(C)C3
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a slurry of 26.4 mg. (1.1 mmoles) of sodium hydride in 2 ml. of benzene was added 231 mg. (1 mmole) of 2,2-dimethyl-5-ethyl-6-oxo-2,3,6,7-tetrahydro-furo[2,3-f]indole and the resultant reaction mixture stirred for 5 minutes. To the reaction mixture was added 0.13 ml. (1.1 mmoles) of diethyl carbonate, and the mixture allowed to stir 18 hours. The reaction is then added to methylene chloride and 4N hydrochloric acid, and the organic phase separated, washed with water and a saturated brine solution and dried over magnesium sulfate. The extract was subsequently treated with 1N sodium hydroxide solution and the basic layer separated. The aqueous basic layer was acidified and the product extracted with methylene chloride. The organic phase was separated, dried with magnesium sulfate and concentrated to give 155 mg. (51% yield) of the titled intermediate as an oil.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Si:10]([O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: Fc1cc(Br)cnc1Br
Reactant: CC(C)(C)[Si](Oc1ccc(B(O)O)cc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](Oc1ccc(-c2ncc(Br)cc2F)cc1)(c1ccccc1)c1ccccc1

Procedure:
2,5-dibromo-3-fluoropyridine and 4-tert-butyldiphenylsilyloxybenzeneboronic acid are reacted analogously to Example 1 to give 5-bromo-2-(4-tert-butyldiphenylsilyloxyphenyl)-3-fluoropyridine. ##STR31##