Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(Cl)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-chlorophenylboronic acid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][NH:36][CH2:37][CH3:38]>C(Cl)Cl>[CH3:32][N:33]([CH3:39])[CH2:34][CH2:35][N:36]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:37][CH3:38]
Reactant: CCNCCN(C)C
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: CCN(C=C1C(=O)OC(COC)C2(C)C1=C(O)C(=O)C1=C2C(OC(C)=O)CC2(C)C(O)CCC12)CCN(C)C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
17-Hydroxywortmannin (129 mg, 0.3 mmol) is dissolved in 5 ml methylene chloride and stirred at room temperature under nitrogen atmosphere as N,N-dimethyl-N′-ethyl-ethylenediamine (0.31 mmol, 56 μl) is added. The reaction solution turns orange immediately. After 30 min, the solvent is evaporated and the solid is recrystallized from ethyl acetate/hexane (3:1). After filtration, the solid is washed with hexane and dried under vacuum to yield 115 mg of the title compound as an orange powder. UV λmax (CH3CN/H2O): 250 nm, 320 nm, 397 nm; Positive ESI-MS: m/z 547 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[C:28](=[O:30])=[O:29]>CCOCC>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:28]([OH:30])=[O:29])[CH:3]=[C:4]2[CH2:10][CH2:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)N1CCc2cc(Br)cnc21
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)N1CCc2cc(C(=O)O)cnc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred and cooled (−78° C.) solution of the bromide 4 (205 mg, 0.65 mmol) in Et2O (4 mL) was added dropwise a 1.5 M solution of tert-butyllithium in pentane (0.92 mL, 1.37 mmol). After 40 min., dry gaseous CO2 was introduced into the reaction vessel. Progress of the reaction was followed by TLC analysis. After complete consumption of starting material 4 the reaction was quenched by the addition of saturated aqueous NaHCO3 solution. The mixture was allowed to warm to room temperature, and diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organic solutions were dried (MgSO4), filtered and concentrated. The residual yellow oil was dissolved in CH2Cl2:MeOH=20:1 and filtered through silicagel pad. The filtrate was concentrated and used directly in the next step.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:13][C:12]([CH2:15][CH3:16])([OH:14])[CH2:11][CH2:10][C:9]=2[C:17]=1[CH3:18])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].Cl>C1C=CC=CC=1.CS(C)=O.C(OCC)C.O>[C:1]([O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]([O:13][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]([CH2:10][CH2:11][C:12](=[O:14])[CH2:15][CH3:16])[C:17]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: CCC1(O)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Reactant: CCOC(=O)CCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCCCOc1c(C)c(C)c(OC(C)=O)c(C)c1CCC(=O)CC
Temperature: 5 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution containing 10.0 g (0.036 moles) of 6-acetoxy-3,4-dihydro-2-ethyl-2-hydroxy-5,7,8-trimethyl-2H-1-benzopyran in 100 ml of benzene and 30 ml of dimethylsulfoxide is rapidly dripped, under nitrogen atmosphere, into a suspension containing 1.0 g (0.040 moles) of 97% sodium hydride in 50 ml of dimethylsulfoxide. The solution, after 60 minutes, is cooled to 5° C. and added, by slow dripping, to 50 ml of benzene containing 8.3 g (0.040 moles) of ethyl 5-bromovalerate, while keeping a temperature lower than 25° C. After 24 hours the reaction mixture is diluted with ethyl ether and water, acidified with a 10% aqueous solution of hydrochloric acid and the crude product is recovered by evaporating the organic layer. The pure product, 9.06 g with a yield of 62%, obtained in form of a thick oil by chromatography on a column of silica gel with eluent methylene chloride-ethyl ether in 96:4 ratio, shows the following chemical-physical characteristics:
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[CH3:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:21][CH3:22])[N:12]=[CH:11][CH:10]=[C:9]2[O:8][C:7]1[C:2]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)=[N:3][C:4]([CH3:23])=[CH:5][CH:6]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(C)cc3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 4-methylphenylboronic acid (136 mg), and tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, then the solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using methanol-chloroform to give the title compound (77 mg, yield 100%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]2[O:12][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=3)=[N:14][N:15]=2)[CH:5]=1.O.[OH-].[Na+].Cl>CO>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[O:12][C:11]([CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])=[N:15][N:14]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: COC(=O)c1cccc(Cc2nnc(-c3ccc(C#N)cc3)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2nnc(Cc3cccc(C(=O)O)c3)o2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Suspend of 3-[5-(4-cyano-phenyl)[1,3,4]oxadiazol-2-ylmethyl]-benzoic acid methyl ester (0.120 g, 0.376 mmol) in 4 mL of a 1:1 mixture of H2O:MeOH. Heat the mixture to 60° C., and add 10% aqueous solution of NaOH (0.28 mL, 0.70 mmol). Stir at 60° C. for 30 minutes, cool to room temperature and adjust the pH to 5 by the addition of a 2 N solution of HCl. Concentrate the mixture overnight under a stream of air, dilute crude residue with H2O and extract with methylene chloride. Wash the combined organic phase with brine, dry over anhydrous sodium sulfate and concentrate to provide 0.11 g 4% yield of 3-[5-(4-cyano-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-benzoic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=[C:48](C=CC=1)[CH2:49][N:50]1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.BrCC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:48][C:49]#[N:50])[CH2:28][CH2:27]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC#N)CC5)nc4)cnc32)cc1
Yield: 75 %

Procedure:
Using similar reaction conditions as described in step-i of example-126, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (75 mg, 0.123 mmol) was alkylated using 2-bromoacetonitrile (23 mg, 0.185 mmol) and potassium carbonate (43 mg, 0.308 mmol) in DMF (1 ml) to afford 60 mg (75.0% yield) of the titled compound. MS: m/z=647.1 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]=1[CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[C:17]1([N:16]2[C:12]3[C:9](=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:15]=[CH:14][CH:13]=3)[CH2:10][NH:11][C:23]2=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1c(Nc2ccccc2)cccc1Oc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1NCc2c(Oc3ccccc3)cccc2N1c1ccccc1
Temperature: 25 °C

Procedure:
The product of example 1c above, 2-phenoxy-6-(phenylamino)benzyl amine, (0.165 g 0.57 mmol) was dissolved in dry tetrahydrofuran (5 mL) and stirred under argon at room temperature. 1,1′-Carbonyldiimidazole (0.120 g, 0.74 mmol) dissolved in dry tetrahydrofuran (2 mL) was added and the mixture stirred at room temperature. The solvent was evaporated in vacuo, to give the crude product which was flash chromatographed on silica gel eluted with 0–2% methanol in methylene chloride to give to the title compound as a white amorphous solid. mp 225–227° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10](C)([O-])[CH3:11].[K+].C(Br)C=C.O>O1CCCC1>[CH2:1]([O:8][CH2:11][CH:10]=[CH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 870 g of tetrahydrofuran were dissolved 218 g (2 mol) of benzyl alcohol and 224 g (2 mol) of potassium t-butoxide. With stirring at room temperature, 242 g (2 mol) of allyl bromide was added dropwise so that the temperature might not exceed 60° C. At the end of addition, the solution was heated at 60° C. on an oil bath and ripened for one hour at the temperature. The solution was allowed to cool down to room temperature, and 11.2 g (0.1 mol) of potassium t-butoxide was added. With stirring at room temperature, 12.1 g (0.1 mol) of allyl bromide was added dropwise. The solution was heated at 60° C. on an oil bath and ripened for one hour at the temperature. The solution was cooled in an ice bath, and 550 g of water was added. The organic layer was collected. The solvent was distilled off in vacuum, yielding 299 g of a crude end product. The product was used -in the subsequent reaction without further purification.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30](OS(C(F)(F)F)(=O)=O)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH:17]=1.[C:45]([C:47]1([OH:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)#[CH:46]>C(#N)C.[Cu]I>[CH3:8][O:9][C:10](=[O:44])[CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([CH2:42][CH3:43])([C:27]3[CH:32]=[CH:31][C:30]([C:46]#[C:45][C:47]4([OH:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[C:29]([CH3:41])[CH:28]=3)[CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH:17]=1
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Reactant: C#CC1(O)CCCCC1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(C#CC2(O)CCCCC2)c(C)c1
Temperature: 160 °C
Yield: 67.1 %

Procedure:
Triethylamine (0.156 mL, 1.12 mmol), tetrakistriphenylphosphine palladium (43.0 mg, 0.036 mmol) and copper (I) iodide (7.0 mg, 0.037 mmol) were added to a solution of (5-{4-[1-ethyl-1-(3-methyl-4-trifluoromethanesulfonyloxy-phenyl)-propyl]-phenyl}-pyridin-3-yl)-acetic acid methyl ester (Example 144-(2); 0.1 g, 0.186 mmol) and 1-ethynyl-cyclohexanol (69.6 mg, 0.56 mmol) in acetonitrile (0.9 mL), and the mixture was stirred with microwave heating at 160° C. for five minutes. The reaction solution was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (63.6 mg, 66%).
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Li]CCCC.Cl[CH2:25][CH2:26][O:27][CH2:28][CH2:29]Cl>C1COCC1.CCCCCC>[C:1]12([O:11][C:12]3[CH:13]=[CH:14][C:15]([N:16]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:17][CH:18]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: ClCCOCCCl
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1cc(N2CCOCC2)ccc1OC12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
To 12.2 g (0.050 mole) of 4-(1-adamantyloxy)aniline dissolved in 200 ml of THF cooled in an ice bath was added dropwise with stirring 47 ml of a 1.07 M solution of n-BuLi in hexane. During the addition 100 ml of THF was added to the reaction mixture, and the mixture was stirred for one hour. 7.16 g (0.050 mole) of bis(2-chloroethyl)ether was added (as a solution in THF) and the mixture was refluxed for nineteen hours and allowed to cool. An additional 47 ml of the 1.07 M solution of n-BuLi in hexane was added dropwise with stirring to the reaction mixture cooled in an ice bath, and the mixture was stirred for one hour at room temperature and refluxed for twenty-three hours.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH:8]=[C:7]1[CH2:12][OH:13].C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:13][CH2:12][C:7]1[O:6][CH2:11][CH2:10][CH2:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: OCC1=CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1=CCCCO1
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (17.9 mL, 232 mmol) was added dropwise to a solution of (5,6-dihydro-4H-pyran-2-yl)methanol (25.51 g, 193 mmol) [see Synlett, Vol. 5, p. 533 (1997)] and triethylamine (40.4 mL, 290 mmol) in dichloromethane (600 mL) under salt ice cooling over 15 minutes. After stirring at the same temperature for two hours, triethylamine (18.8 mL, 135 mmol) and methanesulfonyl chloride (7.5 mL, 97 mmol) were added, and the mixture was further stirred for 30 minutes. Water (300 mL) was added to the reaction solution, followed by extraction with ethyl acetate (1.5 L). The resulting organic layer was washed with water (300 mL) and brine (300 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting crude title compound was used for the next reaction without purification.
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH:7]([C:6]1[CH:9]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[CH:4][C:5]=1[OH:10])=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.3 %

Procedure:
In an atmosphere of argon, 496 g (2.46 mol) of 5-bromosalicylaldehyde, 361 g (2.96 mol) of phenylboronic acid, 57 g (49.0 mmol) of tetraxis(triphenylphosphine)palladium(0), 8.6 L of DME and 784 g of sodium carbonate/3.7 L of water were charged, and subjected to heating under reflux with stirring for 17 hours. After cooling the resultant to room temperature, 3 L of toluene was added, and then an aqueous layer was removed. An organic layer was washed with water, and dried with magnesium sulfate. The solvent was distilled off under a reduced pressure. The crystals were purified by silica gel chromatography, whereby 382 g of 3-formyl-4-hydroxybiphenyl was obtained (yield: 78%).
Reaction SMILES: [C:1](=[O:18])([O:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])[O:2]N1C(=O)CCC1=O.[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=1.O.CCOCC>CC#N.C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:2][C:1](=[O:18])[O:10][N:11]2[C:12](=[O:17])[CH2:13][CH2:14][C:15]2=[O:16])=[CH:22][CH:21]=1
Reactant: Cc1ccc(CO)cc1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Disuccinimidyl carbonate (5.03 g, 19.65 mmol) in 30 mL MeCN and 30 mL DCM was treated with 4-methylbenzyl alcohol (2.4 g, 19.6 mmol) followed by DMAP (1.20 g, 9.82 mmol). The resulting cloudy reaction mixture was stirred overnight at rt, poured into 100 mL water, and partitioned. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated. The solid thus obtained was stirred with approx. 25 mL ether, filtered, and the resulting product was washed with a small volume of ether and dried.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:29]([O-])=O)[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][O:27][CH3:28])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Fe].CO.O>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([NH2:29])[C:18]([NH:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([CH2:26][O:27][CH3:28])[CH2:24][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Fe]
Solvent: O
Solvent: CO
Product: COC[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1

Procedure:
A mixture of trans (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(4-methoxymethyl-cyclohexyl)-amine (1.92 g, 4.32 mmol), iron powder (0.96 g, 17.3 mmol) ammonium chloride (1.39 g, 26.0 mmol) and methanol/water (90 mL, 3:1) was stirred and heated at reflux for 1 hour. The cooled mixture was filtered through a pad of Celite® washing the filter cake with methanol. The combined filtrate was concentrated to dryness and the residue dissolved in DCM then purified by column chromatography on silica gel (eluting with 20%-50% ethyl acetate in DCM) affording 1.79 g (99%) of trans 1-benzenesulfonyl-N*4*-(4-methoxymethyl-cyclohexyl)-1H-pyrrolo[2,3-b]pyridine-4,5-diamine as a grey solid. LCMS (Method I, ESI): RT=2.49 min, m+H=415.2; 1H NMR (300 MHz, CDCl3): δ 8.14 (d, 2H), 7.81 (s, 1H), 7.57-7.39 (m, 4H), 6.55 (d, 1H), 4.70 (br s, 1H), 3.72-3.55 (m, 1H), 3.35 (s, 3H), 3.24 (d, 2H), 2.22-2.11 (m, 2H), 1.95-1.85 (m, 2H), 1.76-1.50 (m, 3H), 1.33-1.07 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Li]CCCC.Cl[Si:15]([CH3:26])([CH3:25])[CH:16]1[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]1[CH3:24]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][Si:15]([CH3:25])([CH3:26])[CH:16]2[C:20]([CH3:21])=[C:19]([CH3:22])[C:18]([CH3:23])=[C:17]2[CH3:24])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2ccc(Br)cc2)C(C)=C1C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, to a solution of 14.8 g (86.0 mmol) of 4-bromoaniline in 250 ml of THF, 34.0 ml of 2.5 M (86.0 mmol) nBuLi in hexanes were added at −80° C. This mixture was stirred for 30 minutes at this temperature and then warmed for ca. 1 hour to ambient temperature. The resulting solution was added dropwise over ca. 1 hour, while vigorous stirring, to a solution of 18.4 g (86.0 mmol) of chloro(dimethyl)(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane in 100 ml of THF. The resulting mixture was stirred overnight at ambient temperature, then, evaporated to dryness. To the residue 100 ml of toluene were added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 170° C./0.4 mm Hg. The product crystallizes slowly at ambient temperature. Yield 21.3 g (70%).
Reaction SMILES: C(O[O:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:13]=[CH:14][CH:15]=1)C1C=CC=CC=1.[N:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:40][CH2:39][CH:35]([C:36](Cl)=[O:37])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[N:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:40][CH2:39][CH:35]([C:36]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([NH:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:11]=3)=[O:25])=[O:37])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: Nc1ccccc1C(=O)Nc1cccc(OOCc2ccccc2)c1
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 164.8 %

Procedure:
Using the procedure described in Example 138, N-(3-benzyloxyoxyphenyl)-2-aminobenzamide (0.97 mmol) and N-(4-pyridyl)isonipecotoyl chloride (1.9 mmol), yielded 405 mg (82%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:18])([CH3:17])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])=[CH:7][CH:6]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([Cl:31])[C:29]=1[OH:30])[C:23](OC)=[O:24]>C([O-])(=O)C.[Ca+2].C([O-])(=O)C.[Sb]=O>[C:8]1([CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][O:14][C:23]([C:22]2[CH:27]=[C:28]([Cl:31])[C:29]([OH:30])=[C:20]([Cl:19])[CH:21]=2)=[O:24])[CH:9]=[CH:10][C:5]([CH2:4][C:3]([CH3:18])([CH3:17])[CH2:2][O:1][C:23]([C:22]2[CH:27]=[C:28]([Cl:31])[C:29]([OH:30])=[C:20]([Cl:19])[CH:21]=2)=[O:24])=[CH:6][CH:7]=1
Reactant: CC(C)(CO)Cc1ccc(CC(C)(C)CO)cc1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: CC(=O)[O-]
Agent: O=[Sb]
Agent: [Ca+2]
Product: CC(C)(COC(=O)c1cc(Cl)c(O)c(Cl)c1)Cc1ccc(CC(C)(C)COC(=O)c2cc(Cl)c(O)c(Cl)c2)cc1
Temperature: 200 °C
Yield: 743.8 %

Procedure:
A mechanically stirred mixture of 0.6 g of calcium acetate, 0.6 g of antimony oxide, 3.75 g (0.15 M) of 1,4-bis(3-hydroxy-2,2-dimethylpropyl)benzene and 132 g (0.6 M) of methyl 3,5-dichloro-4-hydroxybenzoate was heated under nitrogen atmosphere at 200° C. for 18 hours. The reaction mixture was washed three times with benzene in a Waring Blendor and extracted for 5 days with 2 liters of hot benzene. The extract, on cooling, yielded 70 g of 4,4'-[1,4-phenylenebis([2,2-dimethyl-1,3-propanediyl]oxycarbonyl)]bis(2,6-dichlorophenol) melting at 203°-204° C. The infrared spectrum was consistent with the indicated structure. The compound contained 3.185 meq. of OH/g indicating a molecular weight of 628 for the bisphenol.