Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].[H-].[Na+].[Na].[Cl:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>CN(C)C=O>[CH3:1][N:2]([C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[Cl:15])[S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CNS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
1.71 g (0.01 mole) of N-methylbenzenesulfonamide was added to 0.58 g (0.012 mole) of 50% sodium hydride in 15 ml of dry N,N-dimethylformamide. The mixture was stirred at room temperature for 30 minutes to react them. To the resulting sodium salt was added 2.10 g (0.012 mole) of 2-chlorobenzoyl chloride, and the mixture was stirred at room temperature for 1 hour. The N,N-dimethyl formamide was distilled off under reduced pressure. Cold water was added, and the resulting oil layer was extracted with benzene. The benzene layer was dried over anhydrous magnesium sulfate, and concentrated to afford almost pure N-methyl-N-(2-chlorobenzoyl)benzenesulfonamide in a yield of 92%. For further purification, this compound was subjected to chromatography or high vacuum distillation. This compound is designated as compound No. 16 in Table 2, and its melting point and elemental analysis values are shown in Table 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](O)=[O:32].CCN=C=NCCCN(C)C>>[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:32]
Reactant: O=C(O)c1cccs1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)c4cccs4)c3)c2c1
Yield: 27.6 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-thiophenecarboxylic acid (0.92 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 56 mg (26% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.4 (s, 1H), 8.6 (s, 1H), 8.4 (br s, 1H), 8.1 (br s, 1H), 8.0 (d, 1H), 7.94–7.86 (m, 2H), 7.8 (d, 1H), 7.6 (d, 1H), 7.5 (t, 1H), 7.3 (br s, 1H), 7.2 (t, 1H); ES-MS (m/z) 363 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:6]([CH3:15])=[CH:7][N:8]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[N:41][CH:42]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CCOC(C)=O.O>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:37]3[CH:42]=[N:41][C:40]([N:43]4[CH2:44][CH2:45][NH:46][CH2:47][CH2:48]4)=[CH:39][CH:38]=3)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]=2[C:6]([CH3:15])=[CH:7]1)([CH2:13][CH3:14])[CH3:12]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: CCC(C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)n1cc(C)c2c(C(=O)NCc3c(C)cc(C)[nH]c3=O)cc(-c3ccc(N4CCNCC4)nc3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Added sequentially to a reaction vial were 6-bromo-1-(sec-butyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-methyl-1H-indole-4-carboxamide (0.15 g, 0.338 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.127 g, 0.439 mmol), and potassium phosphate (tribasic) (0.287 g, 1.350 mmol), followed by 1,4-Dioxane (3 mL) and water (0.75 mL). The suspension was stirred under N2 degassing for 10 min., and then added PdCl2(dppf)-CH2Cl2 adduct (0.028 g, 0.034 mmol). The reaction vial was sealed, placed into a heat block at 95° C., and stirred for 1.5 h. The contents were removed from heating and allowed to cool to room temperature. The aq layer was removed from bottom of the reaction vial via pipette. The reaction mixture was diluted into EtOAc (20 mL) followed by addition of 0.2 g each of Thiol-3 silicycle resin and silica gel. The volatiles were removed in vacuo and the residue dried on hi-vac for 1 h. The contents were purified by silica gel chromatography (dry loaded, eluent: A: Dichloromethane, B: 10% (2M Ammonia in Methanol) in Chloroform, Gradient B: 8-95%). The obtained solid was concentrated from TBME and dried in vacuum oven at 45° C. for 18 h. The product was collected as 129 mg (70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.73 (t, J=7.33 Hz, 3H), 1.40 (d, J=6.57 Hz, 3H), 1.80 (dq, J=10.07, 7.08 Hz, 2H), 2.11 (s, 3H), 2.14-2.19 (m, 3H), 2.24 (s, 3H), 2.76-2.85 (m, 4H), 3.41-3.49 (m, 4H), 4.35 (d, J=5.05 Hz, 2H), 4.54-4.67 (m, 1H), 5.87 (s, 1H), 6.88 (d, J=8.84 Hz, 1H), 7.17 (d, J=1.26 Hz, 1H), 7.26 (s, 1H), 7.73 (d, J=1.26 Hz, 1H), 7.91 (dd, J=8.84, 2.53 Hz, 1H), 8.16 (t, J=5.05 Hz, 1H), 8.50 (d, J=2.53 Hz, 1H), 11.48 (br. s., 1H); LCMS MH+=527.3.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([C:11]1[CH:81]=[CH:80][CH:79]=[CH:78][C:12]=1[CH2:13][O:14][C:15]([NH:17][CH2:18][C@H:19]([S:75][S:76][CH3:77])[CH2:20][CH2:21][C@@H:22]([NH:67]C(OC(C)(C)C)=O)[C:23]([O:25][C@H:26]1[C@@H:30]([OH:31])[C@@H:29]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH2:41])[O:28][C@H:27]1[CH2:42][O:43][P:44]([O:47][C@H:48]1[CH2:52][C@H:51]([N:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55][C:54]2=[O:60])[O:50][C@@H:49]1[CH2:61][O:62][P:63]([OH:66])([OH:65])=[O:64])([OH:46])=[O:45])=[O:24])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:67][C@H:22]([CH2:21][CH2:20][C@@H:19]([S:75][S:76][CH3:77])[CH2:18][NH:17][C:15]([O:14][CH2:13][C:12]1[CH:78]=[CH:79][CH:80]=[CH:81][C:11]=1[N:8]=[N+:9]=[N-:10])=[O:16])[C:23]([O:25][C@H:26]1[C@@H:30]([OH:31])[C@@H:29]([N:32]2[CH:40]=[N:39][C:38]3[C:33]2=[N:34][CH:35]=[N:36][C:37]=3[NH2:41])[O:28][C@H:27]1[CH2:42][O:43][P:44]([O:47][C@H:48]1[CH2:52][C@H:51]([N:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[N:55][C:54]2=[O:60])[O:50][C@@H:49]1[CH2:61][O:62][P:63]([OH:66])([OH:65])=[O:64])([OH:46])=[O:45])=[O:24]
Reactant: CSS[C@H](CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSS[C@H](CC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O)CNC(=O)OCc1ccccc1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A 10% solution of trifluoroacetic acid in dichloromethane (0.1 mL) was added to a solution of (2S,5S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((((2-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk17) (2.8 mg, 2.504 μmol) in dichloromethane (0.1 mL), and the mixture was stirred at room temperature for 60 minutes. Following concentrated under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S,5S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-((((2-azidobenzyl)oxy) carbonyl)amino)-5-(methyldisulfanyl)hexanoate (Lys(5S-SSMe) (oAcbz)-pdCpA) (Compound tk18) (1.4 mg, 55%).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[S:3]([CH2:6][C:7](OC)=O)(=[O:5])=[O:4].[Cl:17][C:18]1[N:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]1[CH:32]=[N:31][CH:30]=[CH:29][C:21]=1C(Cl)=[N:23]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Cl:17][C:18]1[N:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]1[CH:32]=[N:31][CH:30]=[CH:29][C:21]=1[C:7]([CH2:6][S:3]([N:2]([CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])=[O:4])=[N:23]2
Reactant: COC(=O)CS(=O)(=O)N(C)c1ccccc1
Reactant: Clc1nc2ccnc(Cl)c2c2cnccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)S(=O)(=O)Cc1nc2ccnc(Cl)c2c2cnccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl {[methyl(phenyl)amino]sulfonyl}acetate (1021 mg, 4.20 mmol) and 1,6-dichloropyrido[4,3-c]-1,6-naphthyridine (350 mg, 1.400 mmol) in toluene (14.0 mL) at 0° C., LHMDS (4.20 mL, 4.20 mmol, 1 M in THF) was added dropwise. The reaction was allowed to warm to room temperature and was stirred for 5 h. The reaction mixture was then heated to 50° C. for 1 h. The reaction mixture was then stirred at room temperature for 72 h. To the reaction mixture, LHMDS (1.400 mL, 1.400 mmol, 1 M in THF) was added, and the reaction was stirred at room temperature overnight. This mixture was poured into aqueous ammonium chloride (saturated). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were filtered through a frit, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes, to afford 1-(1-chloropyrido[4,3-c]-1,6-naphthyridin-6-yl)-N-methyl-N-phenylmethanesulfonamide as a brown solid. LRMS (APCI) calc'd for (C19H16ClN4O2S) [M+H]+, 399.1; found 399.0.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[C:26]([F:34])[CH:25]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:31](=[O:32])[CH2:30][C:27]2[CH:28]=[CH:29][C:24]([Br:23])=[CH:25][C:26]=2[F:34])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Yield: 88.5 %

Procedure:
A suspension of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (668 mg, 2.146 mmol) in DCM (35 mL) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (500 mg, 2.146 mmol) in DCM (35 mL). HOBt (493 mg, 3.22 mmol), EDC (617 mg, 3.22 mmol) and Et3N (0.897 mL, 6.44 mmol) and the mixture was at 26° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=10/1). All fractions found to contain product by TLC (PE/EA=5/1, Rf 0.6) were combined and concentrated to yield a light yellow solid of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2-fluorophenyl)acetamide (1 g, 1.900 mmol, 89.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.83-7.82 (d, J=2.8 Hz, 1H), 7.33-7.24 (m, 10H), 4.83 (s, 1H), 4.23-4.21 (m, 2H), 3.84-3.83 (m, 2H), 3.71-3.67 (m, 2H); ES-LCMS m/z 525.9 (M+H).
Reaction SMILES: S([O-])([O-])(=O)=O.[K+].[K+].[C:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Cl-].[Pt+4].Cl[Pd]>[C:8]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCCC1
Agent: Cl[Pd]
Agent: [Pt+4]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: Oc1ccccc1-c1ccccc1

Procedure:
The same procedure as in Example 1 is repeated except that in place of 1g of chloroplatinic acid hexahydrate, 2.5g of potassium sulfate and at a rate of 15.5 ml/hr. of cyclohexanone dimer, 1.25g of chloropalladium, 2.0g of potassium sulfate and at a rate of 8.0 ml/hr. are employed. The conversion is found to be always 100% over the reaction period of 2,000 hours. Table 2 gives the selectivity for o-phenylphenol measured.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:9]2[CH2:10][S:11](=[O:14])[CH2:12][CH2:13][C:8]=2[S:7][C:6]=1[C:15]([OH:17])=O)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>CN(C=O)C>[NH:32]1[C:31]([NH:30][C:15]([C:6]2[S:7][C:8]3[CH2:13][CH2:12][S:11](=[O:14])[CH2:10][C:9]=3[C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[O:17])=[N:35][N:34]=[N:33]1
Reactant: Nc1nnn[nH]1
Reactant: CC(C)Oc1c(C(=O)O)sc2c1CS(=O)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)Oc1c(C(=O)Nc2nnn[nH]2)sc2c1CS(=O)CC2
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.4 %

Procedure:
To a stirred solution of 0.494 g (1.8 mM) of 3-isopropoxy-5-oxo-6,7-dihydro-4H-thieno[3,2-c]thiopyran-2-carboxylic acid (from Preparation 13) in 10 mL of DMF were added 0.438 g (2.7 mmol) of 1,1'-carbonyldiimidazole. The reaction mixture was heated at 80° C. for 60 minutes, followed by addition in one portion of 0.283 g (3.33 mmol) of 5-aminotetrazole. The reaction mixture was heated at 80° C. for 5 hours, cooled to 24° C., and stirred for an additional 18 hours. The mixture was concentrated to dryness by evaporation of the solvent under reduced pressure. The residue was dissolved in 100 mL of chloroform, washed with 2N HCl, water, brine, dried over MgSO4, and the solvent was removed by evaporation under reduced pressure. The solid residue was recrystallized from methanol/diethyl ether to afford 0.279 g of 3-isopropoxy-5-oxo-6,7-dihydro-4H-thieno[3,2-c] thiopyran-2-carboxylic acid (1H-tetrazol-5-yl) amide, mp 225°-226° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[N:16][CH:15]=[CH:14][N:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2cnccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol) and 3,4-methylenedioxyaniline (39 mg, 0.288 mmol) similar to Example 76 and isolated as a pink solid (21 mg, 30%). 1H NMR (CDCl3): 9.72 (d, J=1.2 Hz, 1H), 8.76 (dd, J=1.5, 2.7 Hz, 1H), 8.71 (d, J=2.7 Hz, 1H), 7.60 (s, 1H), 6.88 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.83 (s, 1H), 6.78 (dd, J=1.8, 8.1 Hz, 1H), 6.05 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16](Cl)=[O:17])[CH:5]=[CH:4][C:3]1=2.[OH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=1>>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]([O:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:23][CH:22]=3)=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C#CC(=O)Cl)ccc21
Product: CC(C)(C)OC(=O)c1ccc(OC(=O)C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a similar manner to that of Example 1(d), by reaction of 1.4 g (5 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propynoyl chloride with 950 mg (4.9 mmol) of tert-butyl 4-hydroxybenzoate, 1.75 g (83%) of the expected tert-butyl ester are obtained in the form of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:13]([CH3:30])[C@@H:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=1)[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:12])([O-])=O.O.NN.Cl>[Ni].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([N:13]([CH3:30])[C@@H:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)[CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:12]
Reactant: CN(C(=O)Cc1ccccc1[N+](=O)[O-])[C@H](CN1CCCC1)c1cccc([N+](=O)[O-])c1
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C(=O)Cc1ccccc1N)[C@H](CN1CCCC1)c1cccc(N)c1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
With stirring at 55° C., Raney nickel was added in small quantities to a mixture of 10 (0.9857 g, 2.3899 mmol) and hydrazine hydrate (55%, 2 mL) in EtOH (30 mL) until gas evolution stopped in about 10 min. The mixture was then filtered through celite, and the Raney nickel was washed with hot MeOH (100 mL). The filtrate was evaporated and dried in vacuo before the residue was partitioned between sat'd NaHCO3 and CH2Cl2, which was dried (Na2SO4), filtered through celite, and evaporated. The product was gravity column chromatographed eluting with CHCl3:2% NH3:2% MeOH before it was converted to the HCl salt with Et2O—HCl to yield 9 3HCl.(0.3159 g, 29%, unoptimized): m.p. (HCl salt) 219-222° C.; 1H NMR (HCl salt, DMSO-d6) δ1.98 (br s, 4H, —CH2CH2—), 2.87 (s, 3H, —NCH3), 3.2-4.3 (complex, 8H, 4 —CH2—), 6.1 (m, 1H, —CH—), 7.11-7.45 (complex, 8H, aromatic). MS(FAB) m/z 353. Anal. (C, H, N) C21H28N4O. 3HCl0.25H2O.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1.[H-].[Na+]>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:3]2[N:2]([CH3:1])[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]=2)=[C:18]([F:23])[CH:17]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Product: Cn1c(Oc2ccc(Br)cc2F)nc2cccnc21
Temperature: 180 °C

Procedure:
A suspension of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (700 mg), 4-bromo-2-fluorophenol (0.399 mL) and NaH (60% in oil, 159 mg) was heated at 180° C. for 30 min under microwave irradiation. The mixture was quenched with water at room temperature and extracted with AcOEt. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (691 mg).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:23]=[CH:22][C:12]([C:13]([C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]([C:12]2[CH:22]=[CH:23][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][CH:11]=2)=[O:14])=[CH:27][CH:26]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccccc2C(=O)c2ccc(C#Cc3ccccc3)cc2)cc1

Procedure:
The phenylethynyl group has two important advantages over the ethynyl group. These are stability towards conditions of aromatic nucleophilic displacement reactions and stability at moderate temperatures (i.e. 150-250° C.). For example, when 4-phenylethynyl-4'-fluorobenzophenone was treated with a slight excess of 3 or 4-aminophenol in the presence of an alkali metal base such as potassium carbonate in a polar aprotic solvent such as N,N-dimethylacetamide (DMAc) at 143° C., 3 or 4-aminophenoxy-4'-phenylethynylbenzophenone was afforded in nearly quantitative yield. However, several attempts to make the 3-aminophenoxy-4'-ethynylbenzophenone from the 4-ethynyl-4'-fluorobenzophenone under similar reaction conditions afforded a mixture of products. In addition, imide model compounds of the phenylethynyl endcapper react at a moderate to fast rate in air at 300° to 350° C. whereas analogous model compounds containing the ethynyl group react at a moderate to fast rate in air at 200° to 250° C. Phenylethynyl containing imide model compounds are reasonably stable at 200° C. (see Example 6) whereas thynyl containing imide model compounds react at 200° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)[C:4]([C:19]2[N:27](S(C3C=CC(C)=CC=3)(=O)=O)[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:3]1.[OH-].[K+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:8][CH:9]=2)[C:4]([C:19]2[NH:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[CH:20]=2)=[CH:3]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(NC(=O)OC(C)(C)C)cc34)cc3cccnc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NC(=O)OC(C)(C)C)ccc21
Yield: 95 %

Procedure:
A solution of {1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-yl}-carbamic acid, tert-butyl ester [0.3 g, Reference Example 13(f)] in methanol (15 mL) was treated with potassium hydroxide solution (5N, 2 mL) then heated at reflux for 4 hours. The reaction mixture was evaporated and the residue triturated with water to give the title compound (0.2 g) as a tan solid. MS: 263 (MH+). TLC: RF=0.3 (ethyl acetate).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(N(C(C)C)CC)(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.O>CN1CCCC1>[CH2:18]([N:15]1[C:4]2=[N:5][C:6]([CH2:13][CH3:14])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:35][CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[C:3]2[CH:17]=[N:16]1)[CH3:19]
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Agent: CN1CCCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Yield: 111.3 %

Procedure:
To a solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (380 g) in 1-methylpyrrolidine (3166 mL) was added diisopropylethylamine (469.8 mL) and tetrahydro-2H-pyran-4-ylamine (163 g) and the mixture was heated at reflux for 16 h. The cooled mixture was treated with water (12 liters) and extracted with ethyl acetate (6×1250 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness to afford 520 g of a dark brown oil. The product was purified by flash chomatography on silica using ethyl acetate/cyclohexane @1:4-1:2 as eluant to afford 336 g of the title compound. LC-MS m/z 347 (M+H)+, 3.02 min (ret time).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12](Cl)([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:24][Al](C)C>C1CCCCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:10]2[C:11]3[C:12]([CH3:24])([CH3:20])[C:13]([F:19])([F:18])[CH2:14][C:15]=3[CH:16]=[CH:17][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(Cl)C(F)(F)C3
Reactant: C[Al](C)C
Solvent: C1CCCCC1
Product: CCOC(=O)N1CCc2ccc3c(c2CC1)C(C)(C)C(F)(F)C3
Temperature: 80 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
Into a glass vial the product from step (b) (214 mg, 0.623 mmol) dissolved in cyclohexane (3 ml) was added. To this solution, AlMe3 (2M in hexanes, 1.2 ml, 2.49 mmol) was added. The reaction mixture was heated to 80° C. and stirred for 1 hour. The reaction mixture was allowed to cool to room temperature and was quenched by the addition of 2M HCl (20 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 20% EtOAc in hexanes) gave the sub-title compound as an orange oil (20 mg). NMR (300 MHz, CDCl3) δ 6.99 (s, 2H); 4.15 (q, J=7.2 Hz, 2H); 3.62-3.59 (m, 4H); 3.29 (t, J=14.1 Hz, 2H); 3.01-2.91 (m, 2H); 1.39 (s, 6H); 1.26 (t, J=7.2 Hz, 3H); MS: ESI (positive): 324 (M+1).