Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:15]1([CH2:19][OH:20])[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14].CCN(CC)CC.Cl>ClCCl.O>[CH2:11]([C:15]1([CH:19]=[O:20])[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC1(CO)CCC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CCCCC1(C=O)CCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 101.4 %

Procedure:
To 31.6 mL of 2.0 M (63.3 mmol) of oxalyl chloride in dichloromethane was added 100 mL of DCM followed by 9.0 mL (126 mmol) of dimethylsulfoxide under Ar at −78° C. The mixture was stirred at −78° C. for 30 min. To this mixture was added 6.00 g (42.2 mmol) of (1-butylcyclobutyl)methanol in 10 mL of DCM. The temperature was allowed to warm to −40° C. over 40 minutes. To this mixture was added 35.3 mL (253 mmol) of Et3N dropwise. After the addition was completed, the temperature was allowed to warm to 0° C. over 1 hr. Water (30 mL) was added to the reaction mixture. The pH of the mixture was adjusted to ˜6 using 2N HCl. After extraction with DCM (2×100 mL), the combined organic phase was combined, washed with brine, dried (Na2SO4). Concentration afforded 6.0 g of the crude product as colorless oil, which was used directly for next step.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Br)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1[Cl:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CBr)nc1
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2)c1)c1ccc(CN2CCCCC2)nc1

Procedure:
N-(3-benzamido-4-chlorophenyl)-6-(bromomethyl)nicotinamide (0.11 mmol) was used in general procedure 5 with piperidine (0.12 mmol). The product was purified by RP-HPLC to give N-(3-benzamido-4-chlorophenyl)-6-(piperidin-1-ylmethyl)nicotinamide. MS (Q1) 448.1 (M)+
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.CCOC(C)=O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][CH2:8][C:9]([NH:24][CH:21]2[CH2:23][CH2:22]2)=[O:11])=[CH:12][CH:13]=1
Reactant: NC1CC1
Reactant: O=C(O)CNCc1ccc(Br)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CNCc1ccc(Br)cc1)NC1CC1
Yield: 30.4 %

Procedure:
To a suspension of 2-(4-bromobenzylamino)acetic acid (7H2) (109 mmol, 26.5 g) in dichloromethane (300 ml) was added triethylamine (326 mmol, 33.0 g), cyclopropylamine (7H3) (163 mmol, 9.30 g) and PyBOP (109 mmol, 56.5 g). The suspension was stirred at room temperature overnight before concentration and purification on silica eluting with EtOAc/MeOH 1:0 to 9:1 to give 2-(4-bromobenzylamino)-N-cyclopropylacetamide (7H4) 9.38 g (30.3%); 1H NMR (400 MHz, MeODd4) 7.57 (d, 2H) 7.34 (d, 2H) 4.13 (m, 2H) 3.63 (s, 2H) 2.68 (m 1H) 0.76 (m, 2H) 0.56 (m, 2H).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[C:9](Br)[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[O:16][Si](C)(C)C)([CH2:3][CH3:4])[CH3:2].C(C1C=CC=C(C(C)(C)C)C=1O)(CC)C.BrBr.C([Li])CCC.Cl[Si](C)(C)C.[C:48](=[O:50])=[O:49].[OH-].[Na+]>BrCCBr.C1COCC1>[CH:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])[C:48]([OH:50])=[O:49])([CH2:3][CH3:4])[CH3:2]
Reactant: O=C=O
Reactant: CCC(C)c1cc(Br)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: BrBr
Agent: CCC(C)c1cccc(C(C)(C)C)c1O
Agent: C[Si](C)(C)Cl
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CCC(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
A mixture of Mg (10 mmol), 2-s-butyl-4-bromo-6-t-butyl-1-trimethylsiloxy benzene [which is prepared from 2-s-butyl-6-t-butylphenol by sequential reactions with bromine (CH2Cl2), 0° C., 15 min) and n-butyllithium (THF, -78° C., 15 min)/chlorotrimethylsilane (-78° C. to -25° C., 18 hr)] and a few drops of 1,2-dibromoethane in 25 ml THF is heated at reflux for two hr and then is added to an excess of pulverized dry ice. The resulting slurry is stirred for 1 hr, then added to a 300 ml portion of 1N NaOH and stirred for 1 hr. The resulting mixture is washed with 3×100 ml portions of ether, and then is made acidic with excess 3N HCl. The product is extracted with 3×200 ml portions of ethyl acetate. The combined organic portions are dried (MgSO4), filtered, and concentrated in vacuo to give 3 -s-butyl-4-hydroxy-5-t-butylbenzoic acid, used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13]CC)=O)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][C@H:3]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH3:26]>CO>[NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:26])=[O:13])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[S:4][C@H:3]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)[C@@H](N)[C@H](c2ccccc2)Sc2ccccc21
Reaction time: 24 h

Procedure:
In 600 ml of methanol is dissolved 20 g of ethyl trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, into which ammonia gas is blown to the level of saturation under ice-cooling. The reaction temperature is slowly elevated to room temperature, and the mixture is allowed to stand still for 24 hours. Then, the reaction mixture is concentrated under reduced pressure. By adding isopropyl alcohol to the obtained residue, crystallization is effected. The crystals are collected by filtration to give 18 g of trans-3-amino-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide, m.p. 217°-219° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.FC(F)(F)S([O:38][C:39]1[CH2:44][CH2:43][CH2:42][C:41](=O)[C:40]=1[CH3:46])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O.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]>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:41]4[CH2:42][CH2:43][CH2:44][C:39](=[O:38])[C:40]=4[CH3:46])=[C:19]([CH3:32])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1=O
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCCC1=O
Temperature: 60 °C
Yield: 54.7 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 4 Step B (6.75 g, 15.8 mmol), 3-oxo-2-methylcyclohexen-1-yl trifluoromethanesulfonate (4.49 g, 17.4 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.387 g, 0.474 mmol) were combined in dimethylsulfoxide (79 mL). Aqueous sodium carbonate (2M, 39.5 mL, 79.0 mmol) was added and the reaction heated to 60 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and washed with ethyl acetate. The combined extracts were washed with water and brine. The organic phase was dried over anhydrous sodium sulfate, filtered through silica gel and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane to provide 3.55 g of the title compound as a pale orange foam.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[F:18][C:17]([F:19])([F:20])[C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 36 h
Yield: 100.1 %

Procedure:
To 1-Nitro-4-[3-(trifluoromethyl)phenoxy]benzene (19 g) in ethyl acetate (250 mL) was added 5% palladium on charcoal (1.5 g). The mixture was stirred under hydrogen gas for about 36 h, and then filtered through Celite. The filtrate was concentrated to yield a red oil (17 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([CH2:10][CH3:11])([O-:9])=[O:8].[CH:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=1>C1COCC1>[N+:7]([CH:10]([CH3:11])[CH:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:19])([O-:9])=[O:8]
Reactant: O=Cc1cccnc1
Reactant: CC[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C(O)c1cccnc1)[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To a solution of LiAlH4 (2M in THF) (1.4 mL, 2.8 mmol) in dry THF (110 mL) at 0° C., was slowly added 1-nitroethane (2.00 mL, 28 mmol) under argon. After 20 min at 0° C., nicotinaldehyde (2.64 mL, 28 mmol) was added in one portion. The mixture was stirred for 16 hours, while allowing the temperature to rise from 0° C. to room temperature. The reaction mixture was quenched by addition of 5 mL of 1M HCl, followed by addition of CH2Cl2 and Na2SO4. The resulting suspension was stirred for 15 minutes and then filtered. The filtrate was concentrated. The residue was then purified by column chromatography (40 g of SiO2) using EtOAc in hexane from 0% to 100% in order to give the product as an oil (3.2 g, 63%) as a mixture of diastereoisomers. LC-MS: [M+H] 183.4; Rt 0.41 min; (LCMS method 1). A) 1H NMR (400 MHz, CHCl3-d): 8.58-8.48 (m, 2H), 7.68 (d, 1H) 7.33-7.23 (m, 1H) 5.42-5.38 (m, 1H), 4.70-4.60 (m, 1H), 3.30-2.90 (brs, 1H), 1.46 (d, B) 1H NMR (400 MHz, CHCl3-d): 8.58-8.48 (m, 2H), 7.68 (d, 1H) 7.33-7.23 (m, 1H) 5.04 (d, 1H), 4.76-4.69 (m, 1H), 3.30-2.90 (brs, 1H), 1.31 (d, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[N:3]1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])/[CH:16]=[C:17](/[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1])\[CH3:18])[CH3:13]
Reactant: Cn1ncc2c(O)cccc21
Reactant: CC#CC(=O)OCC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc2c1cnn2C
Yield: 74.2 %

Procedure:
A mixture of 1-methyl-1H-indazol-4-ol (0.130 g, 0.88 mmol), ethyl-2-butynoate (0.59 g, 5.26 mmol), a catalytic amount of 4-dimethylaminopyridine, and potassium carbonate (0.120 g, 0.88 mmol) in tetrahydrofuran (10 mL) in a sealed tube was heated at 80° C. for 14 h. The reaction mixture was then filtered. The solids were washed with a small amount of tetrahydrofuran and the combined filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 0% to 40% ethyl acetate/hexanes) which afforded (E)-3-(1-methyl-1H-indazol-4-yloxy)-but-2-enoic acid ethyl ester (0.170 g, 74%) as a viscous tan oil.
Reaction SMILES: [CH:1]([CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:11][CH2:12][CH2:13][C:14]([O:10][CH:3]([CH:1]=[CH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:15]
Reactant: C=CC(O)c1ccccc1
Reactant: O=C(Cl)CCCl
Product: C=CC(OC(=O)CCCl)c1ccccc1

Procedure:
Vinylbenzyl alcohol is condensed with 3-chloropropionyl chloride by conventional esterification procedures to produce the vinylbenzyl 3-chloropropionate. ##STR24##
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14](=[O:41])[N:15]([C:17]1[CH:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][N:33]([CH2:36][CH3:37])[CH2:32][CH2:31]3)=[CH:26][C:25]=2[N+:38]([O-])=O)[N:20]=[CH:19][N:18]=1)[CH3:16]>C1COCC1.CO.[Ni]>[NH2:38][C:25]1[CH:26]=[C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:36][CH3:37])[CH2:34][CH2:35]2)[CH:28]=[CH:29][C:24]=1[NH:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]([N:15]([CH3:16])[C:14]([NH:13][C:3]2[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])=[O:41])[CH:22]=1
Reactant: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c([N+](=O)[O-])c2)CC1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CCN1CCN(c2ccc(Nc3cc(N(C)C(=O)Nc4c(Cl)c(OC)cc(OC)c4Cl)ncn3)c(N)c2)CC1
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a solution of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-2-nitrophenylamino)pyrimidin-4-yl)-1-methylurea (330 g, 0.546 mmol) in THF (20 mL) and MeOH (20 mL) was added Raney-Ni (suspension in water) at room temperature, the resulting mixture was stirred for 3 hours under hydrogen atmosphere (1 atm). The reaction was filtered and concentrated. The residue was washed twice with MeOH to obtain the title compound (280 mg, purity: 90%), which was used directly in the next step. MS (ESI): 575 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:30][O:31][CH2:32][C@H:33]([CH3:53])[O:34][C:35]1[CH:36]=[C:37]([OH:52])[CH:38]=[C:39]([C:41]2[NH:42][C:43]([C:46]3[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=3)=[CH:44][CH:45]=2)[CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:52][C:37]3[CH:38]=[C:39]([C:41]4[NH:42][C:43]([C:46]5[O:47][C@@H:48]([CH3:51])[CH2:49][N:50]=5)=[CH:44][CH:45]=4)[CH:40]=[C:35]([O:34][C@@H:33]([CH3:53])[CH2:32][O:31][CH3:30])[CH:36]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:14][CH:15]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)S(=O)(=O)c2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
5-Chloro-N,N-bis(4-methoxybenzyl)pyridine-2-sulfonamide (288 mg, 0.67 mmol) synthesized in Example (120b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 1 hour under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0.5%-5%) to afford the desired compound (160 mg, yield 33%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Reactant: COCCOCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: COCCOCn1cc(-c2ccccc2OC)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Under nitrogen 755 mg (2.49 mmol) of 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine was dissolved in 30 ml of anhydrous THF. 200 mg of sodium hydride were added and the resulting mixture was stirred at ambient temperature for 4 h. 0.5 ml of (2-methoxy-ethoxy)methyl chloride was added and the resulting mixture stirred at room temperature for 72 h. 0.75 ml of (2-methoxy-ethoxy)methyl chloride and an excess of sodium hydride were added and the reaction mixture allowed to stir at ambient temperature for am additional 4 h. 250 mg of tetra-n-butylammonium iodide were added and the reaction mixture stirred for 2 h at room temperature. The reaction was then quenched by addition of methanol and distributed between a saturated aqueous solution of ammonium chloride and dichloromethane. The aqueous phase was extracted with pyridinepethane and the combined organic phases dried over sodium sulfate and evaporated. The crude was then purified by chromatography on silica gel using a gradient of ethyl-acetate in hexanes to afford 922 mg (2.36 mmol, 95% yield) of 5-bromo-1-(2-methoxy-ethoxymethyl)-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a yellow oil. 1H-NMR (d6-DMSO): δ 8.40 (d, J=1.9 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.97 (s, 1H), 7.52 (dd, J=1.3 Hz, 7.3 Hz, 1H), 7.34 (dd, J=1.4 Hz, 8.7 Hz, 1H), 7.15 (d, J=8.2 Hz 1H), 7.06 (t, J=7.3 Hz, 1H), 5.71 (s, 2H), 3.83 (s, 3H), 3.57 (m, 2H), 3.41 (m, 2H), 3.20 (s, 3H); MS: m/z 315, 317 [MH+-MeOC2H4O].
Reaction SMILES: CC1(C2C=CC(C(O)C(C)(C)C)=CC=2)OCCO1.CC1(C2C=CC(C(O)C(C)(C)C)=CC=2Cl)OCCO1.[CH2:38]([C:40]1([C:45]2[CH:50]=[CH:49][C:48]([CH:51]([OH:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=2)OCC[O:41]1)[CH3:39]>>[C:40]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]([OH:56])[C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)(=[O:41])[CH2:38][CH3:39]
Reactant: CCC1(c2ccc(C(O)C(C)(C)C)cc2)OCCO1
Agent: CC1(c2ccc(C(O)C(C)(C)C)cc2)OCCO1
Agent: CC1(c2ccc(C(O)C(C)(C)C)cc2Cl)OCCO1
Product: CCC(=O)c1ccc(C(O)C(C)(C)C)cc1

Procedure:
When the above reaction is carried out using in place of 2-methyl-2-(4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)1,3-dioxolane, and equivalent amount of 2-methyl-2-(2-chloro-4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)-1,3-dioxolane, or 2-ethyl-2 -(4-[1-hydroxy-2,2-dimethylpropyl]-phenyl)-1,3-dioxolane, there is obtained 1-(2-chloro-p-acetophenyl)-2,2-dimethylpropanol or 1-(p-propionylphenyl)-2,2-dimethylpropanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[CH:4][CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.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>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=3)=[CH:3][CH:4]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 38.3 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 40 mg, 0.094 mmol), 4-nitrobenzeneboronic acid (19 mg, 0.10 mmol), potassium carbonate (40 mg, 0.290 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes, diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (16.8 mg, 0.036 mmol, 38% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.90 (s, 1H), 12.96 (br. s., 1H), 10.19 (t, J=5.05 Hz, 1H), 8.30 (ddd, J=9.09, 2.53, 2.27 Hz, 2H), 7.95 (ddd, J=9.35, 2.53, 2.27 Hz, 2H), 7.78 (d, J=8.34 Hz, 2H), 7.45 (d, J=8.34 Hz, 2H), 5.33 (s, 2H), 4.10 (d, J=5.56 Hz, 2H), 3.20 (qq, J=7.07, 6.87 Hz, 1H), 1.22 (d, J=6.82 Hz, 6H). MS (ES+) m/e 467 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[N:28]=[CH:27][C:26]([OH:29])=[CH:25][C:22]=1[C:23]#[N:24].[CH3:30][O:31][CH2:32][CH2:33]O.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:20][C:21]1[N:28]=[CH:27][C:26]([O:29][CH2:33][CH2:32][O:31][CH3:30])=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: COCCO
Reactant: N#Cc1cc(O)cnc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cnc(Cl)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 100 mL round bottom flask under N2 were dissolved triphenylphosphine (19 g, 73 mmol), 2-chloro-5-hydroxynicotinonitrile (7.5 g, 49 mmol), and 2-methoxyethanol (5.7 ml, 73 mmol) in THF (130 mL) followed by a slow addition of DEAD (27 ml, 68 mmol), and then stirred at room temperature. After 2 h the reaction showed full conversion to the desired compound. The crude mixture was purified by MPLC eluting with 100% DCM to 90% DCM: 10% MeOH to afford 2-chloro-5-(2-methoxyethoxy)nicotinonitrile (6.46 g, 63% yield) as a tan solid.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[C:15]([NH:18][C:19]1[S:20][C:21]([C:25](=[O:28])[CH2:26]Br)=[C:22]([CH3:24])[N:23]=1)(=[O:17])[CH3:16]>C(N(CC)CC)C>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][CH2:26][CH:25]([OH:28])[C:21]2[S:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[N:23][C:22]=2[CH3:24])=[CH:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Reactant: CCOC(=O)c1ccc(CCN)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCNCC(O)c2sc(NC(C)=O)nc2C)cc1

Procedure:
Prepared analogously to Example 3 by reaction of 2-(4-carboethoxyphenyl)ethylamine and stoichiometric amounts of triethylamine with 2-acetylamino-4-methyl-5-bromoacetyl-thiazole, followed by reduction and purification of the base on a silica gel column using ethyl acetate/methanol=19:1 as eluant and trituration with ether.