Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C@:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]([CH3:45])[C:28]([C:30]1[N:39]([CH:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[C:33]2[N:34]=[C:35](Cl)[N:36]=[CH:37][C:32]=2[CH:31]=1)=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][CH2:23][C@:10]2([O:14][C:13](=[O:15])[N:12]([C:16]3[CH:17]=[N:18][C:19]([NH:22][C:35]4[N:36]=[CH:37][C:32]5[CH:31]=[C:30]([C:28](=[O:29])[N:27]([CH3:26])[CH3:45])[N:39]([CH:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)[C:33]=5[N:34]=4)=[CH:20][CH:21]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@]2(C1)CN(c1ccc(N)nc1)C(=O)O2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@]5(CCCN(C(=O)OC(C)(C)C)C5)OC4=O)cn3)nc2n1C1CCCC1
Yield: 43 %

Procedure:
Following general N—C coupling procedure 1, (S)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave (S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butyl ester as a white solid (0.115 g, 0.190 mmol in 43% yield. 1H NMR (400 MHz, CDCl3) δ ppm 1.37-1.51 (m, 13H) 1.51-1.69 (m, 3H) 1.69-1.84 (m, 2H) 1.85-2.15 (m, 11H) 2.47-2.68 (m, 2H) 3.10-3.19 (m, 6H) 3.19-3.33 (m, 2H) 3.43 (d, J=14.05 Hz, 1H) 3.58-3.71 (m, 2H) 3.71-3.80 (m, 2H) 3.85 (d, J=9.03 Hz, 2H) 4.12 (q, J=7.03 Hz, 1H) 4.44 (br. s., 1H) 4.80 (quin, J=8.78 Hz, 1H) 6.46 (s, 1H) 7.87-7.99 (m, 1H) 8.11 (dd, J=9.29, 2.76 Hz, 1H) 8.21 (br. s., 1H) 8.30 (br. s., 1H) 8.52 (d, J=9.03 Hz, 1H) 8.75 (s, 1H). MS m/z 605.5 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C@H:17]1[CH2:21][C@@H:20]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=4[O:41][CH3:42])[C:25]=3[CH:24]=[CH:23]2)[C@H:19]([OH:43])[C@@H:18]1[OH:44].O=[C:46]1[CH2:49][CH:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:47]1.C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:30]1[C:25]2[CH:24]=[CH:23][N:22]([C@@H:20]3[CH2:21][C@H:17]([CH2:16][NH:15][CH:46]4[CH2:47][CH:48]([CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49]4)[C@@H:18]([OH:44])[C@H:19]3[OH:43])[C:26]=2[N:27]=[CH:28][N:29]=1
Reactant: CCOC(=O)CCC1CC(=O)C1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN)[C@@H](O)[C@H]2O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CCC1CC(NC[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@H](O)[C@@H]2O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Sodium triacetoxyborohydride (2.43 g, 11.5 mmol) was added to a solution of (1S,2R,3R,5R)-3-(aminomethyl)-5-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1,2-diol (2.6 g, 5.7 mmol) and ethyl 3-(3-oxocyclobutyl)propanoate (0.976 g, 5.73 mmol) and Acetic acid (0.326 ml, 5.73 mmol) in 1,2-Dichloroethane (20 ml) and reaction was stirred at RT overnight. NaHCO3 was added and the aqueous layer was extracted 3× with DCM. The combined organics were dried with MgSO4, filtered, concentrated and purified by flash chromatography (DCM/7N NH3 in MeOH 90:10) to give the desired compound (1.8 g) as a thick yellow resin.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=1[F:23].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CC(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17]1[C:18]([F:25])=[C:19]([CH:20]=[CH:21][C:22]=1[F:23])[O:24][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]
Reactant: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(O)c2F)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of 3-[(2,3-dimethyl-5-phenyl-phenyl)methylamino]-2,4-difluoro-phenol (120 mg, 0.4 mmol, 1.0 eq) in acetone (4 mL) was added Cs2CO3 (173 mg, 0.5 mmol, 1.5 eq) and the reaction was stirred at room temperature for 30 min. Isopropyl bromoacetate (76 mg, 0.42 mmol, 1.2 eq) was added and the reaction was stirred at room temperature for 1 h. Water was added and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as a colorless oil (117 mg, 75%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(CC(=O)C)C(C)=[O:11].CC(C)=O.C(OO)(=O)C>>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([OH:11])[CH:2]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1ccc(O)cc1
Agent: CC(=O)OO
Solvent: CC(C)=O
Product: Cc1ccc(O)c(O)c1

Procedure:
A reaction flask having an inner volume of 200 ml and provided with a thermometer, a stirrer, a reflux condenser and a dropping funnel was charged with 54.05 g (0.50 mol) of para-cresol and 0.054 g of acetonyl acetone. While the resultant mixture was continuously stirred, 5.59 g (0.025 mol) of an acetone solution of 34.0 percent by weight of peracetic acid was introduced dropwise at a temperature of 80° C over a period of 20 minutes. After termination of the dropwise introduction of the peracetic acid solution, the reaction system was stirred at the same temperature for an additional period of 50 minutes to bring the reaction to completion. Thereafter, the reaction mixture was analyzed for unaltered para-cresol and formed 4-methyl-1,2-dihydroxybenzene by gas chromatography. The results showed the conversion of para-cresol to be 4.19 percent and the selectivity for 4-methyl-1,2-dihydroxybenzene to be 73.6 percent relative to peracetic acid and 88.4 percent relative to para-cresol respectively. From the reaction mixture, acetone, formed acetic acid and para-cresol were recovered by distillation. When the recovered mixture was analyzed for acetonyl acetone by gas chromatography, the recovery ratio of acetonyl acetone was found to be 88 percent.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[CH3:25][OH:26].C[O-].[Na+].Cl>O>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([O:26][CH3:25])[N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cncc(Cl)n2)c2c1C[C@H]1C[C@@H]21
Reactant: CO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cncc(-n2nc(C(=O)NC(C)(C)CO)c3c2[C@@H]2C[C@@H]2C3)n1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
(1aR,5aR)-2-(6-Chloro-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (25 mg, 0.072 mmol) was added to a 3.7 M methanol solution of sodium methoxide (0.583 mL, 2.156 mmol). The white suspension was stirred at 23° C., for 30 min. 1 M HCl (2.5 mL) and water (5 mL) were added. The mixture was extracted with dichloromethane (3×5 mL). The combined organic extracts were concentrated under reduced pressure and purified by silica gel flash chromatography to provide the title compound (12 mg) as a white solid. LCMS m/z=344.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.47 (td, J=4.7, 3.3 Hz, 1H), 1.25 (td, J=7.9, 4.8 Hz, 1H), 1.419 (s, 3H), 1.422 (s, 3H), 2.26-2.32 (m, 1H), 2.71-2.76 (m, 1H), 2.92 (d, J=16.9 Hz, 1H), 3.02 (dd, J=16.6, 6.2 Hz, 1H), 3.71 (s, 2H), 4.03 (s, 3H), 4.70 (bs, 1H), 6.96 (s, 1H), 8.17 (d, J=0.5 Hz, 1H), 8.75 (d, J=0.5 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(CN)CCCCC1.[O:15]=[C:16]1[C:24]2([CH2:28][O:27][C:26]3[CH:29]=[C:30]4[C:34](=[CH:35][C:25]2=3)[CH2:33][CH2:32][O:31]4)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[N:1]1([C:41]([C:40]2[CH:39]=[CH:38][C:37]([CH2:36][N:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:24]4([CH2:28][O:27][C:26]5[CH:29]=[C:30]6[C:34](=[CH:35][C:25]4=5)[CH2:33][CH2:32][O:31]6)[C:16]3=[O:15])=[CH:45][CH:44]=2)=[O:42])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Reactant: C1COCCN1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1)N1CCOCC1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using morpholine to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, 1′-[4-(morpholin-4-ylcarbonyl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (58%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.44-7.35 (m, 4H), 7.24-7.15 (m, 2H), 7.04 (dd, J=7.5, 7.5 Hz, 1H), 6.76 (d, J=7.5 Hz, 1H), 6.48 (s, 1H), 6.44 (s, 1H), 4.98 (ABq, 2H), 4.85 (ABq, 2H), 4.55 (t, J=8.6 Hz, 2H), 3.87-3.40 (m, 8H), 3.08-2.93 (m, 2H); MS (ES+) m/z 483.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[OH:14]O.O>C(O)(=O)C.OS(O)(=O)=O>[Cl:11][C:10]1[C:2]([Cl:1])=[C:3]2[C:4]([O:12][C:5](=[O:14])[NH:6][C:7]2=[CH:8][CH:9]=1)=[O:13]
Reactant: O=C1Nc2ccc(Cl)c(Cl)c2C1=O
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2ccc(Cl)c(Cl)c2c(=O)o1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 89.6 %

Procedure:
To a suspension of 4,5-dichloroisatin (13f, 216 mg, 1.0 mmol) in glacial acetic acid (5 mL) and 2 drops (about 0.02 mL) of conc H2SO4 was added 0.34 mL (about 3 mmol) of 30% H2O2. The mixture was stirred at 70° C. (bath) for 2.5 h (the mixture turned into a solution, then formed a precipitate), allowed to cool to 22° C. and cold water (10 mL) was added. The precipitate was filtered, washed with water (6×10 mL), dried to give 208 mg (90%) of 14e as an orange-yellow powder, mp 267°-9° C. (dec). IR, 1810, 1779, 1762, 1711, 1600, 1335, 1254, 1041, 1024 cm-1 ; 1H NMR δ 11.952 (bs, 1H), 7.928 (d, J=8.7 Hz, 1H), 7.110 (d, J=8.7Hz, 1H); HRMS Calcd for C8H3Cl2NO3 : 230.9490; Found: 230.9489.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1.C(N(CC)CC)C>C(O)C.[H][H].[Pt]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])=[N:6][CH:7]=1
Reactant: [H][H]
Reactant: COCC#Cc1ccc(Br)cn1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COCCCc1ccc(Br)cn1
Yield: 69.4 %

Procedure:
5-Bromo-2-(3-methoxypropynyl)pyridine (5.652 g) was dissolved in ethanol (150 ml), followed by the addition of triethylamine (2.5 ml) and platinum oxide (230 mg), and the resulting mixture was stirred in hydrogen atmosphere at room temperature for 5 hr. After the platinum oxide was filtered off, the resulting mixture was evaporated and partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a yellow oil (3.991 g, yield; 68%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:17]1[CH:22]=[C:21]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: CON(C)C(=O)c1cc2ccccc2[nH]1
Reactant: OB(O)c1cccc(F)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Yield: 37.1 %

Procedure:
Activated molecular sieves (13 g) 4 Å were placed in an oven dried round bottom flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N-methyl-1H-indole-2-carboxamide (0.97 g, 4.7 mmol), (3-fluorophenyl)-boronic acid (1.5 g, 11 mmol), cupric acetate (1.3 g, 7.3 mmol), methylene chloride (130 mL) and then pyridine (1.5 mL, 19 mmol). The reaction mixture was stirred at room temperature over the weekend. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-30% EtOAc/hexane) to give the title compound (0.52 g, 37%). LCMS calculated for C17H16FN2O2(M+H)+: m/z=299.1. Found: 299.1.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([C:30](=[O:32])[CH3:31])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CC[C@@H](n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1
Reaction time: 1 h

Procedure:
To a solution of 1-({5-chloro-1-[(3R)-(pyrrolidin-3-yl)]-1H-benzo[d]imidazol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (30 mg), acetic anhydride (0.1 mL) in 8 mL of DCM was added DMAP (3 mg, 0.025 mmol). The mixture was stirred for 1 hour. Then 20 mL of DCM and 10 mL of water was added. The organic phase was washed with water and NaHCO3 and then dried over anhydrous Na2SO4. The solvent was evaporated. The residue was purified by preparative-HPLC to afford the title compound (15 mg) as a pale solid.
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[CH2:4].[C:10](=[O:12])=[O:11]>C1COCC1>[CH:3]([C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[C:10]([OH:12])=[O:11])=[CH2:4]
Reactant: O=C=O
Reactant: C=CC1(Br)C=CC=CC1
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)C=CC=CC1
Temperature: 25 °C
Yield: 66 %

Procedure:
Preparation of ##STR89## Mg turnings (1.75g, 0.072 g atom) were placed in an oven dried 250 ml 3 neck flask with condenser and addition funnel (all assembled hot). The entire apparatus was evacuated and filled with argon. The flask was charged with 10 ml of anhydrous THF and the addition funnel was charged with 8.0 gm (43.7 mmol) of 1-bromostyrene in 50 ml of anhydrous THF. Five (5) ml of the 1-bromostyrene solution was added to the Mg turnings and the mixture was heated to 65°-70° C. and the remainder of the solution was added over 1 hour. The mixture was heated an additional 30 min., then cooled to room temperature over 1 hour, then poured over crushed dry ice and the dry ice was allowed to evaporate. The mixture was made strongly acidic with 150 ml of 10% HCl solution. The organic phase was separated and the aqueous phase was extracted three times with ether. The combined organic phase was poured into 150 ml of 20% KOH solution, the solution was separated and the basic phase was filtered to remove polymer. The basic phase was then acidified with 10% HCl solution and extracted three times with 100 ml portions of ether. The extracts were combined, washed with 100 ml of brine and dried over Na2SO4. The solution was filtered and concentrated to a white solid which was recrystallized from chloroform/hexane solution to yield 6.44 g (66%) of 1-vinylbenzoic acid in two crops. ##STR90## Iodine (4.12 g, 16.22 mmol) was added in a single portion to a degassed solution of 1.20 gm (8.11 mmol) of compound 17a in 12 ml of acetonitrile. The solution was stirred for 1 hour, then poured into 50 ml of saturated sodium thiosulfate solution. The solution was extracted three times with 50 ml portions of ethyl acetate. The combined organic phases were washed sequentially with 40 ml portions H2O, saturated NaHCO3 solution and saturated sodium thiosulfate solution then dried over MgSO4. The solution was filtered and concentrated to a yellow solid (1.87 g, 84% yield) which was recrystallized from ethanol. ##STR91##
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17]>CO>[Cl:4][C:5]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:2][NH:3][C:15]=1[CH2:16][CH3:17]
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Reactant: NN
Solvent: O
Solvent: CO
Product: CCc1n[nH]c(CC)c1CCCCCCOc1ccc(OC)cc1Cl

Procedure:
Hydrazine hydrate (15.7 ml, 0.32 m) was added over a 20 min. period to a slurry of 100 g (0.272 m) of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione in 300 ml of methanol. The internal temperature rose to a maximum of 50° C. during the addition. The reaction mixture was heated at reflux for one hour, and the solvent was then removed in vacuo. The residue was dissolved in 300 ml of methylene dichloride and the resulting solution was washed with three 100 ml portions of water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to leave 100 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazole as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=2)=[CH:4][CH:3]=1.N#N.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH:52]=[N:51][CH:50]=[N:49]1>S(Cl)(Cl)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)([N:48]2[CH:52]=[N:51][CH:50]=[N:49]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C
Reactant: c1nc[nH]n1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cn1cncc1C(c1ccc(Cl)cc1)(c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C)n1cncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one (330 mg, 0.633 mMol) was dissolved in 4 mL of thionyl chloride and stirred at ambient temperature under a stream of dry N2 for 2 hours. The reaction mixture was then concentrated under vacuum and toluene (5 mL) was added to the reaction mixture which was subsequently concentrated under vacuum to give a yellow solid. 210 mg of the yellow solid was dissolved in 5.0 mL of anhydrous DMF under an atmosphere of dry N2. To this solution was added 800 mg of potassium carbonate and 300 mg of 1,2,4-triazole and the reaction mixture was subsequently heated to 80° C. and stirred overnight at this temperature. The reaction mixture was then concentrated under vacuum and partitioned between EtOAc and water. The EtOAc layer was washed 3 more times with water and then with brine. The EtOAc layer was then dried over Na2SO4, filtered and concentrated under vacuum to give a yellow solid. The solid was chromatographed on flash silica gel eluting with a gradient of MeOH/DCM/NH4OH (2/98/0.1) to MeOH/DCM/NH4OH (7/93/0.1) to give 150 mg of the titled product as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Yield: 104.8 %

Procedure:
To a solution of 1-acetylpiperazine (48 g) in acetonitrile (100 ml) were added 2,5-difluoronitrobenzene (50 g) and potassium carbonate (44 g) and the mixture was refluxed under heating for 5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent was evaporated to give the title compound (88 g) as a red solid.
Reaction SMILES: [Na].[C:2](OCC)(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+].C(O[C:20](=[O:27])[CH:21]=[C:22]([NH2:26])[CH:23]1[CH2:25][CH2:24]1)C>C(O)C.O>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[C:20]([OH:27])=[CH:21][C:22]([CH:23]2[CH2:24][CH2:25]2)=[N:26][C:2]=1[OH:9])[CH3:8]
Reactant: CCOC(=O)C=C(N)C1CC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)cc(C2CC2)nc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Sodium metal (8.1 g, 119 mmol) was cut into small pieces and added portionwise to stirred ethanol (120 mL) at room temperature under a nitrogen atmosphere. The mixture was then stirred at 60° C. under N2 overnight to ensure complete dissolution of the metal. Diethyl malonate (18.1 ml, 119 mmol) was added to the sodium ethoxide solution at 60° C. and the mixture was stirred at 60° C. under N2 for 1 h. A solution 3-Amino-3-cyclopropyl-acrylic acid ethyl ester (10.3 g, 40 mmol) in ethanol (10 mL) was added dropwise at 60° C. and the mixture was heated at reflux under N2 for 5 days to give an orange suspension. The mixture was allowed to cool to room temperature and the resulting solid collected by filtration. The filtrate was concentrated in vacuo to give more solid. The combined solids were dissolved in water (150 mL) and the solution washed with EtOAc (150 mL). The aqueous was acidified to pH2 using concentrated HCl causing a white solid to precipitate. The solid was collected by filtration, washed with cold water and then Et2O, and then dried in vacuo at 40° C. overnight to give the title product (5.32 g) as a fine white solid. The filtrate was concentrated in vacuo to half its volume causing more product to precipitate. This second crop of solid was collected by filtration, washed with water and Et2O and dried in vacuo at 40° C. to give a further 0.35 g of the title compound as a pale beige solid.