Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[C:15]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])=[N:14][CH:13]=[C:12]([NH2:25])[N:11]=1>CS(C)=O.O>[Br:1][C:13]1[N:14]=[C:15]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=2[Cl:24])[C:10]([NH2:9])=[N:11][C:12]=1[NH2:25]
Reactant: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: O
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1Br
Temperature: 15 °C
Reaction time: 1 h

Procedure:
N-Bromosuccinimide (0.194 g, 1.09×103 mole) was added over 20 min to a mixture of 2,6-diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.3 g, 1.04×10−3 mole) in dimethylsulfoxide (10 ml) and water (0.25 ml) below 15° C. The resulting reaction mixture was stirred at 15° C. for 1 hr, poured onto ice water (150 ml) and extracted with ethyl acetate (2×75 ml). The extract was then washed with 2 M sodium carbonate solution (50 ml) and water (100 ml), dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated in vacuo. The residue was purified by ‘flash chromatography’ using 5-13% ethyl acetate in cyclohexane as the eluent. Yield 0.183 g (48%), M.p. 222-224° C.
Reaction SMILES: CC1C=CC([C:8]2CC[CH2:11][C:10](=[O:14])[CH:9]=2)=CN=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][N:17]=1.C[O-].[Na+].C(C(C)=O)=C>C1C=CC=CC=1.CO>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH:23]([CH2:8][CH2:9][C:10](=[O:14])[CH3:11])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:29])=[CH:18][N:17]=1
Reactant: Cc1ccc(C2=CC(=O)CCC2)cn1
Reactant: CCOC(=O)CC(=O)c1ccc(C)nc1
Agent: C=CC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccc(C)nc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
B-2. 3-(2-Methyl-5-pyridinyl)-2-cyclohexen-1-one--To a stirred solution containing 48 g. of ethyl 3-(2-methyl-5-pyridinyl)-3-oxopropanoate in a mixture of 300 ml. of dry benzene and 100 ml. of dry methanol, said solution kept under nitrogen, was added 0.1 g. of sodium methoxide followed by the dropwise addition over a period of about 1 hour of the solution containing 16 g. of freshly distilled methyl vinyl ketone in a mixture of 60 ml. of benzene and 10 ml. of methanol. After the reaction had proceeded slowly at room temperature overnight, an additional 0.1 g. of sodium methoxide plus 4 ml. of additional methyl vinyl ketone were added and the reaction mixture was heated with stirring at 40° C. for 8 hours. The solvent was distilled-off in vacuo; 300 ml. of benzene was added; the benzene solution was washed once with brine, dried over anhydrous sodium sulfate and heated in vacuo to remove the benzene thereby yielding a quantative yield (63.5 g.) of ethyl 2-(2-methyl-5-pyridinylcarbonyl)-5-oxohexanoate which was added to a mixture containing 95 ml. of concentrated sulfuric acid and 185 ml. of water. The acidic reaction mixture was slowly heated. After about 30 minutes, the temperature reaches 55° C. and the evolution of carbon dioxide became noticeable. The temperature of the reaction mixture was maintained at 65° C. for about 1 hour and then heated to 80° C. and held there for several minutes. By this time the evolution of carbon dioxide appeared to be over. The reaction mixture was cooled and poured into a solution of 305 g. of potassium carbonate in 1 liter of ice water. Chloroform was added; the mixture was shaken well and filtered to remove the precipitated potassium sulfate; and, the layers were separated. The aqueous layer was extracted further with chloroform; the combined chloroform extracts were dried over anhydrous sodium sulfate and filtered; the dried filtrate was heated in vacuo to remove the chloroform to yield, after air-drying, 27.4 g. (80%) of 1-(2-methyl-5-pyridinyl)hexan-1,5-dione, a tan solid melting at 85°-87° C.
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH2:19]([O:24][CH:25]1[CH:27]([C:28](O)=[O:29])[C:26]1([CH3:32])[CH3:31])[CH2:20][CH2:21][CH2:22][CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[CH2:19]([O:24][CH:25]1[CH:27]([C:28]([O:18][CH:3]([C:1]#[N:2])[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=2)=[O:29])[C:26]1([CH3:31])[CH3:32])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCOC1C(C(=O)O)C1(C)C
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCOC1C(C(=O)OC(C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of α-cyano-4-fluoro-3-phenoxybenzyl alcohol (437 mg., 1.8 mmol), 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of DMF is added N,N'-dicyclohexylcarbodiimide (2 mmol). The reaction mixture is stirred, under nitrogen, for about two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueons sodium bocarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph eluting with ether/hexane to yield α-cyano-4-fluoro-3-phenoxybenzyl 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][NH:53][CH3:54])=[CH:50][CH:49]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([CH2:52][N:53]([CH3:54])[C:10](=[O:11])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)=[CH:50][CH:49]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: CS(=O)(=O)N1CCN(CCC(C(=O)O)c2ccc(Cl)c(Cl)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(Cl)cc1)C(=O)C(CCN1CCN(S(C)(=O)=O)CC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 61.4 %

Procedure:
A mixture of 25 mg 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid (intermediate 1), 24.1 mg (0.075 mmol) TBTU, 11.67 mg (0.075 mmol) (4-chloro-benzyl)-methyl-amine (commercially available) and 0.06 mL N,N-diisopropyl ethylamine in 0.75 mL DMF was shaken at room temperature and subsequently subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 20.7 mg (67%) of the title compound as yellow viscous oil. MS(m/e): 534.2 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:18][CH3:19])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16])=O.CC1(C)C2C(=C(OC)C=C(C)C=2)C(C)(C)CC1.C(O)(=O)C.P(=O)(O)(O)O.[ClH:46].C=O>C1C=CC=CC=1>[Cl:46][CH2:1][C:3]1[C:4]([O:18][CH3:19])=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]2([CH3:17])[CH3:16]
Reactant: Cl
Reactant: COc1c(C=O)c(C)cc2c1C(C)(C)CCC2(C)C
Agent: C=O
Agent: COc1cc(C)cc2c1C(C)(C)CCC2(C)C
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1c(CCl)c(C)cc2c1C(C)(C)CCC2(C)C
Temperature: 95 °C

Procedure:
To prepare the corresponding 6-carboxaldehyde, 6-formyl-1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene, 1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (23.2 g, 0.1 mol) is added to a stirred solution of acetic acid (18.2 g, 0.3 mol), 85% phosphoric acid (17.6 g, 0.15 mol), hydrochloric acid (28.7 g, 0.3 mol) and paraformaldehyde (7.3 g, 0.24 mol). The mixture is stirred and heated at 95° C. for 16 hr. The reaction mixture is then cooled to 25° C., benzene (50 ml) added, and stirred vigorously. The organic layer is separated, washed with water (2×25 ml), neutralized with 5% sodium bicarbonate solution, and dried (Na2SO4). The solvent is removed by distillation to provide 6-chloromethyl-1,1,4,4,7-pentamethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:38])([F:37])[C:21]1[CH:36]=[CH:35][CH:34]=[CH:33][C:22]=1[CH:23](O)[C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=1[F:31].C(N1CC(OC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2Cl)C1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][CH:23]([C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[F:31])[C:22]2[CH:33]=[CH:34][CH:35]=[CH:36][C:21]=2[C:20]([F:38])([F:37])[F:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1F)c1ccccc1C(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Product: Fc1cc(Br)ccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1C(F)(F)F

Procedure:
This material was prepared from 1-benzhydryl-3-azetidinol (1) (23.0 mmol) and 2-(trifluoromethyl)-2′-fluoro-4′-bromobenzhydrol (112) (34.0 mmol) using the procedure described for compound (3) (8.84 g, 67%).
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([C:7]1[CH:32]=[CH:31][C:10]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:9][CH:8]=1)([OH:6])=[O:5].[C:33]1([CH:39]([CH3:42])[CH:40]=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.S(=O)(=O)(O)[O-].[Na+]>CS(C)=O>[C:4]([C:7]1[CH:8]=[CH:9][C:10](/[CH:11]=[CH:40]/[CH:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:42])=[CH:31][CH:32]=1)([OH:6])=[O:5]
Reactant: CC(C=O)c1ccccc1
Reactant: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [H-]
Solvent: CS(C)=O
Product: CC(/C=C/c1ccc(C(=O)O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of sodium hydride (50% in mineral oil; 3.4 g, 70 mmol) and dimethyl sulfoxide (50 ml) was heated to 75° for 1.5 hours under a nitrogen atmosphere. The solution was cooled to ambient temperature, and (4-carboxybenzyl)triphenylphosphonium bromide (18 g, 37 mmol) was added. The resulting red solution was stirred for 1 hour at ambient temperature. A solution of α-phenylpropionaldehyde (2.5 g, 19 mmol) in dimethyl sulfoxide (10 ml) was added over a ten minute period. Stirring was continued for an additional twenty minutes. The reaction mixture was poured into 0.2M sodium bisulfate, and the resulting mixture was extracted three times with ether. The combined ether extracts were washed with saturated aqueous sodium chloride, dried (sodium sulfate) and evaporated. The residue was subjected to column chromatography on silica gel (E. Merck No. 7734). Elution with 1% acetic acid in 1:1 hexane-ether afforded pure 1-(4'-carboxyphenyl)-3-phenyl-trans-1-butene as a white solid; yield 48 mg (10%); m.p. 127°-130°; mass spectrum m/z 252 (M), 237 (M--CH3).
Reaction SMILES: [CH:1]1([C:18]([O:20][C@@H:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11](OC(C)(C)C)=O.Cl.O1CCOCC1.[Cl:36][C:37]1[CH:38]=[N+:39]([O-:66])[CH:40]=[C:41]([Cl:65])[C:42]=1[CH2:43][C@H:44]([O:55][C:56]([C:58]1[S:59][C:60](C=O)=[CH:61][CH:62]=1)=[O:57])[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[CH:46]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.C(#N)C>[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:18]([CH:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][N:2]1[CH2:11][C:60]1[S:59][C:58]([C:56]([O:55][C@H:44]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[C:47]([O:53][CH3:54])[CH:46]=3)[CH2:43][C:42]3[C:41]([Cl:65])=[CH:40][N+:39]([O-:66])=[CH:38][C:37]=3[Cl:36])=[O:57])=[CH:62][CH:61]=1)=[O:19])[CH2:22]2
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCc2ccccc2C1C(=O)O[C@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CN3CCc4ccccc4C3C(=O)O[C@H]3CN4CCC3CC4)s2)cc1OC
Yield: 18.3 %

Procedure:
o a solution of O2-tert-butyl O1-[(3R)-quinuclidin-3-yl] 3,4-dihydro-1H-isoquinoline-1,2-dicarboxylate (440 mg, 1.14 mmol) in ethyl acetate (1.42 mL) was added 4N HCl/dioxane (1.42 mL, 5.70 mmol) and the resultant solution was stirred at room temperature for 18 h. The solvent was removed in vacuo to give a white solid. The crude material (200 mg, 0.56 mmol) was dissolved in acetonitrile (5 mL) and [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (270 mg, 0.56 mmol) was added followed by acetic acid (67 μL, 1.12 mmol). The resultant solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue azeotroped with toluene. The residue was rediluted with acetonitrile (5 mL) and sodium triacetoxyborohydride (237 mg, 1.12 mmol) was added and the resultant solution was stirred at room temperature for 18 h. The solvent was removed in vacuo and the residue was taken up in water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×20 mL). The combined organic phases were extracted with 0.2 N aqueous hydrochloric acid (40 mL) and water (40 mL). The aqueous extracts were combined and sodium chloride (6 g) was added. The mixture was extracted with chloroform (3×30 mL) and the combined organic extracts were passed through a hydrophobic fit and the solvent was removed in vacuo. Purification of the crude material by preparative HPLC afforded the title compound (77 mg, 18%) as a pale yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[C:11]([CH3:13])[NH:10][C:9](=[O:14])[C:8]=2[C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].II.Cl>C1COCC1>[NH2:16][CH2:15][C:8]1[C:9](=[O:14])[NH:10][C:11]([CH3:13])=[CH:12][C:7]=1[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C2CCCCC2)c(C#N)c(=O)[nH]1
Agent: Cl
Agent: II
Agent: [BH4-]
Solvent: C1CCOC1
Product: Cc1cc(C2CCCCC2)c(CN)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
To an ice-bath cooled THF (100 mL) solution of the product from step 1 (2 g, 9.26 mmol) were added NaBH4 (0.81 g, 21.3 mmol), and I2 (2.3 g, 9.26 mmol), and the mixture stirred for 30 min. The reaction mixture was then heated at reflux for 3 h, and then allowed to cool to room temperature. After cooling to 0° C., the reaction mixture was acidified by slow addition of 3 N HCl (1 mL). The reaction mixture was concentrated in vacuo and the crude product purified by reverse phase HPLC to give the title compound as a solid (0.5 g, 25%). LCMS E-S (M+H)=221.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.8-11.9 (br s, 1H), 7.80-7.93 (br s, 3H), 6.07 (s, 1H), 3.69 (s, 2H), 2.67-2.75 (m, 1H), 2.17 (s, 3H), 1.58-1.72 (m, 5H), 1.19-1.41 (m, 5H).
Reaction SMILES: CC1(C)COB(B2OCC(C)(C)CO2)OC1.C([O-])(=O)C.[K+].Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.Br[C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][C:45]=1[Cl:46])[NH:42][N:41]=[C:40]2[C:47]([OH:49])=[O:48].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1(C)C=CC=CC=1.CCO.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].ClCCl>[Cl:46][C:45]1[CH:44]=[C:43]2[C:39]([C:40]([C:47]([OH:49])=[O:48])=[N:41][NH:42]2)=[CH:38][C:37]=1[C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1
Reactant: O=C(O)c1n[nH]c2cc(Cl)c(Br)cc12
Reactant: CN1CCC(c2ccc(Br)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCO
Product: CN1CCC(c2ccc(-c3cc4c(C(=O)O)n[nH]c4cc3Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
A mixture of 5,5,5′,5′-tetramethyl-2,2′-bi-1,3,2-dioxaborinane (92.0 mg, 0.27 mmol), oven dried potassium acetate (116 mg, 1.18 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (22 mg, 0.027 mmol) and 4-(4-bromophenyl)-1-methylpiperidine (65 mg, 0.26 mmol) in 1,4-dioxane (2.6 mL) was degassed with N2 for 10 minutes, sealed in a pressure tube, and heated to 100° C. for 2 hours. The cooled reaction mixture was filtered through cotton and concentrated in vacuo to give a dark solid. To the dark solid was added 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (59.8 mg, 0.22 mmol), 2 N aqueous potassium carbonate solution (0.4 mL, 0.87 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (18 mg, 0.022 mmol). The reaction mixture was diluted with degassed toluene (0.8 mL) and EtOH (0.8 mL), sealed in a pressure tube and heated at 100° C. for 1.5 hours then 75° C. for an additional 16 hours. The cooled reaction mixture was concentrated in vacuo. The resulting dark solid was purified by reverse phase HPLC (Column: Waters XBridge C18 19×100 mm, 5 μm; Mobile phase A: 0.03% NH4OH in water (v/v); Mobile phase B: 0.03% NH4OH in MeCN (v/v); 95.0% H2O/5.0% MeCN linear to 0% H2O/100% MeCN in 8.5 min, HOLD at 0% H2O/100% MeCN to 10.0 min. Flow: 25 mL/min) to give the title compound (8.2 mg, 9% yield). MS (ES+) 370.2 (M+H)+. Retention time=2.00 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 mL/min).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2.[N+:18]([O-])([O-:20])=[O:19].[Na+].[N+]([O-])(O)=O.[OH-].[NH4+]>>[F:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cc(F)ccc2n1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c([N+](=O)[O-])c(F)ccc2n1
Temperature: 20 °C

Procedure:
To 3.5 l of fuming sulfuric acid was added, with cooling, 600 g (3.73 moles) of 6-fluoroquinaldine in small portions. About 0.1 g of sodium nitrate was added to the mixture, followed by the dropwise addition of 261 ml of fuming red nitric acid over a six-hour period while maintaining the temperature at 5°-10° C. The mixture was stirred at 20° C. for sixteen hours, then poured into 3 gallons of ice. The mixture was basified with ammonium hydroxide with cooling. The precipitated solid was separated by filtration and dissolved in about two liters of warm toluene. The solution was dried over magnesium sulfate, filtered and evaporated to provide a yellow solid, 6-fluoro-5-nitroquinaldine, m.p. 105°-108° C., which was recrystallized from 1,2-dichloroethane. The structural assignment was confirmed by nuclear magnetic resonance and infrared spectral analyses.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[N:3]1.[CH3:18][O-:19].[Na+]>CO>[CH3:1][N:2]1[C:7]([O:19][CH3:18])=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[N:3]1
Reactant: CSc1nc(=O)c(-c2cccc(C)c2)nn1C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(=O)c(-c2cccc(C)c2)nn1C
Yield: 90.9 %

Procedure:
To a solution of 2-methyl-3-methylthio-6-(m-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine (1.0 g) in methanol (10 ml), sodium methoxide (0.5 g) was added, and the resultant mixture was stirred at room temperature for 2 hours. After stirring, the resulting mixture was evaporated to dryness to give a crude product. Recrystallization of the crude product from acetone gave 0.85 g of 2-methyl-3-methoxy-6-(m-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine in 91% yield. M.P., 110° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[CH3:16][CH:17]1[NH:22][C:21]([NH2:23])=[N:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:16][CH:17]1[CH2:18][CH2:19][N:20]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:21]2[NH:22]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC1CCN=C(N)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1CCn2c(nc(-c3ccncc3)cc2=O)N1
Yield: 51.3 %

Procedure:
A mixture of 6 g (31.0 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 4.6 g (31.0 mmol) of 6-methyl-1,4,5,6-tetrahydro-pyrimidin-2-ylamine hydrochloride (prepared according to J. Org. Chem., 20, 1955, 829-838) and 6.44 g (46.0 mmol) of potassium carbonate in 50 ml of ethanol was heated at reflux temperature during 18 h. The reaction mixture was cooled and the solvent removed by evaporation. The residue obtained was treated with water and the precipitate recovered by filtration to give 3.85 g (51%) of product. Mp.: 245-247° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I:12][C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])I.[Cl-].[NH4+].C(Cl)Cl>CS(C)=O.[Cu]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:15]([F:18])([F:17])[C:14]([F:20])([F:19])[C:13]([F:22])([F:21])[I:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(I)C(F)(F)C(F)(F)I
Reactant: CC(=O)Oc1ccc(I)cc1
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)Oc1ccc(C(F)(F)C(F)(F)C(F)(F)I)cc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
A solution of p-iodophenyl acetate (27.5 g, 105 mmol) and 1,3-diiodohexafluoropropane (52.0g, 128.7 mmol) in 100 ml of anhydrous dimethyl sulfoxide was heated to 120° C. under nitrogen. Copper powder (13.5 g, 211 g atoms) was added to the vigorously stirred solution in five approximately equal amounts at 20 minute intervals. After the addition of copper was complete, the reaction mixture was stirred at 120° C. for an additional 1.5 hours. On cooling, saturated aqueous ammonium chloride together with methylene chloride was added to the reaction vessel. The excess copper and cuprous salts were filtered off, the organic layer separated, and the aqueous layer was extracted with more methylene chloride. The organic extracts were combined, washed well with water, dried over anhydrous magnesium sulfate, and reduced in volume to a light yellow oil. The oil was refluxed in 25 ml of acetic anhydride for 45 minutes and the excess acetic anhydride and acetic acid were vacuum distilled. Distillation of the residual oil yielded 24.85 g of crude 4-(perfluoro-3-iodopropyl)phenyl acetate bp126°-127° C./3.4 mm Hg, mp 75°-81° C. Recrystallization of this material from hexane gave 20.8 g (48% yield) of purer material, mp 84.5°-88° C. Repeated crystallization from hexane raised the melting point to 88.5°-89.5° C., which could not be improved upon by further recrystallization.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([CH:11]1[CH2:27][N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18](=O)[CH:13]2[CH2:12]1)=O>C1COCC1>[OH:8][CH2:9][CH:11]1[CH2:27][N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH:13]2[CH2:12]1
Reactant: COC(=O)C1CC2C(=O)N(Cc3ccccc3)CCN2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CC2CN(Cc3ccccc3)CCN2C1
Temperature: 0 °C
Yield: 89.2 %

Procedure:
A suspension of 3.20 g (84.3 mmol) of lithium aluminum hydride in 30 mL of dry THF was cooled to 0° C. and treated dropwise with a solution of 8.00 g (27.7 mmol) of 7-methoxycarbonyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazin-1-one (Jones, R. C. F.; Howard, K. J. J. Chem. Soc., Perkin Trans. 1, 1993, 2391) in 80 mL of dry THF. After 30 min the reaction was carefully quenched with 3 mL of water, 3 mL of 15% NaOH and 9 of mL water. The mixture was filtered, the filtrate evaporated, the residue taken up in ethyl acetate and washed with brine. The organic layer was dried (magnesium sulfate), filtered, and evaporated to give 6.09 g (89%) of the title compound as a mixture of (7RS,8aSR)- and (7SR,8aSR)- isomers of sufficient purity for use in the next reaction (Preparation 2). m/z (MH+) 247.