Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[OH:23][C:24]1[CH:25]=[C:26]([NH:32][C:33]([NH2:35])=[NH:34])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:34]=[C:33]([NH:32][C:26]4[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([OH:23])[CH:25]=4)[N:35]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1O
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1O

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-hydroxy-4-methoxy-phenyl)-guanidine nitrate were converted to I-65 (69%): HRMS Calcd. for C19H11ClN4O3: 383.091, Found 383.0913.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:4][CH:3]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:45](=[O:49])[CH:46]([CH3:48])[CH3:47].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:46]([CH3:48])([CH3:47])[CH:45]2[OH:49]
Reactant: O=[N+]([O-])c1cccc(C=Nc2ccc(Cl)cc2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(O)c2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a mixture of (4-chloro-phenyl)-(3-nitro-benzylidene)-amine (12 g, 46 mmol) and ytterbium(III) triflate hydrate (2.85 g, 4.6 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (4.64 mL, 51 mmol) and water (0.83 mL, 46 mmol) dropwise. The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (14.3 g, 93%) as a light yellow oil: LC/MS m/e calcd for C17H17ClN2O3 (M+H)+: 333.79, observed: 315.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Si](C)(C)C)[O:10][C:3]=12.C1C(=O)N([I:22])C(=O)C1.[F-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:22])[O:10][C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)c1cc2nccc(Cl)c2o1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccnc2cc(I)oc12
Reaction time: 0.08 h

Procedure:
7-Chloro-2-(trimethylsilyl)furo[3,2-b]pyridine (0.250 g, 1.11 mmol) and NIS (2.49 g, 11.1 mmol) were dissolved in 3 mL of ACN and stirred for 5 minutes. Potassium fluoride (0.0708 g, 1.22 mmol) was added and the reaction was stirred at 50° C. for one hour. The reaction was concentrated, redissolved in ethyl acetate, and washed with saturated sodium thiosulfate, water and brine. The organic layer was dried with sodium sulfate, filtered, and concentrated. The crude material was purified via column chromatography (gradient elution 0-100% EtOAc:Hex) to afford 7-chloro-2-iodofuro[3,2-b]pyridine as a white solid. MS: M+H+=280.2.
Reaction SMILES: [C@H:1]12[CH2:8][C@H:4]([CH2:5][CH:6]1[OH:7])[CH2:3][NH:2]2.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[OH:7][CH:6]1[C@H:1]2[CH2:8][C@H:4]([CH2:3][N:2]2[C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:5]1
Reactant: N#Cc1ccc(F)cc1
Reactant: OC1C[C@@H]2CN[C@H]1C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C[C@@H]3CC(O)[C@H]2C3)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 47.2 %

Procedure:
To a round bottom flask was added (1S,4R)-2-azabicyclo[2.2.1]heptan-6-ol (0.5 gm, 3.34 mmol), 4-fluorobenzonitrile (0.405 gm, 3.34 mmol), DMF (6 ml) and K2CO3 (1.386 gm, 10.03 mmol). The reaction was stirred at 80° C. for 5 hrs. After this time, the reaction was diluted with EtOAc. The resulting solution was washed with water (4×) and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give product 4-((1R,4S)-6-hydroxy-2-azabicyclo[2.2.1]heptan-2-yl)benzonitrile (338 mg, 1.578 mmol, 47.2% yield) as a white solid. Anal. Calcd. for C13H14N2O m/z 214.2, found: 215.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][CH2:17][CH3:18])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19]S(O)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:16][CH2:17][CH3:18])([C:14]([NH2:15])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC1(C#N)CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: CCNC1(C(N)=O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 1-benzyl-4-ethylaminopiperidine-4-carbonitrile 1-(7A-80)d (0.58 g, 2.38 mmol) in methylene chloride (2 ml) cooled in an ice bath was treated with H2SO4 (1.8 ml, 33 mmol), dropwise, while keeping the internal temperature below 20° C. The reaction was then warmed to room temperature and stirred for 19 hr. After stirring was discontinued, the thick pale orange H2SO4 bottom layer was separated, cooled in an ice bath and then carefully quenched with concentrated NH4OH keeping internal temperature below 55° C. The aqueous layer was extracted with methylene chloride (2×10 ml), the combined organic layers were washed with brine (20 ml), dried (Na2SO4), and then concentrated in vacuo to afford I-(7A-80)e as a pale orange oil that solidifies to a peach colored solid upon standing (0.54 g, 87%): +APCI MS (M+1) 262.2; 1H NMR (400 MHz, CD2Cl2) δ 7.34–7.30 (m, 4H), 7.29–7.21 (m, 1H), 7.16 (br s, 1H), 3.48 (s, 2H), 2.71–2.68 (m, 2H), 2.47 (q, J=7.0 Hz, 2H), 2.17–2.02 (m, 4H), 1.62–1.58 (m, 2H), 1.41 (br s, 1H), 1.09 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:34](OCCCC)(=O)[CH:35]=[O:36].CC(O)=O>CCO>[C:24]([O:23][C:21]([NH:20][CH:17]1[CH2:18][CH2:19][N:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:5]3[N:6]=[CH:7][C:2]4[N:1]=[CH:34][C:35](=[O:36])[N:28]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33]5)[C:3]=4[N:4]=3)=[CH:14][CH:13]=2)[CH2:16]1)=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(N)c(NC4CCCC4)n3)cc2)C1
Reactant: CCCCOC(=O)C=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)C1
Yield: 28.5 %

Procedure:
A mixture of 0.70 g (1.5 mmol) of 5-amino-2-[[4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]phenyl]amino]-4-(cyclopentylamino)-pyrimidine, 0.52 g (4 mmol) of butyl glyoxylate (F. J. Wolf, J. Weijlard, Org. Synth. Coll., 1963;4:124–125) and 0.5 mL HOAc in 15 mL of EtOH is heated under reflux for 14 hours, and the solvent is removed under vacuum. The residue is diluted with aqueous ammonia solution and extracted into EtOAc. Chromatography on silica, eluting with hexane/EtOAc (3:2), gives 0.21 g (28%) of the title compound (Compound 53): mp (MeOH) 226–228° C.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:18])[N:3]=1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[N:24]=1>>[Br:25][C:23]1[N:24]=[C:20]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:18])[N:3]=2)[S:21][CH:22]=1
Reactant: Brc1csc(Br)n1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(I)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nc(Br)cs2)n1

Procedure:
The title compound was prepared from 2-iodo-6-methyl-4-(4-trifluoromethyl-phenyl)pyridine (example A.31) (4.0 g, 9.36 mmol) and commercially available 2,4-dibromo-thiazole (2.53 g, 10.41 mmol) according to the general procedure IVc protocol b. Obtained as a light yellow solid (1.22 g, 31%). MS (ISP) 399.1 [(M+H)+] and 401.1 [(M+2+H)+].
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:17]1([C:23]([C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:17]1(/[C:23](/[C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[CH:9]\[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(c1ccccc1)c1ccnnc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\c1ccccc1)c1ccnnc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.46 g, 7.93 mmol) in THF (40 mL) was added NaH (476 mg, 11.9 mmol) in portions at 0° C., the resulting mixture was stirred at 0° C. for 20 minutes, then, the phenyl(pyridazin-4-yl)methanone was added in portions, the resulting mixture was stirred at 0° C. for 4 hour. The LC-MS showed the MS signal of desired product was detected, then, the reaction solution was added sat. aq. NH4Cl at 0° C., then, extracted with AcOEt (3×50 ml), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to get the crude product, which was purified by column chromatography on silica gel (petroleum Ether: EtOAc=2:1) to afford (E)-ethyl 3-phenyl-3-(pyridazin-4-yl)acrylate (1.68 g, yield: 83.2%). 1H NMR (CDCl3 400 MHz): δ9.25 (d, J=5.2 Hz, 1H), 9.06 (s, 1H), 7.47-7.32 (m, 4H), 7.30-7.20 (m, 2H), 6.55 (s, 1H), 4.95 (q, J=7.2 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34](Cl)=[O:35]>ClCCl>[CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=3)[C:34]([C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)=[O:35])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc(NC2CCN(CC3CCCCC3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CC3CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-[1-(cyclohexylmethyl)piperidin-4-ylamino]-5-methylpyridine (216 mg) prepared in Preparation Example 1A-1 and triethylamine (152 mg) in dichloromethane (3 mL) was added 2-furoyl chloride (0.11 mL) dropwise under ice cooling. The solution was stirred at room temperature for 18 hours. Silica gel (NH silica gel) was added to the reaction solution, and it was concentrated under reduced pressure. The resulting residue was purified by chromatography (NH silica gel, hexane:ethyl acetate=2:1) to give the title compound as a colorless crystal (271 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Reactant: OB(O)c1cccc(F)c1
Product: COc1cc2ncn(-c3nc(-c4cccc(F)c4)c(C(=O)O)s3)c2cc1OC
Yield: 19.5 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-fluorophenylboronic acid (21 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3-fluoro-phenyl)-thiazole-5-carboxylic acid (7.8 mg, 20%) as a white solid. MS 400 m/z (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[NH:7]2.[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][C:6](=[O:12])[NH:7]3)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCc2c(O)cccc2N1
Reactant: O=S(=O)(CCCCBr)c1ccccc1
Product: O=C1CCc2c(cccc2OCCCCS(=O)(=O)c2ccccc2)N1

Procedure:
Prepared analogous to Example 4 from 5-hydroxy-3,4-dihydro-carbostyril and 4-phenylsulfonyl-butyl bromide.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]2[CH:24]=[CH:23][NH:22][C:21]=2[C:25]([O:27]CC)=O)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([N:19]2[C:20]3[CH:24]=[CH:23][NH:22][C:21]=3[C:25](=[O:27])[NH:9][C:10]2=[S:11])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]ccc1Nc1cccc(Cl)c1
Solvent: ClCCl
Product: O=c1[nH]c(=S)n(-c2cccc(Cl)c2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.2 %

Procedure:
Benzoyl isothiocyanate (0.035 g, 0.22 mmol) in CH2Cl2 (0.5 mL) was added to ethyl 3-[(3-chlorophenyl)amino]-1H-pyrrole-2-carboxylate (0.052 g, 0.20 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at r.t. overnight. Additional benzoyl isothiocyanate (0.035 g+0.035 g+0.035 g) were added over 6 h and the reaction was continued stirring at 50° C. for 3 days. The solvent was removed in vacuo and the residue was dissolved in ammonia (7N in methanol, 4 mL). The reaction was heated at 50° C. for 2 h. The crude product was purified by preparative chromatography, obtaining 0.009 g (15%) of the title compound as a solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:6][C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:13]=3)[CH:8]=2)[CH2:30][CH2:29]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCc1cc2ncc(C(F)(F)F)cc2s1
Product: COc1ccccc1N1CCN(Cc2cc3ncc(C(F)(F)F)cc3s2)CC1

Procedure:
The solution from Example 25C (2 mL) and 1-(2-methoxyphenyl)piperazine (192 mg) were processed as described in Example 25D to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 3.11 (4H, t, J=4.8 Hz), 3.45 (4H, J=4.8 Hz), 4.19 (s, 3H), 4.30 (s, 2H), 6.90 (4H, m), 7.80 (1H, s), 8.63 (1H, m), 9.20 (1H, m). MS (DCI/NH3) m/z 408.2 (M+H)+. Anal. Calcd for C20H20N3F3OS: C, 58.96; H, 4.95; N, 10.31. Found: C, 58.98; H, 4.95; N, 10.53.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2N=C(N)S[CH:12]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[S:16]C(C(OCC)=O)=C[N:19]=1>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[S:16][C:15]([NH2:19])=[N:14][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cnc(N)s1
Reactant: Nc1nc(CN2CCOCC2)cs1
Product: Nc1ncc(CN2CCOCC2)s1

Procedure:
5-(morpholinomethyl)thiazol-2-amine 61 was prepared using the same synthetic sequence outlined above for 4-(morpholinomethyl)thiazol-2-amine employing ethyl 2-aminothiazole-5-carboxylate 60 as the starting material.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:47]1[C:52](O)=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:54].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:48]1([CH3:54])[CH:49]=[CH:50][CH:51]=[C:52]([O:1][CH2:2][C@H:3]([NH:8][C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]([O:6][CH3:7])=[O:5])[CH:47]=1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](COc1cccc(C)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (S)-methyl 3-hydroxy-2-(tritylamino)propanoate (10.0 g, 27.7 mmol), triphenylphosphine (7.98 g, 30.4 mmol) and toluene (100 mL). The solution was stirred at room temperature for 30 min., then to the solution was added m-cresol (3.78 mL, 36.0 mmol) and diisopropylazodicarboxylate (“DIAD”, 5.92 mL, 30.4 mmol). The solution was heated at 80° C. with stirring for 18 h. The solution was cooled to room temperature and concentrated and the resulting residue was subjected to silica gel chromatography (hexanes:EtOAc) to afford (S)-methyl 3-(m-tolyloxy)-2-(tritylamino)propanoate, 8.28 g (66%). 1H-NMR (400 MHz, CDCl3) δ 7.53 (d, J=7.6 Hz, 6H), 7.29-7.23 (m, 5H), 7.21-7.11 (m, 4H), 6.77 (d, J=7.3 Hz, 1H), 6.73-6.64 (m, 2H), 5.30 (s, 2H), 4.25 (dd, J=9.3, 4.9 Hz, 1H), 4.01 (dd, J=9.2, 6.7 Hz, 1H), 3.76-3.68 (m, 1H), 3.22 (s, 3H), 2.88 (d, J=10.5 Hz, 1H), 2.32 (s, 3H).
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[NH:13][C:12](=S)[CH2:11][N:10]=1.CO>O1CCCC1>[NH2:1][C:12]1[CH2:11][N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[N:13]=1
Reactant: N
Reactant: Fc1ccccc1C1=NCC(=S)Nc2ccc(I)cc21
Solvent: C1CCOC1
Solvent: CO
Product: NC1=Nc2ccc(I)cc2C(c2ccccc2F)=NC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
50 ml of 25% aqueous ammonia solution were added to a solution of 2.3 g of 5-(2-fluorophenyl)-7-iodo-3H-1,4-benzodiazepine-2(1H)-thione (A. Walser, T. Flynn, C. Mason, H. Crowley, C. Maresco, B. Yaremko & M. O'Donell, J.Med.Chem., 1991, 34, 1209) in 120 ml of tetrahydrofuran. After the addition of 5 ml of methanol the solution was stirred at room temperature for 24 h. and then evaporated in a vacuum. The residue was partitioned between saturated aqueous sodium hydrogen carbonate solution and chloroform. The aqueous phase was extracted a further three times with chloroform. The chloroform extracts were dried over sodium sulphate and evaporated in a vacuum. The residue was recrystallized from ethyl acetate. There were obtained 2.73 g of 2-amino -7-iodo-5-(2-fluorophenyl)-3H-1,4-benzodiazepine of m.p. 219-221° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13].S(=O)(=O)(O)[OH:15]>O>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:15])=[C:6]([Cl:10])[C:5]([Cl:11])=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: O
Product: NC(=O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
In a preferred embodiment of the invention, pentachlorobenzonitrile is interacted with a molar excess of sulfuric acid having at least 75% by weight H2SO4 at a temperature of between about 130° and 160° C. for about fifteen (15) to ninety (90) minutes. The reaction mixture is then cooled and diluted with water to form a solid pentachlorobenzamide precipitate. The resultant pentachlorobenzamide is recovered in yields on the average of above about 90%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1>[C:25]([O:24][C:22](=[O:23])[CH2:21][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: NCc1ccc([N+](=O)[O-])cc1N
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 2-aminomethyl-5-nitro-phenylamine (2.84 g, 17 mmol) in dry THF (150 mL) and triethylamine (12 mL, 85 mmol) was added tert-butyl bromoacetate (5 mL, 34 mmol). The mixture solution was stirred at room temperature for 16 hours and concentrated. Chromatography of the resulting residue on silica gel with methylene chloride and methanol (50:1) gave 2.15 g of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (45%): 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, 1H), 7.55 (5, 1H), 7.22 (d, 1H), 5.2 (br, 2H) 3.95 (s, 2H), 3.39 (s, 2H), 1.58 (s, 9H); MS (m/e): 282.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[O:1]([CH2:2][C@H:3]1[CH2:18][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: OC[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(OC[C@@H]2CC[C@H]3CN(c4ncccn4)CCN3C2)cc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
A solution of 0.385 g (1.55 mmol) of (7R,9aS)-7-hydroxymethyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 4), 0.220 g (2.34 mmol) of phenol, and 0.488 g (1.86 mmol) of triphenylphosphine in 30 mL of dry THF was treated with 0.324 g (1.86 mmol) of diethyl azodicarboxylate, and the mixture stirred at 23° C. for 16 h. The solvent was evaporated, the residue dissolved in ethyl ether and treated with HCl(g) in ether. The precipitate was collected on a Büchner funnel, and washed with 1:1 ether:ethyl acetate three times. The solid was dissolved in water, basified with 1 M NaOH and extracted with chloroform. The organic layer was washed with 1 M NaOH (2×) and water (1×), dried (magnesium sulfate), filtered and evaporated to give 0.310 g of (7R,9aS)-7-phenoxymethyl-2,3,4,6,7,8,9,9a-octahydro-2-pyrimidin-2-yl-1H-pyrido[1,2-a]pyrazine. mp (HCl) 203-205° C. 13C NMR (base, CDCl3): δ27.0, 29.0, 36.4, 43.6, 49.1, 54.9, 58.8, 60.8, 70.9, 109.8, 114.5, 120.6, 129.4, 157.7, 159.0, 161.5. HRMS calcd for C19H24N4O: 324.195. Found: 324.194.
Reaction SMILES: COP([CH2:7][C:8]([O:10][CH3:11])=[O:9])(OC)=O.[H-].[Na+].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=O)[CH2:15]2>C1COCC1>[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[CH:7][C:8]([O:10][CH3:11])=[O:9])[CH2:15]2
Reactant: O=C1CN2CCC1CC2
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CN2CCC1CC2
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(dimethoxyphosphoryl)acetate (2.70 g, 14.8 mmol) in THF (200 ml) at 0° C. was added NaH [60% dispersion in mineral oil] (600 mg, 15.0 mmol). After 1 h of stirring, quinuclidin-3-one (2.00 g, 12.4 mmol) was added and the resultant mixture was stirred at room temperature for 18 h. The reaction was quenched with 50 ml water at 0° C. and the mixture was extracted with EtOAc. The organic layers were combined and concentrated under reduced pressure to afford crude methyl 2-(quinuclidin-3-ylidene)acetate, which was used in next step without purification (1.2 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=2)[C:32](O)=[O:33])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:35]=[C:27]([C:25]4[S:26][C:22]([C:20](=[O:21])[C:19]([F:36])([F:18])[F:37])=[CH:23][CH:24]=4)[CH:28]=[N:29][CH:30]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)n[nH]1
Product: CC(C)(CNC(=O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1)c1nc(-c2ccc(F)cc2)n[nH]1
Yield: 20 %

Procedure:
This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and 5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinic acid as described in example 8 step 6 (28 mg, yield 20%) as a yellow viscous liquid. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=2.3 Hz, 1H), 9.01-8.98 (m, 1H), 8.80-8.77 (m, 1H), 8.51-8.48 (m, 1H), 8.21-8.19 (m, 1H), 8.01-7.96 (m, 4H), 7.24-7.19 (m, 2H), 3.59-3.57 (d, J=6.2 Hz, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C24H19F4N6O2S: 517.12. found: 516.4 (M−H)−.