Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[C:8]([N:17]2[CH2:21][CH2:20][O:19][C:18]2=[O:22])[C:7]([CH3:23])=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(C)c(N2CCOC2=O)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1N1CCOC1=O
Temperature: 65 °C

Procedure:
A mixture of 3-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)-1,3-oxazolidin-2-one (14 mg, 0.040 mmol) and ammonium acetate (31 mg, 0.40 mmol) and sodium cyanoborohydride (5 mg, 0.08 mmol) in methanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65° C. overnight in a sealed tube. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude product was used directly in next step (10 mg, 70%). LCMS calculated for C18H16ClFNO2 (M−NH2)+: m/z=332.1. found: 332.1.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[CH:24][N:23]=3)=[O:20])=[C:14](F)[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].CNC(C1C=C(OC2C=CC(N)=CC=2)C=CN=1)=O>CCOC(C)=O>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:25]=[CH:24][N:23]=3)=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ncn3)c(F)c2)ccn1
Agent: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ncn3)cc2)ccn1

Procedure:
The title compound was prepared in the same manner as 4-{3-fluoro-4-[3-(6-trifluoromethylpyrimidin-4-yl)ureido]phenoxy}pyridine-2-carboxylic-acid methylamide, replacing 4-(4-amino-3-fluoro-phenoxy)pyridine-2-carboxylic acid methylamide for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylamide. LC-MS m/z 433.1 [M+H]+; TLC Rf=0.8 (EtOAc).
Reaction SMILES: C([CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])#N.[NH3:13]>C(O)C.[Ni]>[NH2:13][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12]
Reactant: N
Reactant: COc1ccccc1OCC#N
Agent: [Ni]
Solvent: CCO
Product: COc1ccccc1OCN
Yield: 35 %

Procedure:
A solution of the 2-cyanomethoxyanisole (5.6 g, 0.034 mol) in anhydrous ammonia (25 ml) and ethanol (50 ml) was heated to 120° C. at 500 psi for 12 h in the presence of raney nickel (1.4 g). The reaction mixture was filtered, concentrated under reduced pressure, the residue taken up in ether, and washed with 1.2 M HCl. The acidic phase was then rendered basic (pH=12) with careful addition of solid KOH and the alkaline solution extracted with ether. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give the product (1.99 g, 35%) as an oil. IR. NMR. MS.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH:10]=[CH2:11])=[O:4].[SiH:14]([Cl:17])([Cl:16])[Cl:15]>>[F:1][C:2]([F:12])([F:13])[C:3]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][Si:14]([Cl:17])([Cl:16])[Cl:15])=[O:4]
Reactant: C=CCOCCOC(=O)C(F)(F)F
Reactant: Cl[SiH](Cl)Cl
Product: O=C(OCCOCCC[Si](Cl)(Cl)Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
In a heavy-walled tube equipped with a magnetic stir bar, ester (19) (3.97 g, 20.0 mmol, 1.0 equiv.) and H2PtCl6.6H2O (104 mg, 0.20 mmol, 1.0 mol. %) were loaded. The tube was transferred into a glovebox and HSiCl3 (4.10 mL, 40.2 mmol, 2.0 equiv.) was added to the solution. The tube was tightly fastened then removed from the glovebox. The resulting solution was stirred at room temperature for 20 h behind a protecting shield. Purification was achieved by Kugelrohr distillation under high vacuum and provided 5.46 g (82%) of 7-OEG (20) as a colourless oil; bp=115-120° C. (0.09 Torr); 1H NMR (400 MHz, CDCl3) δ 4.52 (m, 2H), 3.76 (m, 2H), 3.56 (t, J=6.2 Hz, 2H), 1.85 (m, 2H), 1.48 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.7 (q, J=42.3 Hz), 114.7 (q, J=284.1 Hz), 71.8, 67.9, 67.0, 22.8, 21.0.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:10].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: CC1(C)OB(c2cncnc2)OC1(C)C
Reactant: Cc1cc(I)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cncnc2)cc(C)c1Br
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a microwave vial 2-bromo-5-iodo-1,3-dimethylbenzene (1 g) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (665 mg) are suspended in N,N-dimethylformamide (15 mL) and Na2CO3 (4 mL of a 2 M aqueous solution). The mixture is purged for 5 minutes with argon. [1,1′-Bis(diphenylphosphino)-ferrocene]-dichloropalladium dichloromethane complex (85 mg) is added, the vial is sealed and the mixture is stirred at 60° C. for 3 hours. After cooling to room temperature the mixture is Partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with brine. Then the organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. Yield: 446 mg; LC (method 9): tR=1.05 min; Mass spectrum (ESI+): m/z=263 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][CH:22]=[C:16]2[N:15]=1.[N+:23]([O-])([OH:25])=[O:24]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:16]2[N:15]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(F)c([C@H]2CCCN2c2ccn3nccc3n2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine (3.3 g, 10.99 mmol), was dissolved in 25 mL TFA at ambient temperature to give a clear yellowish solution, then nitric acid (3.434 mL, 54.94 mmol) was added drop-wise to the solution with rapid stirring. After addition, the reaction mixture was stirred for another 15 minutes at ambient temperature, then quenched by pouring onto ice with rapid stirring. The resulting yellowish suspension was filtered, rinsed with water, then the solid was triturated with MeOH (50 mL, with brief sonication), and vacuum-filtered, giving the pure product as a fine off-white powder (2.2 g, 58% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][C:31]([NH2:33])=O)([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl.CCN(C(C)C)C(C)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][C:31]#[N:33])([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:34])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC(N)=O)(c2ccc(F)cc2)OC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC#N)(c2ccc(F)cc2)OC1=O
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetamide (60 mg, 0.128 mmol) in anhydrous CH2Cl2 (4 mL) and DIEA (0.3 mL) was added TFAA (55 mg, 0.256 mmol) at 0□. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC to afford 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetonitrile (40 mg, 82%). LC-MS Method 3 tR=1.52, min, m/z=451, 473; 1H NMR (CDCl3): 1.56 (m, 3H), 2.40 (m, 2H), 2.54 (m, 1H), 2.82-2.98 (m, 2H), 3.04 (m, 1H), 5.64 (m, 1H), 6.83-6.94 (m, 5H), 7.09 (m, 2H), 7.21 (m, 1H), 7.28 (m, 1H), 7.37 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=[O:27]>>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:25][C:26]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)=[O:27])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: O=C(CBr)c1ccc(Cl)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(Cl)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-chlorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid was prepared from norfloxacin (0.5 g, 1.56 mmole) and 2-bromo-4′-chloroaceto-phenone(0.43 g, 1.86 mmole) by a method similar to that described for Example 4 (67% yield). Mp: 207° C. (dec). 1H NMR (DMSO-d6) δ 1.41 (7, 3H, J=7.2), 2.73 and 3.29 (two m, 8H), 3.95 (s, 2H), 4.58 (q, 2H, J=7.2 7.19 (d, 1H, J=7.2), 7.59 and 8.02 (m, 4H), 7.92 (d, 1H, J=13.2), 8.95 (s, 1H), 15.41 (br s, 1H). Anal. Calcd. for C24H23ClFN3O4•0.25H2O: C, 60.51; H, 4.97; N, 8.82. Found: C, 60.49; H, 4.96; N, 8.82.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1.ClCC(Cl)=O>[O:19]=[C:13]1[CH:12]([N:5]2[CH2:4][C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:23])[CH2:21][Cl:20])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(NC(=O)CCl)cccc3C2=O)C(=O)N1
Yield: 92.1 %

Procedure:
To a stirred suspension of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (3.89 g, 15.0 mmol) in THF (50 ml) was added chloroacetyl chloride (1.86 g, 16.5 mmol). The mixture was heated to reflux for 45 minutes. To the reaction mixture was added additional chloroacetyl chloride (0.15 g, 0.13 mmol). The reaction mixture was heated at reflux for an additional 30 minutes. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 4.64 g (92%) of product as an off-white solid: 1H NMR (DMSO-d6) δ 11.04 (s, 1H), 10.22 (s, 1H), 7.82 (dd, J=1.6 and 7.2 Hz, 1H), 7.59-7.50 (m, 2H), 5.16 (dd, J=5.1 and 13.2 Hz, 1H), 4.46-4.30 (m, 4H), 3.00-2.85 (m, 1H), 2.65-2.58 (m, 1H), 2.44-2.28 (m, 1H), 2.06-2.01 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[NH:5][C:6]2[N:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=1.[OH:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][NH2:26])=O)=[CH:21][CH:20]=1.C(N(CC)CC)C>CC(N(C)C)=O>[N:26]1[N:25]=[C:23]([C:22]2[CH:27]=[CH:28][C:19]([CH2:18][OH:17])=[CH:20][CH:21]=2)[N:8]2[C:2]=1[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[NH:5][C:6]1[N:12]=[CH:11][CH:10]=[CH:9][C:7]2=1
Reactant: NNC(=O)c1ccc(CO)cc1
Reactant: ClC1=Nc2cccnc2Nc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1

Procedure:
A solution of 6-chloro-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (4.3 g, 19 mmol), 4-(hydroxymethyl)benzohydrazide (3.2 g, 20 mmol) and triethylamine (2.8 mL, 20 mmol) in dimethylacetamide (100 mL) was stirred at 85° C. until the starting material is all consumed (as followed by LC/MS). The reaction mixture was diluted with dichloromethane (100 mL) and water (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic extracts were washed with water (3×100 mL), dried over sodium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate (20 mL) and the solid was collected by filtration. The (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol was obtained as a yellow solid (4.8 g, 74%). M.p.=276-278° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.78 (s, 1H), 8.21 (dd, J=4.8, 1.6 Hz, 1H), 7.96 (dd, J=7.2, 1.6 Hz, 1H), 7.50-7.33 (m, 6H), 7.17-7.12 (m, 2H), 6.91 (dd, J=8.0, 4.8 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H); LCMS [M+H]: 342.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7].[C:34](=[O:37])([O-])[O-].[K+].[K+].[ClH:40]>CN(C)C=O.C(OCC)(=O)C>[ClH:40].[ClH:40].[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:3][C:4]#[C:5][CH2:6][N:8]2[CH2:13][CH2:34][O:37][CH2:10][CH2:9]2)[CH2:10][C@H:9]1[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc2ccccc2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CC#CCN2CCOCC2)C[C@H]1Cc1ccc2ccccc2c1
Reaction time: 17 h

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)piperazine (200 mg) and 1-(4-chloro-2-butynyl)morpholine hydrochloride (95 mg) in N,N-dimethylformamide (0.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (177 mg). After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-morpholino-2-butynyl)-2-(2-naphthylmethyl)piperazine dihydrochloride (257 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[C:11]=2[N+:18]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>CO.[Zn]>[NH2:18][C:11]1[C:12]([F:17])=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[CH3:22])=[O:21]
Reactant: Cc1c(Br)cccc1NC(=O)c1cc(F)cc(F)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1c(Br)cccc1NC(=O)c1cc(F)cc(F)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
A mixture of N-(3-bromo-2-methylphenyl)-3,5-difluoro-2-nitrobenzamide (821 mg, 2.21 mmol), NH4Cl (1.18 g, 22.1 mmol) and zinc (1.45 g, 22.1 mmol) in MeOH (10 mL) was stirred at room temperature for 60 min. The mixture was filtered and the filtrate was concentrated. The residue was suspended in DCM and washed with saturated aqueous NaHCO3. The organic phase, with an insoluble precipitate, was separated from the aqueous phase and concentrated to give 2-amino-N-(3-bromo-2-methylphenyl) -3,5-difluorobenzamide (760 mg), used without further purification. Mass spectrum m/z 341, 343 (M+H)+, 363, 365 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]([CH2:8][O:9][CH3:10])=[CH:6][CH:7]=1.[N+:15]([O-])([O-:17])=[O:16].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:5]([CH2:8][O:9][CH3:10])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: COCc1ccc(Cl)cc1C(=O)OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCc1cc([N+](=O)[O-])c(Cl)cc1C(=O)OC
Reaction time: 1 h

Procedure:
A sample of methyl 4-chloro-α-methoxy-o-toluate (10 g.) is added in small portions at 15°-20° to a solution of potassium nitrate (4.9 g.) in concentrated sulfuric acid. When the addition is complete, the mixture is stirred for 1 hour at 10°-15°, then poured onto ice and the precipitated solid (12.8 g.) collected by filtration. A sample of the damp product is recrystallized from 90% ethanol. After recrystallization, the solid mp is 77°-81°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:22]2[N:26]=[CH:25][O:24][N:23]=2)[CH:3]=1>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]2)[CH:5]=[C:4]([C:22]2[N:26]=[CH:25][O:24][N:23]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(-c3ncon3)cc(Cl)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2cc(-c3ncon3)cc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 1-[6-chloro-4-(1,2,4-oxadiazol-3-yl)pyridin-2-yl]piperidin-4-ylcarbamate (Intermediate 55) (50 mg 0.13 mmol) was dissolved in 4 N HCl in dioxane (2 ml). The mixture was stirred at room temperature for 2 h. The solvent was concentrated in vacuo to afford the crude title compound which was used without further purification. (74 mg).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([O:15][O:16][C:17]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[P:18]([OH:21])([OH:20])=[O:19])[CH2:6][O:7]CC1C=CC=CC=1)=[N+:2]=[N-:3].B(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([O:15][O:16][C:17]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:23])[CH3:24])[P:18]([OH:20])([OH:21])=[O:19])[CH2:6][OH:7])=[N+:2]=[N-:3]
Reactant: CC(C)C(OO[C@H](CN=[N+]=[N-])COCc1ccccc1)(C(C)C)P(=O)(O)O
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(OO[C@@H](CO)CN=[N+]=[N-])(C(C)C)P(=O)(O)O
Temperature: -78 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
(R)-3-Azido-1-O-benzyl-2-O-(diisopropyl phosphonomethoxyl)-1,2-propanediol (6.15 g, 15.96 mmol) was dissolved in 35 mL of anhydrous methylene chloride under nitrogen atmosphere. To this solution, boron trichloride (1M in methylene chloride) (48 mL, 48 mmol) was slowly added at -78° C. The mixture was stirred at -78° C. for 4 hour, and then saturated aqueous sodium bicarbonate (100 mL) and methylene chloride (150 mL) were added. The aqueous layer was separated and extrated with methylene chloride (150 mL×2). The combined methylene chloride extracts were dried over magnesium sulfate. Filtration and concentration under reduced pressure gave a residue which was purified by flash chromatography on silica gel (methylene chloride:acetone=5:1 to 1:1) to provide 4.39 q (93% yield) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.O.C(Cl)Cl>[CH3:3][C:2]([CH3:18])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:20]2[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCCCNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCN(c1ncccc1[N+](=O)[O-])C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 24 h

Procedure:
A mixture of 1-(1,1-dimethylethoxycarbonyl)-4-(butylamino)piperidine (VIII, EXAMPLE 86, 1.30 g), 2-chloro-3-nitropyridine (804 mg) and diisopropylethylamine (1.77 ml) in N-methyl-2-pyrrolidinone (15 ml) is stirred at 85° for 24 hrs, diluted with water (75 ml) and methylene chloride (150 ml), and the layers are separated. The aqueous phase is extracted with methylene chloride (2×25 ml) and the combined organic phase is washed with saline (25 ml), dried over sodium sulfate, and concentrated under reduced pressure at approximately 75°. The residue is chromatographed on silica gel (230-400 mesh, 100 g; eluting with ethyl acetate/hexane (5/95)) to give the title compound, NMR (CDCl3) 8.33, 8.05, 6.73, 4.20, 3.82, 3.30, 2.73, 1.84-1.71, 1.47, 1.40-1.20 and 0.86δ.
Reaction SMILES: Cl[C:2]([S:4][Cl:5])=[O:3].[CH3:6][CH:7]([OH:10])[CH2:8][CH3:9]>>[CH3:6][CH:7]([O:10][C:2]([S:4][Cl:5])=[O:3])[CH2:8][CH3:9]
Reactant: O=C(Cl)SCl
Reactant: CCC(C)O
Product: CCC(C)OC(=O)SCl
Yield: 39.1 %

Procedure:
Chlorocarbonylsulfenyl chloride (13.1 g, 0.1 mol) was mixed with 2-butanol (6.7 g, 0.09 mol)and warmed to about 35° to 40° C. for one hour. Distillation resulted in the tithe compound (5.93 g) Bp. 70° C./0.8 mm Hg. NMR spectrum was consistent with the structure.
Reaction SMILES: [H-].[Na+].[Cl-].[C:4]([CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:5].[CH2:26]([C:29]1[CH:34]=[C:33]([CH:35]=O)[CH:32]=[CH:31][N:30]=1)[CH2:27][CH3:28].CO>O1CCCC1.CN(C)C=O>[CH2:26]([C:29]1[CH:34]=[C:33]([CH:35]=[CH:6][C:4]#[N:5])[CH:32]=[CH:31][N:30]=1)[CH2:27][CH3:28]
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCc1cc(C=O)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCc1cc(C=CC#N)ccn1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a suspension of 1.39 g (0.03 mol) sodiumhydride in 40 ml tetrahydrofurane and 40 ml dimethylformamide were added 10.13 g (0.03 mol) (cyanomethyl)triphenylphosphonium chloride. After sirring for 1 hour at room temperature a solution of 4.48 g (0.03 mol) 2-propyl-4-pyridinecarboxaldehyde in 15 ml tetrahydrofuran were added and stirring was continued for 15 hours. Then 10 ml methanol were added) the solvents were evaporated and the residue chromatographed on aluminiumoxide with dichloromethane to yield 2.42 g 3-(2-propyl-pyridin-4-yl)-acrylonitrile as yellow oil. MS m/e (%): 173 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:33])[C:29](Br)([CH3:31])[CH3:30])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:33])[C:29]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:9]([CH3:24])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: CCCCCCn1c(C)c(-c2ccc(F)cc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCCCCn1c(C)c(-c2ccc(F)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-fluoro-phenyl)-1-hexyl-2-methyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[S:9][CH:10]=1.[CH2:14](O)[CH3:15]>>[Br:5][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:9][CH:10]=1
Reactant: CCO
Reactant: O=C(O)c1cc(Br)cs1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)cs1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
Thionyl chloride (8.8 mL, 121 mmol) was added slowly to a solution of 4-bromothiophene-2-carboxylic acid (5.0 g, 24.2 mmol) in ethanol (30 mL) at room temperature. The reaction mixture was warmed up to 65° C. and stirred for 4 hours. Removal of solvent and excess reagent under vacuum afforded the crude product ethyl 4-bromothiophene-2-carboxylate (1015), which was used in the next step without further purification.