Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]#[N:7])(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1.[CH3:24]I>CC(C)=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([S:23][CH3:24])=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]#[N:7])=[CH:17][CH:16]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: CS(=O)(=O)CC#N
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSC(Nc1ccc(Cl)cc1)=C(C#N)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 80 %

Procedure:
To a solution of methanesulfonylacetonitrile (0.55 g, 4.9 mmol) in dry acetone (5 ml) first dry potassium carbonate (1.28 g, 9.3 mmol) and then 4-chlorophenyl isothiocyanate (0.78 g, 4.6 mmol) were added. The resulting mixture was stirred at room temperature under nitrogen for 22 h, and then filtered. To the filtrate methyl iodide (0.86 ml, 13.9 mmol) was added. The mixture was stirred at room temperature for 2 h. The precipitate was filtered off, the filtrate was concentrated. The residue was taken up into dichloromethane and water. The organic layer was washed with water (2×), dried (sodium sulfate) and concentrated. Crystallisation from ethyl acetate gave 1.114 g (80%) of the title compound. 1H NMR (200 MHz, CDCl3): δ=2.25 (s, 3H), 3.20 /s, 3H), 7.25 (d, 2H), 7.41 (d, 2H), 9.70 (br s, 1H); EI SP/MS: 302 (M+), 304 (M+2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][S:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Reaction time: 1 h

Procedure:
(ab) 23 ml of thiomorpholine are slowly added dropwise at about 80° to 17.17 g of p-fluoronitrobenzene in such a manner that the internal temperature does not rise above 110°. The mixture is then stirred at 120° for an additional 1 hour, whereupon it is extracted three times with 1 l of dichloromethane each time and the organic phases are washed three times with 500 ml of water each time, dried over sodium sulfate and evaporated. By recrystallization of the crude product from dichloromethane/ether, there is obtained 4-(p-nitrophenyl)-tetrahydro-4H-1,4-thiazine of melting point 142°-144°.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]([Cl:16])([Cl:15])[C:12](Cl)=[O:13]>ClCCCl>[Cl:10][C:11]([Cl:16])([Cl:15])[C:12]([C:2]1[NH:1][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1)=[O:13]
Reactant: c1cc2c([nH]1)CCCC2
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=C(c1cc2c([nH]1)CCCC2)C(Cl)(Cl)Cl
Temperature: 85 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, condenser and nitrogen inlet was purged with nitrogen and charged with 4,5,6,7-tetrahydro-1H-indole (3.00 g, 24.8 mmol), trichloroacetyl chloride (13.5 g, 74.4 mmol) and 1,2-dichloroethane (50 mL). The solution was stirred at 85° C. for 2 h. After that time, the reaction mixture was concentrated under reduced pressure to afford a 100% yield (6.50 g) of 104f as a black semi-solid: 1H NMR (500 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.05 (s, 1H), 2.62 (t, 2H, J=6.0 Hz), 2.47 (t, 2H, J=6.0 Hz), 1.80 (m, 2H), 1.65 (m, 2H); MS (ESI+) m/z 266.0 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([CH:9]2[CH2:11][CH2:10]2)=[N:6][C:7]=1Cl.[NH3:15].Cl>O>[NH2:15][C:7]1[N:6]=[C:5]([CH:9]2[CH2:11][CH2:10]2)[N:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]=1[Cl:1]
Reactant: N
Reactant: O=C(O)c1nc(C2CC2)nc(Cl)c1Cl
Agent: Cl
Solvent: O
Product: Nc1nc(C2CC2)nc(C(=O)O)c1Cl
Temperature: 80 °C
Yield: 105.3 %

Procedure:
A 3-L flask was charged with 5,6-dichloro-2-cyclopropyl-4-pyrimidinecarboxylic acid (280 g, 1.2 mol), ammonia (28 wt % in water, 350 g, 5.76 mol) and water (1.26 L). The reaction mixture was heated at 80° C. for 5 h, and excess water (about 600 mL) was removed by distillation at 50° C./9 kPa. After cooling to 20° C., the reaction mixture was acidified to pH 2 with aqueous hydrochloric acid (132 g, 110 mL, 1.32 mol), cooled to 5° C., and filtered. The filtered wet cake was washed with water (2×200 mL) and dried in a vacuum-oven at 55° C. to give about 270 g of the title compound as a monohydrate, which contained 8.3 wt % of water measured by Karl Fischer titration, and decomposed at 152° C. (after crystallization from hot ethanol).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[CH:25][CH:26]=1
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of compound 30 (3.50 g, 12.9 mmol) and 4-methoxybenzyl trichloroacetimidate (4.65 g, 17.3 mmol) in DCM (100 mL) was added camphorsulfonic acid (450 mg, 1.92 mmol). The mixture was stirred overnight at room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and dried over Na2SO4. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 70 min, 85 mL/min) to give the product 32 (4.01 g, 81%) as a colorless liquid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1)[CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[CH:11])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude 1-(4-(2-propyl)phenyl)-2-trimethylsilylacetylene was dissolved in methanol (100 mL). Aqueous 1M potassium carbonate solution (25 mL) was added and the reaction stirred at room temperature for 2 hours. The reaction mixture was then diluted with water and extracted with pentane. The organic layers were combined, dried with magnesium sulfate, and evaporated under reduced pressure without heating to give crude 4-(2-propyl)phenylacetylene.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Cl[CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)=[O:30]>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH:18]([C:14]3[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH:8]([CH3:24])[CH3:7])[CH:17]=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[CH:32][CH:33]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: COc1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 4-chloro-1-(4-methoxyphenyl)-1-butanone: ESMS m/e: 423.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1>CN(C)C=O>[NH:26]1[CH:27]=[C:23]([CH2:22][C:8]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]#[N:10])[N:24]=[CH:25]1
Reactant: ClCc1c[nH]cn1
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(Cc1c[nH]cn1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
As described in Example 1, 7.26 g. of 2,2-bis(4-chlorophenyl)acetonitrile, 1.33 g. of 50% sodium hydride and 2.12 g. of 4-chloromethylimidazole hydrochloride were reacted in 50 ml. of dimethylformamide. The mixture was stirred for 2 hours at 60° C. and then 21 hours at ambient temperature. The solvent was then evaporated off under vacuum and the reaction mixture was worked up as described in Example 1 to obtain 5.2 g. of the free base named above, which was converted to the maleate salt and crystallized from acetone/diethyl ether to obtain 5.73 g. of the maleate salt of the product named above, m.p. 151.5°-153° C.
Reaction SMILES: [Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH:12][NH:13][C:14]([C:16]3[C:17](Cl)=[C:18]4[CH:24]=[CH:23][NH:22][C:19]4=[N:20][CH:21]=3)=[O:15])[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.O>CN1CCCC1=O>[Br:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[N:12]3[C:17]4=[C:18]5[CH:24]=[CH:23][NH:22][C:19]5=[N:20][CH:21]=[C:16]4[C:14](=[O:15])[NH:13]3)[CH2:3]1)[CH2:9]2
Reactant: O=C(NNC1C2CC3CC1CC(Br)(C3)C2)c1cnc2[nH]ccc2c1Cl
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1[nH]n(C2C3CC4CC2CC(Br)(C4)C3)c2c1cnc1[nH]ccc12
Temperature: 200 °C
Yield: 49.8 %

Procedure:
To a solution of N′-(5-bromoadamantan-2-yl)-4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbohydrazide (200 mg) in 1-methyl-2-pyrrolidone (1.5 ml) was added triethylamine (0.2 ml), and the mixture was stirred at 200° C. using a microwave reaction system for 2 hours. After the reaction solution was cooled, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 1-(5-bromoadamantan-2-yl)-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine-3(2H)-one (91 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](=S)[NH2:5].[NH2:12][NH2:13]>CCO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](=[NH:5])[NH:12][NH2:13]
Reactant: NN
Reactant: NC(=S)c1cc(F)ccc1F
Solvent: CCO
Product: N=C(NN)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
To a stirred solution of 2,5-difluorobenzothioamide (22.5 g, 129.7 mmol) in EtOH (150 mL) was added hydrazine (6.1 mL, 194.5 mmol). After stirring at room temperature for 30 min, reaction was complete by LC/MS and white solid precipitated. The precipitate was filtered and washed with Hexanes to afford 2,5-difluorobenzimidohydrazide (5.52 g, 94%).
Reaction SMILES: Br[C:2]1C(C)=[N:4][CH:5]=[CH:6][CH:7]=1.[Se](=O)=[O:10].[O:12]1[CH2:17][CH2:16]OCC1>>[N+:4]1([O-:10])[C:16]([CH:17]=[O:12])=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: C1COCCO1
Reactant: Cc1ncccc1Br
Reactant: O=[Se]=O
Product: O=Cc1cccc[n+]1[O-]
Yield: 29 %

Procedure:
To a solution of 3-bromo-2-picoline (prepared as described by Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem. 1987, 30, 871-880) (249 mg, 1.45 mmol) in dioxane (2 mL) was added selenium(IV) oxide (212 mg, 1.91 mmol) and the mixture stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (Hexanes/ether, 3:1) to afford the title compound (78 mg, 29%) as a pale yellow solid. 1H NMR (CDCl3): δ7.38 (dd, 1H, J=9, 6 Hz), 8.05 (d, 1H, J=9 Hz), 8.76 (d, 1H, J=3 Hz), 10.25 (s, 1H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7](C)=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.[C:29](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30]>C1COCC1>[Cl:1][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(CN)cc1C(=O)O
Reactant: Cl
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(aminomethyl)-2-methylbenzoic acid hydrochloride (3.2 g, 14 mmol), BSTFA (2.26 mL, 14 mmol) and 50 mL THF was heated to reflux for 1 h and cooled to 0° C. 10 mL of TEA were added, followed by 1.77 mL (14 mmol) Piv-Cl in 50 mL THF. The mixture was stirred overnight at rt, concentrated i.vac., diluted with water and acidified with 22 mL glacial acetic acid. After 30 min it was extracted 3× with DCM, the organic phase was dried with Na2SO4, concentrated i.vac and purified via MPLC. Yield: 2.57 g (66%). MS [M+H]+=270 (Cl-isotope pattern); HPLC: Rt=4.09 min (Method MC-2).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH2:13].[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:19](Cl)=[O:20].[OH-].[Na+]>ClCCl.O>[CH3:9][O:10][C:11](=[O:14])[CH2:12][NH:13][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:16]([Cl:15])[CH:17]=1
Reactant: COC(=O)CN
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 2 °C

Procedure:
Dichloromethane (150 mL) and then triethylamine (33.0 mL, 234 mmol, 2.0 eq.) were added to glycine methyl ester hydrochloride (14.7 g, 117 mmol, 1.0 eq.). The mixture was stirred and cooled to 2° C. using an ice/water bath. A solution of 3,4-dichlorobenzoyl chloride (24.55 g, 117 mmol, 1.0 eq.) in dichloromethane (75 mL) was added over 7 minutes. The mixture was stirred for 1 hour at 2° C., then left to stir at room temperature overnight (16 hours). Water (225 mL) was added and the mixture was stirred rapidly for 30 minutes at room temperature. The layers were separated. The organic layer was washed with water (225 mL), then evaporated to dryness using a rotary evaporator to give an off-white solid. The isolated solid (26.18 g, 85%) was added to dichloromethane (300 mL, 10 vols.) with 1 M sodium hydroxide solution (300 mL, 10 vols). The lower organic layer was concentrated to dryness in vacuo (25.91 g, 84%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:31]([C:33]([CH3:36])([CH3:35])[CH3:34])#[C-:32]>CO.O>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]2[N:6]([C:32]([NH:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:14]([C:13]3[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=3)[N:8]=2)[CH:7]=1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Cc1cc(N)ncc1Br
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1cc2nc(-c3cccc(Cl)c3)c(NC(C)(C)C)n2cc1Br
Reaction time: 0.08 h
Yield: 35.2 %

Procedure:
5-bromo-4-methylpyridin-2-amine (200 mg, 1.07 mmol, Eq: 1.00), 3-chlorobenzaldehyde (158 mg, 128 μl, 1.12 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (61.0 mg, 321 μmol, Eq: 0.3) were dissolved in MeOH (1.5 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (88.9 mg, 122 μL, 1.07 mmol, Eq: 1.00) and the corresponding yellow solution was stirred for 3 h. To the reaction solution was added water dropwise, leading to a milky suspension (product oiled out). The water/MeOH phase was removed and the oily residue was treated with MeOH (1 mL) and dropwise addition of water. Again a milky suspension was formed and the product oiled out. Upon standing for an hour crystals formed from the oily phase. The crystals were filtered off and washed with water and MeOH, dried under high vacuum to yield the product (148 mg, 35.2%). MS: 394.1 [M+H]+; 1H-NMR (D6-DMSO): δ 8.62 (s, 1H), 8.27 (s, 1H), 8.16 (d, 1H), 7.51 (s, 1H), 7.44 (t, 1H), 7.34 (d, 1H), 4.77 (s, 1H), 2.40 (s, 3H), 1.03 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[N:7][CH:8]=1.[NH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=O.CCN(C(C)C)C(C)C>C(#N)C>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[N:7]=[CH:8][C:3]([CH2:2][N:29]4[CH2:30][CH2:31][CH2:32][C:33]4=[O:35])=[CH:4][CH:5]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cn4)sc23)c(F)c1
Reactant: CCOC(=O)CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A mixture of 102 (500 mg, 1.202 mmol), ethyl 4-aminobutanoate (403 mg, 2.405 mmol) and DIPEA (0.630 mL, 3.61 mmol) under nitrogen in acetonitrile (12 mL) was heated to reflux for 3 days, then cooled to RT. The reaction mixture was then concentrated. The crude product was purified by Biotage (25M column; MeOH/DCM: 0/100 to 20/80 over 20 CV). The desired fractions were collected, concentrated and dried under high vacuum to afford the title compound 103 (270 mg, 0.58 mmol, 48% yield). MS (m/z): 465.5 (M+H).
Reaction SMILES: CC1ON=C(C(NC(C2C=CC(N[C:22](=[O:41])[CH2:23][C:24]3[CH:40]=[CH:39][C:27]4[N:28]=C(NC5C=CC=CC=5C)[O:30][C:26]=4[CH:25]=3)=CC=2)CC(O)=O)=O)C=1.C([O-])=[O:43].[NH4+].[CH2:46](O)[CH3:47]>[Pd]>[NH2:28][C:27]1[CH:39]=[CH:40][C:24]([CH2:23][C:22]([O:41][CH2:46][CH3:47])=[O:43])=[CH:25][C:26]=1[OH:30]
Reactant: CCO
Reactant: Cc1cc(C(=O)NC(CC(=O)O)c2ccc(NC(=O)Cc3ccc4nc(Nc5ccccc5C)oc4c3)cc2)no1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Product: CCOC(=O)Cc1ccc(N)c(O)c1
Temperature: 50 °C

Procedure:
A solution of ethyl 3-hydroxy-4-nitrophenylacetate (5.0 g, Reference Example 3) was dissolved in ethanol (approximately 200 mL) was treated with ammonium formate (approximately 20 g). The mixture was warmed to 50° C. and then treated cautiously with palladium on charcoal (approximately 1 g, 5%)—effervescence was observed. After 30 minutes the mixture was filtered hot through a pad of celite and the filtrate was concentrated to give the title compound (3.3 g) as a black solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(O)C1C=C([N+]([O-])=O)C=CC=1OC>>[CH2:13]([O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=1[CH2:2][OH:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)c(CO)c1
Agent: COc1ccc([N+](=O)[O-])cc1C(O)OC
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(CO)c1
Yield: 84 %

Procedure:
This intermediate was prepared by alkylation of 2-hydroxymethyl-4-nitrophenol with benzyl bromide following the method described for preparation of 2-methoxy-5-nitrobenzaldehyde methyl hemiacetal in a yield of 84%: MP 81-83° C.; 1H NMR δ (DMSO-d6, 500 MHz) 8.26 (d, 1H, J=2.9 Hz H-6), 8.15 (dd, 1H, J=2.9 and 9.1 Hz, H-4), 7.46 (d, 2H, J=7.0, 2′, 6′-Hs) 7.41 (dd, 2H, J=7.0 and 7.7, 3′,5′Hs), 7.34 (d, 1H, J=7 Hz, 4′-H), 7.25 (d, 1H, J=9.1 Hz, 3-H), 5.4 (br, 1H, OH), 5.29 (s, 2H, CH2), 4.57 (s, 2H, CH2).
Reaction SMILES: [PH2:1](=[O:3])[OH:2].[CH2:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)NC=3C=CC=2)C=CC=CC=1>[C:6]1([CH2:5][CH2:4][P:1]([OH:2])[OH:3])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=Cc1ccccc1
Reactant: O=[PH2]O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2cccc3c2Oc2c(cccc2P(c2ccccc2)c2ccccc2)N3)cc1
Solvent: CC#N
Product: OP(O)CCc1ccccc1
Yield: 94.2 %

Procedure:
Example 1 is repeated with 99 g of phosphinic acid, 156 g of styrene, 8.7 mg of bis(dibenzylideneacetone)palladium and 5.7 mg of 4,6-bis(diphenylphosphino)-phenoxazine in 400 g of acetonitrile to obtain 240 g (94% of theory) of 2-phenyl-ethylphosphonous acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([C:32]([F:31])([F:40])[F:41])=[CH:34][CH:35]=3)=[O:15])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.200 g, 0.604 mmol; Example 58D) in dichloromethane (2 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.453 mL, 0.905 mmol). After stirring for 30 minutes, the reaction was concentrated. The residue was dissolved in dichloromethane (2 mL) and 4-(trifluoromethyl)aniline (0.056 mL, 0.453 mmol) followed by 4-methylmorpholine (0.100 mL, 0.905 mmol) were added. After stirring for 1 hour, the reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 65% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.51 (d, J=8.6, 2H), 7.40 (d, J=8.5, 2H), 7.34-7.27 (m, 4H), 7.06-6.96 (m, 4H), 4.16 (s, 2H), 3.60 (t, J=6.5, 2H), 2.82 (t, J=6.5, 2H); MS (ESI+) m/z 474.8 (M+H)+.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(O[CH:21](N(C)C)[N:22]([CH3:24])[CH3:23])(C)C>C1(C)C=CC=CC=1>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[C:8](=[O:13])[C:9](=[CH:21][N:22]([CH3:24])[CH3:23])[CH2:10][CH2:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OC1=CCCCC1=O
Solvent: Cc1ccccc1
Product: CN(C)C=C1CCC=C(O[Si](C)(C)C(C)(C)C)C1=O
Temperature: 115 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(tert-butyl-dimethyl-silanyloxy)-cyclohex-2-enone (6.9 g, 30.48 mmol) in dry toluene (50 mL) was treated with Bredereck's reagent (9.44 ml, 45.72 mmol) was stirred at 115° C. for 24 hours. The mixture was concentrated under reduced pressure to give 2-(tert-butyl-dimethyl-silanyloxy)-6-dimethylaminomethylene-cyclohex-2-enone as a semi-solid brown residue which was used as such in the next step.