Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25]>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:28][C@@H:23]([CH3:22])[C:24]([F:27])([F:26])[F:25])=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(N)C(F)(F)F
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)N[C@@H](C)C(F)(F)F)cn1
Yield: 61 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using L-2,2,2-trifluoro-1-(methyl)ethylamine (ABCR AB146651) instead of L-2,2,2-trifluoro-1-(methyl)ethylamine (ABCR F07820EFA), to the title compound (81 mg, 61%) which was obtained as a light yellow oil after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=384.3 [M−H]−.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:15][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[N:11]=1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: Cc1nc(Cl)c2ccccc2n1
Yield: 60.5 %

Procedure:
To a mixture of 2-methylquinazolin-4(3H)-one (9.2 g, 0.0574 mol) and phosphorous oxychloride (5.8 g, 0.037 mol) in dry toluene (250 ml) was added N,N-dimethyl aniline (13.9 g, 0.14 mol) and the mixture was refluxed for 3 h. The reaction mixture was cooled and washed with water, brine and dried. The solvent was removed under vacuum and the residue was purified by chromatography (silica gel, 60-120 mesh) eluting with pet ether/ethyl acetate (9/1) to afford 4 g (39%) of the titled compound as a solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:17]=[CH:16][C:15]([C:18](=[O:24])[NH:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)=O.S(Cl)(Cl)=O>C(OCC)(=O)C>[CH3:22][CH:21]([CH3:23])[CH2:20][NH:19][C:18]([C:15]1[CH:16]=[CH:17][C:7]([C:7]2[C:8]([C:9]([OH:11])=[O:10])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:14]=1)=[O:24]
Reactant: CCOC(=O)c1cc(C(=O)NCC(C)C)ccc1OS(=O)(=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)NCC(C)C)ccc1-c1ccccc1C(=O)O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
4′-((2-methylpropyl)carbamoyl)-2′-ethoxycarbonyl-2-biphenyl carboxylic acid (1.0 g) which was prepared by the same procedure as a series of reaction of Reference Example 4→Reference Example 5, using ethyl 2-trifluoromethylsulfonyloxy-5-((2-methylpropyl)carbamoyl)benzoate, was dissolved into ethyl acetate (20 ml). Thionyl chloride (0.22 ml) was dropped into the above solution. The mixture was stirred for 15 minutes at 50° C. The reaction mixture was cooled to room temperature, and concentrated. A solution of the prepared acyl chloride compound in methylene chloride (10 ml) and triethylamine (0.57 ml) were added to a solution of 4-(N2-t-butoxycarbonyloxyamidino)aniline in methylene chloride (10 ml) at 0° C. The mixture was stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (150 ml), and washed with a saturated aqueous solution of sodium chloride (75 ml, 2 times). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (methylene chloride:methanol=100:1) to give the present compound (1.56 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([C:7](=[CH:10]NC1C=CC=CC=1)[C:8]#[N:9])=[O:6].FC(F)(F)C(O)=O.[CH:28]1([NH:31][C:32](=[O:42])[C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([NH:40][NH2:41])[CH:34]=2)[CH2:30][CH2:29]1.C(N(CC)CC)C>C(O)C>[NH2:9][C:8]1[N:40]([C:35]2[CH:34]=[C:33]([CH:38]=[CH:37][C:36]=2[CH3:39])[C:32]([NH:31][CH:28]2[CH2:30][CH2:29]2)=[O:42])[N:41]=[CH:10][C:7]=1[C:5](=[O:6])[C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([Cl:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NN
Reactant: N#CC(=CNc1ccccc1)C(=O)c1cccc(Cl)c1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(Cl)c2)c1N

Procedure:
A solution of 2-(3-chlorobenzoyl)-3-phenylaminoacrylonitrile (63 mg, 0.22 mmol, 1.0 eq), N-cyclopropyl-3-hydrazino-4-methylbenzamide trifluoroacetate (72 mg, 0.22 mmol, 1 eq), and triethylamine (31 μL, 0.22 mmol, 1.0 eq) in 10 mL of ethanol was heated to 65° C. for 20 h. After cooling, the mixture was concentrated and the residue purified by flash chromatography on silica gel packed and eluted with 7/3 hexanes/ethyl acetate to remove byproducts followed by 3/2 ethyl acetate/hexanes to elute the title compound (33 mg, 38%) as a brown solid. HPLC (4 minute 10-95 gradient) tR 2.35 min; MS m/z 395.1 [M+H]+; 1H NMR (CD3OD), δ 7.92 (d, J=7.2 Hz, 1H), 7.77 (m, 4H), 7.55 (m, 3H), 2.85 (m, 1H), 2.23 (s, 3H), 0.80 (d, J=5.5 Hz, 2H), 0.63 (d, J=2.0 Hz, 2H) ppm; 13C NMR (CD3OD), δ 187.1, 168.1, 151.9, 141.0, 140.9, 140.0, 134.9, 133.8, 132.8, 130.9, 130.5, 129.4128.1, 127.0, 126.1, 125.6, 102.6, 22.1, 15.7, 4.6 ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.Br[C:19]1[C:28]2[C:23](=C[CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:19][C@@H:28]1[CH2:23][N:22]([CH3:21])[CH2:25][CH2:26][N:27]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CN(C)CCN1c1nccc(N)n1
Temperature: 220 °C
Yield: 18.4 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol), Hunig's base (809 μl, 4.63 mmol) and (3R)-1,3-dimethylpiperazine (Ref.: WO2009061879 (A1)) (650 mg, 3.47 mmol) in N,N-dimethylformamide (DMF) (3 ml) was heated in a microwave reactor at 220° C. for 60 min. The reaction mixture was purified by RP-HPLC to yield 2-[(2R)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (88 mg, 0.425 mmol, 18% yield). MS (ES+) m/z 208.0 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[O:16][CH2:17][C:18](=[O:20])[NH2:19])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH2:17][C:18]([NH2:19])=[O:20])=[C:9]([CH:14]=1)[CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)ccc1OCC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(Cl)ccc1OCC(N)=O
Yield: 96.1 %

Procedure:
Compound 79 (200 mg, 0.63 mmol) was treated with a solution at 15% of TFA in CH2Cl2 at room temperature for 45 min. The solution was concentrated in vacuo and water (10 mL) was added. The aqueous phase was washed with Et2O, basified with aqueous 2N NaOH, and extracted with CHCl3 (10 mL×3) obtaining 130 mg of a white solid (80) (yield 96%). 1H NMR (CDCl3, 300 MHz) δ8.37 (br s, 1H), 7.29-7.22 (m, 2H), 6.82 (d, J=9.3 Hz, 1H), 5.44 (br s, 1H), 3.8(s, 2H), 3.89 (s, 2H). MS (m/e) (API-ES) 215 (M+H)+, m.p. 135-137° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[CH:23]=1.[CH2:24]([N:26]([CH2:28][CH3:29])O)[CH3:25].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]([CH2:28][CH3:29])[CH2:24][CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[CH:23]=1
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Reactant: CCN(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 15, 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine is treated with a cold mixture of N,N-diethylhydroxylamine and sodium hydride in dimethylformamide to give 8-bromo-1-[(diethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a ][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([N:27]=[C:28]=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[S:29])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=S)Nc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and phenylisothiocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 209°-211° C.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.O>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Temperature: 65 °C

Procedure:
KOH (8.19 g, 146 mmole), 5-chloroindole (5.0 g, 33 mmole) and piperidine-4-one hydrochloride (10.22 g, 85.7 mmole) were suspended in methanol (50 ml) and heated for 8 hours at 65° C. under argon. Water (50 ml) was added dropwise at RT to the mixture over a period of 40 minutes. The solid thereby formed was filtered off, washed with water (3×20 ml) and recrystallised from methanol (20 ml). 5-chloro-3-(1,2,3,6-tetrahydropyridine-4-yl)-1H-indole was obtained in a yield of 6.4 g (90%) as a yellow solid with an m.p. of 166°-168° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH:23]C(C)(C)C)(=[O:22])=[O:21])(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[I-].[Na+].Cl[Si](C)(C)C>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20](=[O:22])(=[O:21])[NH:23]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(Cc2ccccc2)C1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=S1(=O)NC2(CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a solution of 2-(1-benzyl-3-hydroxypyrrolidin-3-yl)-N-(tert-butyl)benzene sulfonamide (350 mg, 0.00090 mol) in acetonitrile (15 mL, 0.29 mol) were added sodium iodide (418 mg, 0.00279 mol) and chlorotrimethylsilane (0.354 mL, 0.00279 mol). The reaction mixture was refluxed under nitrogen for 1 hour and then cooled down to room temperature, then quenched with 10% aqueous sodium thiosulfate solution (10 mL), and then extracted with EtOAc. The organic phase was washed with water then brine, and then dried over MgSO4 followed by filtration. The filtrate was concentrated to give the desired compound (170 mg, 60% yield). MS (ESI): 315.0 (M+H+).
Reaction SMILES: [Cl: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]([CH3:18])[C:9]=2[CH3:19])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1ccc(Cl)cc1)c(C)n2C

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-chloro-phenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[NH2:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=1.O>C(O)C>[Br:21][C:17]1[CH:18]=[C:19]([CH3:20])[C:14]2[N:15]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[N:13]=2)[CH:16]=1
Reactant: Cc1cc(Br)cnc1N
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1cn2cc(Br)cc(C)c2n1
Temperature: 80 °C
Yield: 54.1 %

Procedure:
A mixture of 2-bromo-2′-methoxyacetophenone (0.500 g, 2.183 mmol) and 2-amino-5-bromo-3-methylpyridine (0.408 g, 2.183 mmol) in ethanol (8 mL) was heated to 80° C. for 16 hours in a pressure vessel. A yellow thick precipitate formed. Water was added and the solid was extracted with ethyl acetate (some DCM and MeOH were added to help in the dissolution). The organic extracts were then washed with brine, dried over Na2SO4, filtered and concentrated and the residue was purified by silica gel chromatography (Biotage SNAP 100 g, 10 to 20% ethyl acetate in hexanes) to give 220 (0.375 g, 1.182 mmol, 54.2% yield) as a white solid. LRMS (ESI): calc. 316.02 found 317.1 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13](=[O:29])[N:14](C1C=CC(F)=CC=1C)[C:15](=[O:20])[CH2:16][CH2:17][C:18]#[CH:19])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13](=[O:29])[NH:14][C:15](=[O:20])[CH2:16][CH2:17][C:18]#[C:19][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: C#CCCC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1C
Reactant: Brc1ccccn1
Product: CC(C)(C)OC(=O)NC(=O)CCC#Cc1ccccn1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (129 mg, 0.82 mmol) and (4-fluoro-2-methyl-phenyl)-pent-4-ynoyl-carbamic acid tert-butyl ester 250 mg, 0.82 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 190 mg (0.50 mmol, 61%) of 4-fluoro-2-methyl-phenyl)-(5-pyridin-2-yl-pent-4-ynoyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:10](=O)[O:9][C:7](=[O:8])[C:6]2=[CH:12][N:13]=[CH:14][CH:15]=[C:5]12)[CH:2]=[CH2:3].[C-]#N.[K+].O>CN(C=O)C>[CH2:1]([N:4]1[C:5]2[C:6](=[CH:12][N:13]=[CH:14][CH:15]=2)[C:7](=[O:8])[C:10]1=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)oc(=O)c2cnccc21
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1C(=O)C(=O)c2cnccc21
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A solution of N-allyl-5-azaisatoic anhydride (20 mmol) in DMF is added dropwise to a suspension of pulverized potassium cyanide (21 mmol) in DMF at 100° C. The reaction mixture is stirred at 100° C. for an additional 5 min after which time the mixture is poured into cold water and extracted with ether. The organic layer is dried (Na2SO4), filtered and the solvent is removed. Stirring the resulting residue in 2N hydrochloric acid overnight and adjusting the pH to 7 gives, upon filtration, N-allyl-5-azaisatin.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=[CH2:15].[Li]CCCC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: C=Cc1ccc2ccccc2c1
Agent: [Li]CCCC
Product: Fc1ccc(N2CCN(CCc3ccc4ccccc4c3)CC2)cc1

Procedure:
According to GP, 2.22 mmol (=0.40 g) of 1-(4-fluorophenyl)piperazine and 2.22 mmol (=0.34 g) of 2-vinylnaphthalene are reacted with 5 mol % (=0.111 mmol=70 μl) of n-BuLi solution. Column-chromatographic separation with ethyl acetate/n-hexane (1:1) gives the product 1-(4-fluorophenyl)-4-[2-(2-naphthyl)-1-ethyl]piperazine as a light-yellow solid.
Reaction SMILES: C([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=2)[C:5]1=[O:31])C=C.O.C[N+]1([O-])CC[O:38]CC1.C[C:43]([CH3:45])=[O:44].OS(O)(=O)=O.O=[Cr](=O)=O>O1CCCC1.[Os](=O)(=O)(=O)=O.CC(O)(C)C>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][N:25]=3)[C:5](=[O:31])[C@:4]([CH2:45][C:43]([OH:38])=[O:44])([CH3:32])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2cc(C)ccn2)C1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccnc(N2C(=O)[C@@](C)(CC(=O)O)C[C@H](c3cccc(Cl)c3)[C@H]2c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl)piperidin-2-one (Example 114, Step A) (73 mg, 0.16 mmol) in 780 μL of tetrahydrofuran was added water (1.0 mL), followed by 2-methylpropan-2-ol (100 μL) at room temperature. The reaction mixture was treated with 4-methylmorpholine 4-oxide (28 mg, 0.24 mmol), followed by osmium tetroxide (2.0 mg, 7.8 μmol) and was stirred at room temperature for 2 hours. The reaction mixture was treated with a 1.25 M solution of Jones reagent (190 μL, 0.24 mmol) at room temperature and was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted (3×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by HPLC on an Eclipse column (Agilent Technologies, Santa, Clara, Calif.) (20 to 80% acetonitrile/water, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CN=CC=1.[O:21]=[S:22](=[O:24])=[O:23]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:11][C:12]([S:22]([OH:24])(=[O:23])=[O:21])=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccco1
Reactant: O=S(=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(S(=O)(=O)O)o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A solution of 2-(tert-butoxycarbonylaminomethyl)-furan (9.8 g, 50 mmol) in 150 mL of dichloromethane was added into a flask, and the reaction mixture was cooled to 0° C. in an ice bath. A solution of pyridine-sulfur trioxide adduct (15.9 g, 100 mmol) in 100 mL of dichloromethane were added dropwise. Upon completion of the addition, the reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for additional 8 h. After the completion of the reaction, the reaction mixture was then extracted with water (400 mL×2). Aqueous hydrochloric acid (10%) was slowly added dropwise to the aqueous layer. The aqueous layer was adjusted to pH 6.5-7, and extracted with dichloromethane (500 mL×2). The organic layer was washed by saturated brine, and concentrated under reduced pressure to give 5.5 g (40.0% yield) of 5-(tert-butoxycarbonylaminomethyl)furan-2-sulfonic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=[CH:51]C=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CCC>C(Cl)Cl>[CH2:48]([NH:47][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:27]([C:10]2[C:11]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=4[F:26])[C:12]=3[N:13]=[C:8]([NH:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:37][CH3:38])[CH2:1][CH3:2])[N:9]=2)[CH:28]=1)[CH2:49][CH2:50][CH3:51]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCN
Solvent: ClCCl
Product: CCCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in methylene chloride (2 mL) were added HBTU (30 mg, 0.079 mmol) and butylamine (0.038 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (29 mg, 66%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[O:13][CH:12]([CH3:14])[NH:11][CH2:10]1.[F:21][C:22]([F:34])([F:33])[C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[O:13][CH:12]([CH3:14])[N:11]([S:29]([C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:21])([F:33])[F:34])=[CH:28][CH:27]=2)(=[O:31])=[O:30])[CH2:10]1
Reactant: CC1NCC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: CC1OC(Cn2cncn2)(c2ccc(Cl)cc2Cl)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
Following the general sulfonylation procedure explained in example 1 but using 5-(2,4-dichlorophenyl)-2-methyl-5-[(1H-1,2,4-triazol-1-yl]methyl)oxazolidine, obtained according to patent ES 334509/91 and 4-trifluoromethylbenzenesulfonyl chloride, the title product is obtained in similar yield as a single isomer. mp 188°-190° C. 1H NMR (80 MHz, CDCl3)δ(TMS) 8.06 (s, 1H, N=CH), 7.80 (s, 1H, N=CH), 7.7-7.2 (m, 5H, arom), 7.02 (s, 2H, arom), 5.20 (q, J=5.3 Hz, 1H, CHMe), 4.60 (AB system, Δv=0.32, J=14.6 Hz, 2H, CH2 -Tr), 4.13 (AB system, Δv=0.62, J=12 Hz, 2H, NCH2), 1.49 (d, J=5.3 Hz, 3H, CHMe). Anal. calcd. for C20H17F3Cl2N4O3S: C 46.08%; H 3.29%; N 10.75%. Found: C 46.34%; H 3.54%; N 10.43%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[C:33]([O:41][CH2:42][CH3:43])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[C:33]([O:41][CH2:42][CH3:43])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:44])=[C:16]([F:22])[CH:17]=1
Reactant: CCOc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 70 °C

Procedure:
In a manner similar to the method described in Example 380, a solution of the above methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-ethoxybenzoate (89.7 mg, ˜0.13 mmol) in THF (8 ml) was treated with lithium hydroxide hydrate (40.9 mg, 0.974 mmol) in water (4 mL) and heated at 70° C. for 3 hrs and then stirred at room temperature to give rac 4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-ethoxy-benzoic acid as a white lyophilized solid (33.5 mg., 38%) after HPLC purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH2:10][CH:11]1[CH2:15][N:14]([CH3:16])[C:13](=[O:17])[CH2:12]1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][CH2:10][CH:11]2[CH2:15][N:14]([CH3:16])[C:13](=[O:17])[CH2:12]2)=[N:3][CH:4]=1
Reactant: CN1CC(CO)CC1=O
Reactant: Brc1ccc(Br)nc1
Product: CN1CC(COc2ccc(Br)cn2)CC1=O

Procedure:
Prepared from 2,5-dibromopyridine and 4-hydroxymethyl-1-methylpyrrolidin-2-one by the method of Example 10 (b).