Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1.C(N(CC)CC)C.[I-].[Na+]>C(O)C>[C:1]1([N:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]3[CH:29]=[CH:28][C:23]4[NH:24][C:25](=[O:27])[O:26][C:22]=4[CH:21]=3)[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1[nH]c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2o1
Yield: 23 %

Procedure:
To a 100 ml round-bottomed flask equipped with magnetic stirrer, condenser, and nitrogen inlet were added 0.618 g (2.10 mmol) of N-(1-naphthyl)piperazine 0.472 g (1.95 mmol) of 6-(2-bromoethyl)-benzoxazolone, 0.411 ml (2.92 mmol) of triethylamine, 50 ml ethanol, and a catalytic amount of sodium iodide. The reaction was refluxed for 3 days, cooled, and evaporated to a brown gum. The gum was partitioned between 50 ml water and 75 ml methylene chloride, the pH adjusted with aqueous 1 N sodium hydroxide solution, and a little methanol added to facilitate phase separation. The methylene chloride layer was dried over sodium sulfate and evaporated, then chromatographed on silica gel. Fractions containing the product were combined and evaporated, the residue taken up in ethyl acetate, treated with hydrochloride gas, and the resulting hydrochloride salt of the product filtered off to give the while solid title compound, m.p. 282°-285° C., 213 mg (23% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cc2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)cc2ccccc12

Procedure:
A solution of ethyl 3-nitro-1-naphthoate (5.371 g, 21.90 mmol) in ethanol (30 ml) was hydrogenated under normal temperature and normal pressure using 10% palladium/carbon (containing water by 50%) (0.5 g) as a catalyst until the starting material disappeared. The catalyst was filtered off and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1−3/1) to give the objective substance.
Reaction SMILES: C(NC(=O)[C@H](C)C[C@H](O)[C@@H](NC(OC(C)(C)C)=O)C[C@@H](C(C)C)[CH2:13][C:14]1[CH:19]=CC=[C:16]([OH:20])[CH:15]=1)CCC.C(OC1C=C(C=CC=1C(C)(C)C)CBr)(=O)C.[CH2:51]([O:58][C:59]1[CH:60]=[C:61]([CH:64]=[CH:65][CH:66]=1)[CH2:62]Br)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>ClCCl.CCCCCC>[CH:14]([C@@H:15]([CH2:62][C:61]1[CH:64]=[CH:65][CH:66]=[C:59]([O:58][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:60]=1)[CH2:16][OH:20])([CH3:19])[CH3:13]
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](C[C@H](Cc1cccc(O)c1)C(C)C)NC(=O)OC(C)(C)C
Reactant: BrCc1cccc(OCc2ccccc2)c1
Agent: CC(=O)Oc1cc(CBr)ccc1C(C)(C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)[C@H](CO)Cc1cccc(OCc2ccccc2)c1

Procedure:
The N-tert-butoxycarbonyl-2(R)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxyphenyl)-octanoic acid (N-butyl)amide used as starting material is prepared analogously to Example 5a)-5l), except that in step k) instead of 3-acetoxy-4-tert-butyl-benzyl bromide there is used 3-benzyloxy-benzyl bromide, so that in step i) 2(R)-isopropyl-3-(3-benzyloxy-phenyl)-propanol, Rf (dichloromethane/hexane=1:1)=0.19, is obtained directly.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][C:19]1([CH:31]=[CH:30][CH:29]=[CH:28][CH2:27]1)[CH2:20][P:21](=[O:26])([O:24][CH3:25])[O:22][CH3:23]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([NH:18][C@@:19]1([CH:27]=[CH:28][CH:29]=[CH:30][CH2:31]1)[CH2:20][P:21](=[O:26])([O:22][CH3:23])[O:24][CH3:25])=[O:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COP(=O)(CC1(N)C=CC=CC1)OC
Agent: Cl
Product: COP(=O)(C[C@@]1(NC(=O)[C@H](C)NC(=O)OCc2ccccc2)C=CC=CC1)OC

Procedure:
In a manner analogous to that given in Example 13 (a), from the N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine and dimethyl 1-aminobenzylphosphonate hydrochloride, there was obtained an isomeric mixture. After chromatography on silica gel with an isopropanol/ethyl acetate eluant, followed by recrystallization from ethyl acetate/ether, there were isolated dimethyl (1S)-1-[(N-benzyloxycarbonyl-L-alanyl)-amino] -benzylphosphonate of melting point 103°-105° C [[α]D20 =- 46.6°(c = 1% in methanol)]and dimethyl (1R)-1-[(N-benzyl-oxycarbonyl-L-alanyl)]-benzylphosphonate of melting point 120°-122° C [[α]D20 =+ 12.3°(c = 1% in methanol)]
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[C:11]1[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=1.[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]3[O:36][CH:35]([CH:37]4[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]4)[CH2:34][C:33]=3[CH:43]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21].ClCCl>CN(C)C=O.O>[CH2:17]([C:14]1[CH:13]=[N:12][C:11]([N:40]2[CH2:41][CH2:42][CH:37]([CH:35]3[CH2:34][C:33]4[CH:43]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=5)[CH:30]=[CH:31][C:32]=4[O:36]3)[CH2:38][CH2:39]2)=[N:16][CH:15]=1)[CH3:18]
Reactant: CCc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4O3)CC2)nc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Ethyldiisopropylamine (50 μL) and 2-chloro-5-ethylpyrimidine (17 μL) are added to a solution of 4-[5-(4-methanesulfonyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidine (50 mg) in N,N-dimethylformamide (1 mL) and the reaction mixture is stirred at 120° C. for 2 h. After cooling to room temperature over night, dichloromethane and water are added. The aqueous phase is separated and extracted with dichloromethane. The combined organic phases are washed with water, 10% NH4Cl solution, and brine, and dried over MgSO4. The solvent is evaporated and the residue is triturated with diethyl ether to give the title compound. LC (method 4): tR=1.26 min; Mass spectrum (ESI+): m/z=464 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH:8]1[CH2:11][CH2:10][CH2:9]1.CN1CCCC1=O.[CH2:19]([O:26][C:27]1[CH:51]=[CH:50][C:49]([O:52][CH2:53][CH2:54]Br)=[CH:48][C:28]=1[C:29]([NH:31][C:32]1[CH:41]=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35])=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.O>[N:8]1([CH2:54][CH2:53][O:52][C:49]2[CH:50]=[CH:51][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:28]([CH:48]=2)[C:29]([NH:31][C:32]2[CH:41]=[C:40]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=[CH:38][C:33]=2[C:34]([O:36][CH3:37])=[O:35])=[O:30])[CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCC2)ccc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 36.8 %

Procedure:
Potassium carbonate (0.15 g) and azetidine hydrochloride (0.046 g) were added to a 1-methyl-2-pyrrolidone (1.3 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.25 g), followed by stirring at 90° C. for 45 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.088 g of methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate as a light yellow oily substance.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].[Cl:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])=[O:13].N1C=CC=CC=1.C(Cl)(Cl)Cl>O1CCCC1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:17](=[O:18])[CH2:16][CH2:15][S:12]([CH2:11][CH2:10][Cl:9])(=[O:14])=[O:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: O=C(Cl)CCS(=O)(=O)CCCl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CC(=O)OCCOC(=O)CCS(=O)(=O)CCCl
Temperature: 5 °C
Reaction time: 1.75 h
Yield: 88.6 %

Procedure:
A mixture of 600 ml of tetrahydrofuran, 46.8 g of hydroxyethyl acrylate, and 72 g of 3-(2-chloroethylsulfonyl)propionic acid chloride was placed in a reactor, and while maintaining the temperature at 5° C. or lower by cooling by ice water, a solution containing 31.2 g of pyridine dissolved in 100 ml of tetrahydrofuran was added dropwise thereto over a period of 1.75 hours. The resulting mixture was further stirred for 2 hours at room temperature. At the end of the time, the reaction mixture was poured into 2.5 liters of ice water, and extraction was performed four times with 300 ml of chloroform. The organic layer thus-extracted was dried over sodium sulfate and concentrated to provide 87 g of 2-[3-(chloroethylsulfonyl)propionyloxy]ethyl acrylate which was a liquid at room temperature (decomposed during distillation). Yield was 88%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1>O1CCOCC1>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:29][CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Reactant: NCc1cccnc1
Solvent: C1COCCO1
Product: COc1ccccc1CNc1ccc2c(NCc3cccnc3)cccc2n1
Temperature: 100 °C
Reaction time: 2.5 h

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 3 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 3-Picolylamine (127 mg, 1.18 mmol), sodium tert.-butylate (144 mg, 1.50 mmol), 1,1′-bis(diphenylphosphin)ferrocen (50 mg, 0.09 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II)chloride (24 mg, 0.03 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 2.5 h. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The title compound was obtained as a light brown solid (183 mg, 85%), MS: m/e=371.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:10](#[N:13])[CH:11]=[CH2:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:12][CH2:11][C:10]#[N:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: C=CC#N
Product: COc1ccc(OCCC#N)cc1

Procedure:
A mixture of 4-methoxyphenol (10 g:80.5 mmol) and Triton B (2.29 ml:14.5 mmol 0. 18 eq.) in acrylonitrile (50 ml) is heated at reflux for 48 hours. After the solvent has been partially removed, the products are extracted with ethyl acetate and washed with water and then with a 6N hydrochloric acid solution. The residual chestnut-brown oil is purified on a flash silica column eluted with an AcOEt/PE gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[H-].[Na+].Br[C:13]1[C:14]2[N:15]([C:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][C:27]=3[F:32])=[O:24])=[CH:21][N:22]=2)[N:16]=[C:17]([Cl:19])[CH:18]=1.CN(C=O)C>C1COCC1.O>[NH2:8][C:6]1[N:5]=[C:4]([NH:9][C:13]2[C:14]3[N:15]([C:20]([C:23]([NH:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][C:27]=4[F:32])=[O:24])=[CH:21][N:22]=3)[N:16]=[C:17]([Cl:19])[CH:18]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Nc1cc(Cl)cc(N)n1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)cc(Nc2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)n1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
To a solution of 4-chloropyridine-2,6-diamine (35.2 mg, 0.245 mmol) in THF (0.5 mL) was added 60% NaH (12.26 mg, 0.307 mmol). The mixture was stirred for 10 min. 5A (40 mg, 0.123 mmol) was added, followed by DMF (0.5 mL). The mixture was stirred at room temperature for 1 h. Water was added and the precipitated solid was collected by filtration, and dried to give crude 40A (42 mg, 59%). HPLC Rt=3.131 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=433.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([CH:22]=1)[NH:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[C:16]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc(Br)cc1NCC(C)C
Product: Cc1ccc(-c2ccc(F)cc2)cc1NCC(C)C
Yield: 83 %

Procedure:
Using the same method as in Example 19-(ii), 4-fluoro-benzene boronic acid was reacted with 5-bromo-2-methyl-N-(2-methylpropyl)aniline to give 4′-fluoro-4-methyl-N-(2-methylpropyl)biphenyl-3-amine (yield: 83%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[C:5]([C:13]#[N:14])=[C:4]([S:15][CH3:16])[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]C[S-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[C:5]([C:13]#[N:14])=[C:4]([S:15][CH2:16][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[N:3]=1
Reactant: [S-]CCc1ccccn1
Reactant: C=C(OCC)c1nc(N)nc(SC)c1C#N
Agent: [Na+]
Solvent: C1COCCO1
Product: C=C(OCC)c1nc(N)nc(SCCc2ccccn2)c1C#N
Temperature: 100 °C
Yield: 1.4 %

Procedure:
To a stirred suspension of 200 mg (0.85 mmol) 2-amino-4-(1-ethoxy-vinyl)-6-methylsulfanyl-pyrimidine-5-carbonitrile in 16 ml dioxane was added 546 mg (3.38 mmol) sodium 2-pyridin-2-yl-ethanethiolate and the mixture heated at 100° C. for 1 hour. The reaction mixture was then concentrated in vacuo and the residue triturated in ether. The crystals were removed by filtration and the mother liquor concentrated in vacuo. The residue was then recrystallised from ethyl acetate/hexane and the crystals additionally purified by HPLC to afford 4.0 mg (1%) 2-amino-4-(1-ethoxy-vinyl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as an off-white crystalline solid. ES-MS m/e (%): 328 (M+H+, 100).
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[N:14]=[CH:15][N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=3)[C:9](=[O:37])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38]I>CC#N>[CH3:38][N:14]1[C:13]([CH2:12][N:10]2[CH2:11][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][C:9]2=[O:37])=[CH:17][N:16]=[CH:15]1
Reactant: CI
Reactant: O=C1CC(c2ccccc2)CN1Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CC#N
Product: Cn1cncc1CN1CC(c2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer, under inert atmosphere, 4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44 (2 g, 4.1 mmol) is dissolved in CH3CN (20 ml) and MeI (283 μL, 4.5 mmol) is added. The mixture is stirred at room temperature and two additional portions of MeI (283 μl and 500 μl) are added after 40 h and 46 h. After stirring for 16 h at room temperature, the mixture is concentrated and dissolved in a 1/1 mixture of AcOH and water. After stirring at room temperature for 48 h, the mixture is filtered and evaporated to dryness (by azeotropic distillation with toluene). The residue is dissolved in a solution of HCl at pH 1 (25 ml) and extracted with CH2Cl2 (3×50 ml). The aqueous phase is brought at pH 10 by adding solid K2CO3 and extracted again with CH2Cl2 (3×50 ml). Combined organic phases are dried over MgSO4, filtered and concentrated to give 1 g of crude product which is purified by chromatography on silicagel (60 g of SiO2, CH2Cl2/EtOH/NH4OH: 94/5.4/0.6 (v/v/v)) to give 0.5 g of 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one. This free base is treated with a 3.6 M solution of HCl (5 ml), and the resulting solid is recrystallized in CH3CN to lead to 1-[(1-methyl-1H-imidazol-5-yl)methyl]-4-phenylpyrrolidin-2-one hydrochloride 119.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:53][C:54]1[CH:60]=[CH:59][C:57]([NH2:58])=[CH:56][CH:55]=1.Cl[C:62]1[N:67]=[CH:66][C:65]([C:68]([N:70]([CH3:92])[C:71]2[CH:76]=[CH:75][C:74]([CH2:77][N:78]3[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[C@@H:80]([CH3:91])[CH2:79]3)=[CH:73][CH:72]=2)=[O:69])=[CH:64][CH:63]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:53][C:54]1[CH:60]=[CH:59][C:57]([NH:58][C:62]2[N:67]=[CH:66][C:65]([C:68]([N:70]([CH3:92])[C:71]3[CH:76]=[CH:75][C:74]([CH2:77][N:78]4[CH2:83][CH2:82][N:81]([C:84]([O:86][C:87]([CH3:89])([CH3:88])[CH3:90])=[O:85])[C@@H:80]([CH3:91])[CH2:79]4)=[CH:73][CH:72]=3)=[O:69])=[CH:64][CH:63]=2)=[CH:56][CH:55]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: Nc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Nc4ccc(F)cc4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
BINAP (0.041 g, 0.0654 mmol), cesium carbonate (0.213 g, 0.654 mmol) and palladium acetate (0.009 g, 0.0436 mmol) were combined in dioxane (1 mL) and sonicated for 1 h under an argon atmosphere. To the red mixture was added 4-fluoroaniline (0.053 g, 0.479 mmol) and 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) (0.2 g, 0.436 mmol). The mixture was stirred at 60° C. for 1 h, the solvent was removed under vacuum and the residues partitioned between EtOAc and water. The EtOAc layer was dried and concentrated. The crude product was purified by chromatography. Elution with a 0-70% EtOAc/petroleum ether gradient yielded the title compound as a pale yellow oil (0.110 g). δH (CDCl3, 400 MHz) 8.10 (1H, m), 7.40 (1H, dd), 7.25 (3H, m), 7.02 (4H, m), 6.92 (1H, s), 6.43 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.48 (1H, d), 3.36 (1H, d), 3.10 (1H, td), 2.70 (1H, d), 2.52 (1H, d), 2.10 (1H, m), 1.98 (1H, m), 1.85 (1H, br.s), 1.45 (9H, s), 1.20 (3H, d). MS (ES): MH+ 534.3.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:35][CH3:36])=[C:8]([C:13]([CH2:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3/[CH:26]=[CH:27]\[CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:9]([O:11]C)=[O:10])=[CH:2]1.O.[OH-].[Li+]>O.O1CCOCC1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:35][CH3:36])=[C:8]([C:13]([CH2:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3/[CH:26]=[CH:27]\[CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:19])=[O:18])=[CH:14][CH:15]=2)[C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)ccc(-c2ccoc2)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2/C=C\CN2CCCCC2)c1C(=O)O
Temperature: 65 °C

Procedure:
(Z)-Methyl 3-(furan-3-yl)-2-methoxy-6-((2-(3-(piperidin-1-yl)prop-1-enyl)benzenesulfonyl)methyl)benzoate (Intermediate 198, 0.069 g) was added to a solution of lithium hydroxide monohydrate (0.051 g) in water (0.7 ml) and dioxane (3 ml) and the resultant mixture was stirred and heated at 65° C. for 4 days. After cooling, the mixture was diluted with water and washed with diethyl ether. The aqueous layer was acidified with 1M HCl and extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by HPLC (C6 phenyl column) eluting with 1:1 methanol:water containing 0.1% formic acid to give (Z)-3-(Furan-3-yl)-2-methoxy-6-((2-(3-(piperidin-1-yl)prop-1-enyl)benzenesulfonyl)methyl)benzoic acid as a white solid.
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH2:9][C:10]1[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH3:8][C:2]1[C:3]([CH2:4][CH2:5][C:6]#[N:7])=[CH:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)CCCC#N
Solvent: CCO
Product: Cc1nc2ncccc2cc1CCC#N

Procedure:
A mixture of 5-oxo-hexanenitrile (5 mL, TCI-US), 2-amino-3-formylpyridine (7 g, J. Org. Chem. 1983, vol. 48, p 3401) and ethanol (100 mL) was heated to reflux for 12 hours. Following evaporation of the solvent, the residue was chromatographed (silica gel, ethyl acetate) to give 4-[1,8]naphthyridin-2-yl-butyronitirile and the title product as colorless solids. 1H (CDCl3) δ 2.29 (3H, s); 2.83 (2H, t); 3.18 (2H, t); 7.48 (1H, dd); 8.04 (1H, s); 8.20 (1H, dd); 9.03 (1H, dd).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.Cl.CC(C)=O>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:16][CH2:17][N:18]([CH:1]2[CH2:2][CH2:3][C:4](=[O:7])[CH2:5][CH2:6]2)[CH2:19][CH2:20]1
Reactant: O=C1CCC(=O)CC1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCC(N2CCN(c3ccccn3)CC2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 1,4-cyclohexanedione monoethyleneketa (50.0 g), 1-(2-pyridyl)piperazine (52.16 g), and p-toluenesulfonic acid (0.5 g) in 500 ml of toluene is refluxed with a Dean-Stark trap until the theoretical amount of water is collected (about four hours). The solvent is evaporated in vacuo and the residue is dissolved in 750 ml of methanol. This solution is cooled in an ice bath and sodium cyanoborohydride (30.1 g) is added in small portions over a two-minute period. The resulting suspension is stirred mechanically and over the next 30 minutes enough concentrated hydrochloric acid solution is added dropwise to the reaction mixture to maintain a pH of about 4. The solvent is removed in vacuo to leave a semisolid residue which is dissolved in 300 ml of a 10% solution of hydrochloric acid in a well ventilated fume hood. This solution is diluted with an equal volume of acetone and refluxed for two hours. The volatile components of the mixture are removed in vacuo and the residue is cooled in an ice bath and made basic with concentrated ammonium hydroxide. The white solid which forms is recrystallized from ethyl acetate-heptane to give 52.4 g of the title compound; mp 142°-144° C.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].C([O-])=O.[NH4+]>CCO.O.CCOC(C)=O.[Fe]>[CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)Cc1ccc(N)cc1
Temperature: 90 °C
Yield: 38.6 %

Procedure:
To a mixture of 1-(methylsulfonylmethyl)-4-nitrobenzene (1.5 g, 7 mmol) in EtOH (20 mL) and H2O (10 mL) was added iron (1.96 g, 35 mmol) and ammonium formate (4.41 g, 70 mmol). After heating at 90° C. for 2 h, it was diluted with EtOAc, washed with saturated NaHCO3, brine, dried and concentrated to give 4-(methylsulfonylmethyl)aniline (0.5 g).