Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN.[C:3]([O-:6])([O-])=O.[K+].[K+].ClC(OC1C=C[C:16]([N+:19]([O-])=O)=CC=1)=O.[OH:22][C:23]([CH3:53])([CH3:52])[CH2:24][C@@:25]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:30][C:29](=[O:31])[N:28]([C@H:32]([C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[CH3:33])[CH2:27][CH2:26]1.N>C(#N)C.CCN(CC)CC>[CH3:16][NH:19][C:3]([N:43]1[CH2:44][CH2:45][CH:40]([C:37]2[CH:38]=[CH:39][C:34]([C@@H:32]([N:28]3[CH2:27][CH2:26][C@:25]([CH2:24][C:23]([OH:22])([CH3:52])[CH3:53])([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:30][C:29]3=[O:31])[CH3:33])=[CH:35][CH:36]=2)[CH2:41][CH2:42]1)=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CN
Agent: N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNC(=O)N1CCC(c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
MeNH2*HCl (27 mg) and K2CO3 (93 mg) were added to a solution of 4-nitrophenyl chloroformate (66 mg) in acetonitrile (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 4 h, before (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (110 mg) and NEt3 (53 μL) were added. The mixture was further stirred at room temperature overnight. Then, diluted aqueous ammonia solution was added and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by HPLC on reversed phase (MeOH/H2O/NH3) to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[ClH:18].N1C=CC=CC=1.[NH2:25][C:26]1[C:31](Cl)=[CH:30][CH:29]=[CH:28][C:27]=1[OH:33]>C(OCCO)C>[Cl:18][C:30]1[CH:29]=[CH:28][C:27]([OH:33])=[C:26]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:31]=1
Reactant: Cl
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1c(O)cccc1Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cc(Cl)ccc3O)c2cc1OC
Yield: 91.7 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 172.3 mg (1.2 mmol) of 2-amino-chlorophenol to give 326.4 mg (91.9%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 355.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([NH:8][NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7].[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23].[OH-].[Na+]>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([NH:8][N:9]([C:22](=[O:23])[C:21]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]([CH3:18])[CH:20]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1cccc(C(=O)NNC(C)(C)C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(=O)NN(C(=O)c2cc(C)cc(C)c2)C(C)(C)C)c1C
Yield: 84.1 %

Procedure:
To a stirred solution of N-(3-methoxy-2-methylbenzoyl)-N'-tert-butylhydrazine (506 g, 2.14 mole) in methylene chloride (1.5 L) at 5° C. were simultaneously added solutions of 3,5-dimethylbenzoyl chloride (360 g, 2.14 moles) in methylene chloride (500 mL) and sodium hydroxide (50% aqueous, 171.2 g, 2.14 moles) diluted with water (400 mL), at such a rate that the temperature of the mixture did not exceed 10° C. Following the addition, the reaction mixture was allowed to reach room temperature and stirred continuously for 1 additional hour, whereupon the reaction mixture was diluted with methylene chloride (12 L), washed with water, dried over magnesium sulfate, filtered and stripped to give N-(3-methoxy-2-methylbenzoyl)-N'-(3,5-dimethylbenzoyl)-N'-tert-butylhydrazine (663 g), melting at 204°-204.5° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:20]=[CH:21][CH:22]=3)[C:14]([NH:16][CH2:17][CH2:18][OH:19])=[O:15])=[C:8]([CH3:23])[C:6]=2[N:7]=1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:36][N:37]=2)[CH:32]=[CH:31]1>>[OH:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[C:13]1[CH:20]=[CH:21][CH:22]=[C:11]([C:9]2[S:10][C:5]3[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:3][C:2]([C:35]4[CH:34]=[C:33]5[CH:32]=[CH:31][NH:30][C:38]5=[N:37][CH:36]=4)=[N:7][C:6]=3[C:8]=2[CH3:23])[CH:12]=1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1c(-c2cccc(C(=O)NCCO)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)NCCO)c2)sc2c(N3CCOCC3)nc(-c3cnc4[nH]ccc4c3)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with ethanolamine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide (74 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 2.6 mg of 426. MS (Q1) 515.2 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)N
Reactant: O=Cc1c(Cl)cc(OCC2CO2)cc1Cl
Product: CC(C)(C)NCC(O)COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
A mixture of 2,6-dichloro-4-(2,3-epoxypropoxy)benzaldehyde (3 gm) and tert-butylamine (20 ml) is heated at 45° for 17 hours. The excess tert-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6 N hydrochloric acid (25 ml) and heated for 1 hour. The acid solution is added to boiling saturated aqueous sodium carbonate with nitrogen ebullition. The basic solution is extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde which is used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])=[CH:15][C:16]([C:17]#[N:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(C(N)=O)=C2CN(S(C3SC(C4C=CC=CN=4)=CC=3)(=O)=[O:36])CCN2C=1C1C=CC=CC=1.[OH-].[Na+].OO>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])=[CH:15][C:16]([C:17](=[O:36])[NH2:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1-c1cc(C#N)c2n1CCN(C(=O)OC(C)(C)C)C2
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(S(=O)(=O)c1ccc(-c3ccccn3)s1)CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccncc1-c1cc(C(N)=O)c2n1CCN(C(=O)OC(C)(C)C)C2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of a 2:3 mixture of 8-cyano-6-(4-methylpyridin-3-yl)-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester and 7-cyano-6-(4-methylpyridin-3-yl)-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester (18.30 g, Reference Example 31) in methanol (538 mL) at 10° C. was treated with a solution of sodium hydroxide (21.35 g) in water (4 mL) dropwise. The reaction mixture was then treated with a 27.5% w/w aqueous solution of hydrogen peroxide (9 mL). After stirring at 50° C. for 2 hours the reaction mixture was allowed to cool to room temperature. The insoluble material collected was washed with ethyl acetate to give the title compound (3.47 g) as a white solid, Rf 0.09 (ethyl acetate). 1H NMR [(CD3)2SO]: δ 8.51 (s, 1H), 7.77 (d, 1H), 7.40–7.25 (bs and d overlapping, 2H), 6.85–6.74 (bs and s overlapping, 2H), 4.83 (s, 2H), 3.98 (t, 2H), 3.66 (t, 2H), 2.50 (s, 3H) and 1.44 (s, 9H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([OH:13])=O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.Cl.[CH3:40][NH:41][C:42]([C@@H:44]1[NH:56][CH2:55][C:47]2[NH:48][C:49]3[C:54]([C:46]=2[CH2:45]1)=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:43]>CC#N.C(OCC)(=O)C>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:10]=[CH:9][O:8][C:7]=1[C:11]([N:56]1[C@@H:44]([C:42]([NH:41][CH3:40])=[O:43])[CH2:45][C:46]2[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[NH:48][C:47]=2[CH2:55]1)=[O:13]
Reactant: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1
Reactant: O=C(O)c1occc1C1OCCO1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CNC(=O)[C@H]1Cc2c([nH]c3ccccc23)CN1C(=O)c1occc1C1OCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a solution of product (3-A) (2.19 g, 11.9 mmol) in CH3CN (200 ml) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (DMTMMCl, 4.9 g, 17.8 mmol), and then 4-methylmorpholine (NMM, 4.8 g, 47.6 mmol) was added drop-wise while maintaining the temperature below 20° C. After stirring for 16 h at rt, product (5-A) (3 g, 13.1 mmol) was added, and the solution was stirred at rt for another 6 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated and purified by CC (DCM:MeOH=200:1 to 100:1) to give product (6-A) (2.2 g, 47%) as a brown solid. LC-MS (M+H)+=396.
Reaction SMILES: C(OC([N:8]([CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[CH:21][S:20][C:19]1=[N:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH2:9][C:10](OCC)=[O:11])=O)(C)(C)C.Cl.[CH2:44]([NH2:46])[CH3:45].C(N(C(C)C)CC)(C)C.N=C=N>ClCCl.CN(C)C=O>[CH2:44]([NH:46][C:10](=[O:11])[CH2:9][NH:8][CH2:15][CH2:16][CH2:17][N:18]1[C:22]([C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:27][CH:28]=2)=[CH:21][S:20][C:19]1=[N:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[CH3:45]
Reactant: CCN
Reactant: CCOC(=O)CN(CCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)CNCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized by combinatorial chemistry technique. That is, to a solution of the compound obtained in Example 329 (2) in dichloromethane (43.8 μmol/ml) (1 ml) were added a solution of ethylamine hydrochloride in N,N-dimethylformamide (35.0 μmol/ml) (1 ml), a solution of diisopropylethylamine (35.0 μmol/ml) (1 ml) and a suspension of carbodiimide resin in dichloromethane (79.2 mg/ml, manufactured by Argonaut) (1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane (1 ml), and the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2 ml), and then washed twice with water (2 ml). The organic layer was passed through a filter containing magnesium sulfate, and the filter was washed twice with dichloromethane (1 ml), and the filtrate was concentrated. To the residue was added a 90% trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 2 hours, and concentrated. The residue was dissolved in dichloromethane (2 ml), and excess amount of ion-exchange resin (Dowex 1-X8, OH-type) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane (1 ml), and the filtrate was concentrated to give the title compound (6 mg).
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:77]1([O:83][C:84]([N:86]2[CH2:91][CH2:90][NH:89][CH2:88][CH2:87]2)=[O:85])[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>CN(C=O)C>[C:77]1([O:83][C:84]([N:86]2[CH2:91][CH2:90][N:89]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]3[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[C:30](=[O:36])[NH:31][CH:32]4[CH2:33][CH2:34][CH2:35]4)=[O:24])[N:18]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:17]=3)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:88][CH2:87]2)=[O:85])[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: O=C(Oc1ccccc1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)Oc2ccccc2)CC1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 55 μl DIPEA, 64 mg HATU and 54 mg piperazine-1-carboxylic acid phenyl ester hydrotrifluoroacetate. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 190 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 40 mg MS (ES+): m/e=730.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].N1CCCCC1.C([O-])(=O)C=C>C(Cl)(Cl)Cl>[CH3:12][O:11][C:7]([CH2:8][S:9][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[O:10]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CS
Agent: C=CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: COC(=O)CCSCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Methyl acrylate (4.25 g, 49.5 mmol) was added dropwise over 20 min to a stirred solution of methyl thioglycolate (5 g, 47.16 mmol) and piperidine (0.10 mL) at rt. When about half of the acrylate had been introduced, more piperidine (0.10 mL) was added. After completion of the addition of the acrylate, the reaction mixture was stirred for 1 h at rt. The mixture was diluted with 100 mL of chloroform. The chloroform layer was washed with water, brine and dried over Na2SO4. The solution was filtered and evaporated the solvent to give the product as an oil (9 g, 100%).
Reaction SMILES: O[C:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:18][C:2]([CH3:19])=[CH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[OH:17]
Reactant: CC(C)(O)CCCCc1ccc2ccccc2c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=CCCCc1ccc2ccccc2c1O
Reaction time: 18 h
Yield: 93.6 %

Procedure:
A solution of the compound of Example 119 (0.45 g, 0.002 mole) and p-toluenesulfonic acid (4-5 crystals) in toluene (20 mL) was heated at reflux with azeotropic removal of water. After 18 hours, the cooled solution was washed with saturated aqueous sodium bicarbonate and evaporated to provide the title compound (0.45 g, 100%) as an oil; mass spectrum: m/z 240.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C@H:15]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:20]1)=[O:17])(OC(C)(C)C)=O.[CH2:44]=O>>[CH3:44][CH:13]([NH:14][C@H:15]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:16]([NH:18][N:19]1[CH2:23][CH2:22][C@H:21]([N:24]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:20]1)=[O:17])[C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2C(=O)OC(C)(C)C)C1
Reactant: C=O
Product: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(C)[C@H]2CCCN2)C1

Procedure:
The title compound was prepared following the procedure described in Example 3 using (2R)-2-{[(2R)-1-(BOC)pyrrolidine-2-yl]methyl}amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 3 and formaline.
Reaction SMILES: [OH:1][N:2]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])=[CH:8][CH:7]=1)[CH3:5])[OH:3].[C:22](Cl)(=[O:24])[CH3:23].C([N:28]([CH2:31]C)CC)C>C1COCC1>[OH:3][N:2]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])=[CH:8][CH:7]=1)[CH3:5])[C:22](=[O:24])[CH3:23].[OH:1][N:2]([CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:14])=[CH:8][CH:7]=1)[CH3:5])[C:31]([NH2:28])=[O:24]
Reactant: CC(Oc1ccc(C(C)N(O)O)cc1)c1ccc(F)cc1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)N(O)C(C)c1ccc(OC(C)c2ccc(F)cc2)cc1
Product: CC(Oc1ccc(C(C)N(O)C(N)=O)cc1)c1ccc(F)cc1

Procedure:
N-Hydroxy-N-(1-(4-(1-(4-fluorophenyl)ethoxy)-phenyl)ethyl]acetamide was prepared by the reaction of the hydroxylamine compound prepared in step (d) above with two equivalents of acetyl chloride in the presence of triethylamine in THF. The intermediate N,O-diacetyl compound was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, after which the solvent was evaporated. The residue was taken up in isopropyl alcohol and a solution of lithium hydroxide in water was added. The mixture was stirred until the reaction was complete, and then neutralized by the addition of 2N HCl. This mixture was extracted with ether, the ether solution dried over anhydrous magnesium sulfate, and evaporated to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Br:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.C[O-].[Na+]>CO>[Br:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:8](/[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:11])\[C:9]#[N:10])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: O=Cc1cccc(Br)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Br)c1F)c1ccc(Cl)cc1F
Yield: 79.1 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (1.39 g, 8.2 mmol) was reacted with 3-bromo-2-fluorobenzaldehyde (Apollo) (2 g, 9.9 mmol), methanolic solution (25 wt %) of sodium methoxide (2 g, 9 mmol) in methanol (40 mL) at 50° C. for 3 h to give (Z)-3-(3-bromo-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a white powder (2.3 g, 79%).
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[NH:10]1[CH2:11][CH2:12][CH:7]([N:1]2[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC=CCC2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1=CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-(5,6-dihydropyridin-1 (2H)-yl)piperidine-1-carboxylate (800 mg, 3 mmol) was dissolved in dichloromethane (54 ml). To this was added trifluoroacetic acid (7.9 ml) and triethyl silane (1.2 ml). The mixture was stirred at room temperature for 3 h. Solvent was removed from the mixture en vacuo. The residue was dissolved in saturated sodium bicarbonate (50 ml) and stirred for 30 min. Sodium hydroxide (50 ml, 50% in water) was added to the solution which was then extracted with dichloromethane (3×100 ml). The organic extract was dried over sodium sulfate and the solvent evaporated to give 370 mg (74%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ 5.74-5.70 (m, 1H), 5.68-5.64 (m, 1H), 3.14-3.07 (m, 4H), 2.64-2.53 (m, 4H), 2.43-2.37 (m, 1H), 2.15 (m, 2H), 1.85-1.82 (m, 2H), 1.73 (s, 1H), 1.47-1.38 (m, 2H).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:24]([O:25]C(=O)C)=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1.C[Si]([C:35]#[CH:36])(C)C>ClCCl.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:35]([C:2]1[O:3][C:4]2[C:24]([OH:25])=[C:23]([O:29][CH3:30])[CH:22]=[CH:21][C:5]=2[C:6]=1[C:7](=[O:20])[C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)#[CH:36]
Reactant: C#C[Si](C)(C)C
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1oc2c(O)c(OC)ccc2c1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.2 %

Procedure:
To a stirred solution of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (50 mg, 0.10 mmol) in dichloromethane (1 ml) and triethylamine (0.5 ml) was added Pd(Ph3P)2Cl2 (3.5 mg, 5 mol %) and the reaction vessel was evacuated and backfilled with nitrogen three times. Trimethylsilylacetylene (30 mg, 0.30 mmol) and copper (I) iodide (3 mg, 15 mol %) were added sequentially and the resulting dark mixture was stirred for two hours at room temperature. After this time the reaction was concentrated under vacuum and treated with methanol (1 ml) and potassium hydroxide (30 mg, excess). Stirring was continued for 0.5 hours then the crude mixture was concentrated onto silica and chromatographed (silica gel, gradient elution—2:1 hexanes:ethyl acetate, 1:1 hexanes:ethyl acetate) to afford the product as a tan solid (10 mg, 26%); 1H NMR (CDCl3) δ 7.26 (d, J=8.6 Hz, 1H), 7.20 (s, 2H), 6.98 (d, J=8.6 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (s, 6H), 3.51 (s, 1H); LRMS (ESI) m/z=383 (M+H+).
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][NH:19][CH3:20]>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][N:19]([CH3:20])[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1
Reactant: CNCCN(C)C
Reactant: CSc1nc2cc([N+](=O)[O-])ccc2o1
Product: CN(C)CCN(C)c1nc2cc([N+](=O)[O-])ccc2o1
Yield: 44.5 %

Procedure:
The title compound was prepared according to the procedure described in General Method A using 2-methylsulfanyl-5-nitro-benzooxazole (5.0 g, 23.8 mmol) and N,N,N′-Trimethyl-ethane-1,2-diamine (15.4 mL, 118.9 mmol) at 140° C. The product was purified by silica gel flash column chromatography (330 g column, eluting with 5% 2N NH3 in MeOH/CH2Cl2) to yield the desired product (2.8 g, 44%). mass spectrum (m/e): 265.3 (M+1).