Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH2:10])[CH:4]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>C(Cl)Cl.O=C=O.C([Rh]CCCCCCC)CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH:13]2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: C=Cc1cccc(OC)c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CCCCCCC[Rh]CCCCCCC
Agent: O=C=O
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To a mixture of 1-methoxy-3-vinylbenzene (3.10 g, 23.1 mmol) and dioxomethane-diheptylrhodium (4:2) (0.090 g, 0.12 mmol) in DCM (100 mL) under an atmosphere of argon at rt was added a solution of ethyl diazoacetate (1.22 mL, 11.6 mmol) in DCM (6 mL) dropwise via syringe. The reaction mixture as allowed to stir at rt for 2 h and then concentrated. The residue was purified by column chromatography to give the desired product (1.63 g) as a mixture of cis and trans isomers, along with recovered starting material (1.50 g). LCMS: (FA) ES+ 221.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]3)=[C:8]([CH3:22])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]4)=[C:8]([CH3:22])[C:6]=3[N:7]=2)=[CH:38][CH:39]=1
Reactant: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc12
Yield: 33.8 %

Procedure:
1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone (60 mg) was reacted with 34 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A. The product was purified by reverse phase HPLC to yield 23 mg of 179. MS (Q1) 484.1 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C([O-])([O-])=O.[K+].[K+].O.[Cl-].C([NH3+])(C)(C)C>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][CH:4]=1
Reactant: COc1ccc(Br)nc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[NH3+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1ccc(OC)cn1
Temperature: 160 °C
Yield: 72.4 %

Procedure:
To a 25-mL microwave vial was added 2-bromo-5-methoxy pyridine (1.88 g, 10 mmol), ethyl acrylate (5.44 ml, 50.0 mmol), Pd(OAc)2 (0.225 g, 1.000 mmol), K2CO3 (4.15 g, 30.0 mmol), and t-butylammonium chloride hydrate (2.96 g, 10.00 mmol). The slurry was heated in the microwave at 160° C. for 1 h. Upon cooling to room temperature, the mixture was diluted with EtOAc (100 mL) and washed with sat. aq. NaHCO3 (100 mL). The aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were then washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by gradient elution on silica gel (0 to 50% EtOAc in hexanes) to afford the title compound (1.5 g, 72%). 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=3.0 Hz, 1H), 7.65 (d, J=15.7 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.18 (dd, J=8.6, 3.0 Hz, 1H), 6.76 (d, J=15.7 Hz, 1H), 4.26 (q, J=7.1 Hz, 2H), 3.89 (s, 3H), 1.33 (t, J=7.1 Hz, 3H) ppm; LRMS m/z (M+H) 208.0 found, 208.2 required.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][NH:15][CH3:16])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[F:19][C:20]([F:36])([F:35])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][C:32]([OH:34])=O)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]([CH3:16])[C:32](=[O:34])[CH2:31][CH2:30][C:29]#[C:28][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:36])[F:35])=[CH:27][CH:26]=2)=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNC)cc1
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(C)C(=O)CCC#Cc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
In analogy to the procedures described in example 29A], 2-methyl-2-(4-methylaminomethyl-phenoxy)-propionic acid ethyl ester was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid (example 29D]) to give the title compound as light brown oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:12][CH3:13])[C:9]([CH3:11])=[N:10][C:6]=2[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[Cl:18].OS(O)(=O)=O.[CH2:24]=O.[NH4+].[OH-]>>[Cl:18][C:3]1[C:4]([C:14]([F:16])([F:17])[F:15])=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH3:13])[C:7]=2[C:2]=1[NH:1][CH3:24]
Reactant: C=O
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c(N)c21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c(NC)c21
Yield: 73.3 %

Procedure:
To 1.0g. of 7-amino-6-chloro-1-ethyl-2-methyl-5-trifluoromethylbenzimidazole (Example IV) dissolved in 10 ml. of concentrated H2SO4 was added 1.0g. of paraformaldehyde. The resultant mixture was stirred at 80°C. for 2 hours and then poured onto ice. The resultant brown solution was made basic by addition of concentrated NH4OH, precipitating a light brown solid. The mixture was extracted with chloroform and the chloroform extracts washed with water and dried over Na2SO4. After removal of the chloroform by evaporation, the residue was extracted with hexane and the hexane extract distilled to dryness. The solid residue was recrystallized from hexane to give 0.77g. (73.3%) of the desired product, m.p. 116.5°-119°C.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C@H:3]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])[CH2:14]1)[C:4]([O:6]C(C)(C)C)=[O:5].[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(O)=O>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:1][CH:2]([CH3:34])[C@H:3]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[O:24][C:25]=2[CH3:26])[CH2:14]1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)cc1
Solvent: O=CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)O)C(C)C)C3)c(C)o2)cc1
Temperature: 25 °C

Procedure:
40 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyrate are dissolved in 1 ml of formic acid, and 0.5 ml of trifluoroacetic acid is added. The solution is stirred at room temperature for 18 and then concentrated completely. The residue is purified by HPLC, which gives 28.2 mg of (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]amino}butyric acid trifluoroacetic acid salt as a colorless solid. C24H34N2O2.C2HF3O2 (414.55); MS (ES−): 413.28 (M+−H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][O:11]C(=O)C)[CH:5]=1)([O-:3])=[O:2].[OH-].[Na+]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:10][OH:11])[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OCc1cc([N+](=O)[O-])ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccnc(CO)c1
Reaction time: 0.5 h

Procedure:
To a solution of acetic acid 4-nitro-pyridin-2-ylmethyl ester (16)(0.49 g, 2.5 mmol) in methanol (5 mL), was added a solution of sodium hydroxide (2N, 1.6 mL) and the reaction was stirred for 30 minutes and then concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined extracts were washed with brine (10 mL) and concentrated in vacuo to afford a crude oil which solidified upon standing. Single peak in LC-MS analysis, (0.13 g 33%); m/z (LC-MS, ESP), RT=2.67 mins, (M+H) 155.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([C:21](=[O:24])[CH2:22]C)[CH:11]=[CH:12][C:13]=1[O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(OC1C=C(C(=O)C)C=CC=1OC(=O)C(C)(C)C)(=O)C(C)(C)C.OC1C=C(C(=O)CC)C=CC=1O.C(Cl)(=O)C(C)(C)C.[Br:67]Br>C(N(CC)CC)C>[Br:67][CH2:22][C:21]([C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[CH:9]=1)=[O:24]
Reactant: CCC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Reactant: BrBr
Agent: CC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Agent: CC(C)(C)C(=O)Cl
Agent: CCC(=O)c1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)CBr)cc1OC(=O)C(C)(C)C

Procedure:
3',4'-Bis(pivaloyloxy)propiophenone was first prepared as a mobile liquid (63.6 g.), in a similar manner to 3',4'-bis(pivaloyloxy)acetophenone in Example 1, starting from 3', 4'-dihydroxypropiophenone (40 g.), pivaloylchloride (63.3 ml.) and triethylamine (73.2 ml.). This mobile liquid (40.1 g.) was then reacted with bromine (7.2 ml.) in a similar manner to that used in Example 1 to obtained 2-bromo-3',4'-bis(pivaloyloxy)acetophenone. The crude bromo compound thus obtained was purified by dry column chromatography on silica gel as described in Example 1 to give pure 2-bromo-3',4'-bis(pivaloyloxy)propiophenone as a solid (18.4 g), m.p. 58°-60° C.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](=O)[CH2:20][C:21](OC)=[O:22])=[C:14]([CH3:26])[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)=[C:14]([CH3:26])[CH:13]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)CC(=O)Cc1ccc(F)cc1C
Product: Cc1cc(F)ccc1Cc1cc(O)n(-c2cc(C#N)ccn2)n1

Procedure:
The title compound was prepared from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 4-(4-fluoro-2-methylphenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:11][C:12](=[O:34])[N:13]([C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(O)C>[CH2:3]([NH:11][C:12](=[O:34])[N:13]([C:15]1[CH:16]=[C:17]([C:21]2[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2)c1
Temperature: 50 °C
Yield: 71.2 %

Procedure:
684 mg (17.1 mmol, 10 eq) of sodium hydroxide are added to a solution of 750 mg (1.71 mmol, 1 eq) of ethyl 3-[3′-(3-octyl-1-methylureido)biphenyl-4-yl]propanoate in 15 mL of ethanol. The reaction mixture is heated at 50° C. for 6 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the orange oil obtained is chromatographed on silica gel (30 g FlashSmart Pack column) eluted with 30/70 heptane/ethyl acetate and then crystallized from ethyl ether, filtered and dried. 500 mg of 3-[3′-(3-octyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=86-88° C.). Yield=71%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.C[Si]([N:21]=[C:22]=[O:23])(C)C.Cl>CCCCCC.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22]([NH2:21])=[O:23])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=O
Reaction time: 1 h
Yield: 32.6 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g., 0.05 mol.) in hexane (50 ml.) was cooled to 0° C and treated dropwise with 15w/w butyllithium in hexane (26 ml., 0.06 mol.) in a nitrogen atmosphere. The reaction mixture was allowed to stand at 0° C for 1 hour and was then added dropwise over 30 minutes to a solution of trimethylsilylisocyanate (19.5 g., 0.17 mol.) in hexane (50 ml.) keeping the internal temperature at -20° C. The reaction mixture was allowed to stand at -20° C for 1 hour and was then diluted with water (50 ml.) and the pH adjusted to 2.0 with conc. HCl. The hexane layer was separated and discarded and the aqueous solution adjusted to pH 10.0 with sodium carbonate and extracted with chloroform (3 × 25 ml.). The combined extracts were washed with saturated brine, dried and the solvent removed in vacuo. The residue was triturated with n-hexane, filtered and the solid crystallised from ethyl acetate to give the title compound as colourless needles (3.1 g., 35%) m.p. 104° C. identical in all respects to the authentic material (when crystallised from ethyl acetate). Analysis: Found C, 69.1; 7.4; N, 14.7. C11H14N2O requires C, 69.5; H, 7.4; N, 14.7. The hexane soluble material was distilled to give recovered 3-methyl-5,6,7,8-tetrahydroquinoline (4.2 g.) b.p. 120°/15 mm.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O[CH2:43][C:44]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46](C(=O)C2C=CC=CC=2)[CH:45]=1)(=O)C1C=CC=CC=1.Cl>C(OCC)(=O)C>[C:1]([O:9][C:10]1([CH2:43][C:44]2[C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[N:12]([CH2:20][CH2:21][CH3:22])[C:11]1=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1cn(C(=O)c2ccccc2)c2ccccc12)c1ccccc1
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCN1C(=O)C(Cc2c[nH]c3ccccc23)(OC(=O)c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 43 %

Procedure:
To an oven dried flask cooled under argon equipped with a stir bar was added 5-chloro-2-oxo-1-propylindolin-3-yl benzoate (0.08 grams, 0.24 mmol, 0.2 M in toluene). While stirring at 0° C. KHMDS (0.3 mL, 0.26 mmol, 0.87 M, purchased from Fisher Scientific) was added. After approximately fifteen minutes a solution of (1-benzoyl-1H-indol-3-yl)methyl benzoate (0.02 grams, 0.06 mmol, 0.3 M in anhydrous DMF (purchased from Fisher Scientific)) was added. The reaction continued to stir overnight. The next day the reaction was acidified with 0.1M HCl, diluted with ethyl acetate and the two layers were separated. The aqueous layer was salted out and washed twice more with ethyl acetate. The combined organic solution was dried with sodium sulfate, filtered and concentrated. Purification was done on a Teledyne ISCO with silica gel using a hexanes ethyl acetate gradient. This was followed by a subsequent reverse phase purification using Teledyne ISCO with a C18 column and a water with 0.1% formic acid, acetonitrile gradient. 43% yield. 1H-NMR δ 8.05 (bs, NH), 8.00 (d, 2H), 7.57 (t, 1H), 7.50 (d, 1H), 7.42 (t, 2H), 7.30 (d, 1H), 7.18 (m, 2H), 7.08 (m, 2H), 6.78 (d, 1H), 6.61 (d, 1H), 3.71 (d, 1H), 3.60 (m, 1H), 3.51 (d, 1H), 3.40 (m, 1H), 1.35 (m, 2H), 0.74 (t, 3H). Calculated mass for C27H23ClN2O3, 458.14. Observed 481.1 (M+Na).
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:7]([CH2:9][NH2:10])[OH:8]>N1C=CC=CC=1>[OH:8][CH2:7][CH2:9][NH:10][CH:3]([CH3:4])[CH2:2][C:1]([OH:6])=[O:5]
Reactant: C/C=C/C(=O)O
Reactant: NCCO
Solvent: c1ccncc1
Product: CC(CC(=O)O)NCCO

Procedure:
A solution of 86 g of crotonic acid (1 mole) and ethanolamine (1 mole) in pyridine (200 ml) was refluxed for 2-3 hours and subsequently cooled. The resulting product was filtered and recyrstallized to yield the title compound having a m.p. (melting point) of 178-180° C. (compound 1.1, List of Compounds).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.CC1(C)C(C)(C)OB([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33]C)=[O:32])=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:10]1([C:4]2[N:3]=[C:2]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][C:31]([OH:33])=[O:32])=[CH:28][CH:29]=3)[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CCc1cc(Cl)nc(C2CCCC2)n1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(Cc2ccc(CC(=O)O)cc2)nc(C2CCCC2)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 39.3 %

Procedure:
A mixture of 4-chloro-2-cyclopentyl-6-ethylpyrimidine (0.200 g, 0.95 mmol), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate 0.275 g, 0.95 mmol), Pd(dppf)Cl2 (0.078 g, 0.095 mmol), and powdered Na2CO3 (0.302 g, 2.85 mmol) in dioxane (5 mL) and water (3 mL) was stirred under argon at 90° C. for 24 h. After this time, the mixture was cooled and filtered through celite washing with ethyl acetate. The filtrate was washed with brieme (3×15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.121 g, 61%) as a brown oil. MW=324.42. 1H NMR (DMSO-d6, 500 MHz) δ 12.26 (s, 1H), 7.25-7.18 (m, 4H), 7.01 (s, 1H), 3.95 (s, 2H), 3.51 (s, 2H), 3.22 (t, J=8.1 Hz, 1H), 2.67-2.59 (m, 2H), 2.01-1.92 (m, 2H), 1.88-1.71 (m, 4H), 1.67-1.58 (m, 2H) 1.17 (t, J=7.6 Hz, 3H); APCI MS m/z 325 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:15][O:14][CH2:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([C:16]([O:18][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[O:22])=[O:17])[CH2:10]1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC[C@H]1C[C@@H](C(=O)OCC(=O)c2ccc(Br)cc2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
To a solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (10 g, 38.61 mmol) in DCM (100 mL) was added (2-bromo-1-(4-bromophenyl)-ethanone (11.8 g, 42.47 mmol) and triethylamine (7.8 g, 77.22 mmol). The reaction mixture was stirred at RT for 3 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate, concentrated, and purified by column chromatography to provide the title intermediate (12 g, 56% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ(ppm) 1.438-1.466 (d, 9H, J=11.2 Hz), 2.024-2.056 (t, 1H, J=12.8 Hz), 2.553 (s, 2H), 3.214-3.776 (m, 6H), 4.410-4.850 (t, 1H, J=15 Hz), 5.155-5.549 (m, 1H), 7.270-7.278 (t, 1H, J=1.6 Hz), 7.636-7.654 (d, 1H, J=7.2 Hz), 7.765-7.774 (d, 1H, J=3.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[Br:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Nc1cc(OCc2cccc(Br)c2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(OCc4cccc(Br)c4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (57 mg, 0.319 mmol) was reacted with 4-[2-Amino-4-(3-bromo-benzyloxy)-phenylsulfanyl]-phenol (128 mg, 0.319 mmol) for 28 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (118 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (3H) 5.15 (s, 2H) 6.25 (d, J=6.99 Hz, 1H) 6.65 (d, J=8.46 Hz, 2H) 7.06-7.68 (m, 8H) 7.80 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.45 Hz, 1H) 9.78 (s, 1H) 11.02 (br s, 1H) 14.39 (br s, 1H); MS (ESI+) m/z 544, 546 (M+H−TFA)+; (ESI−) m/z 542, 544 (M−H−TFA)−.
Reaction SMILES: Br[C:2]1[C:7]([N:8](COC)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:25])=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:37]=[CH:38][CH:39]=1)[C:31](N(OC)C)=[O:32].Cl.O1CCOCC1>O.CCOC(C)=O>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:7]2[C:2]([C:31](=[O:32])[C:30]3[CH:37]=[CH:38][CH:39]=[C:28]([O:27][CH3:26])[CH:29]=3)=[N:3][CH:4]=[C:5]([Cl:25])[CH:6]=2)(=[O:11])=[O:10])=[CH:17][CH:16]=1)([CH3:20])([CH3:19])[CH3:21]
Reactant: COc1cccc(C(=O)N(C)OC)c1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2-Bromo-5-chloro-pyridin-3-yl)-4-tert-butyl-N-methoxymethyl-benzenesulfonamide (140 mg, 300 mmol) was placed in a dry 2-neck 10 mL round-bottom flask. The flask was evacuated and purged with nitrogen, followed by the addition of THF (1 mL). The homogeneous mixture was lowered to −5° C. and iPrMgCl (0.33 mL, 2.0 M) was added dropwise. Upon completion of the addition, the reaction was stirred 90 minutes, followed by the slow addition of 3,N-dimethoxy-N-methyl-benzamide (146 mg, 750 mmol). The reaction was stirred overnight, during which the ice-bath warmed to room temperature. The following day, the reaction was quenched with a small quantity of MeOH and the solvents evaporated in vacuo. The residue was subsequently treated with 4.0 M HCl in dioxane (1 mL, 4.0 mmol) and H2O (0.33 mL), and then stirred at 80° C. for two hours. The resultant solution was diluted with EtOAc, washed with water, saturated sodium bicarbonate, and brine; dried with MgSO4, and evaporated employing reduced pressure. The crude residue was subsequently purified via reverse phase HPLC (Column: Varian Dynamax 250×21.4 mm Microsorb100-8 C18, 0.1% TFA/H2O (Eluent A): 0.1% TFA/MeCN (Eluent B)): 1H NMR (400 MHz, CDCl3) δ 10.61 (s, 1 H), 8.29 (d, 1 H), 8.20 (d, 1 H), 7.74 (d, 2H), 7.58 (s, 1 H), 7.50 (d, 1 H), 7.42 (d, 2H), 7.37 (d, 1 H), 7.29 (t, 1 H), 2.40 (s, 3H), 1.25 (s, 9H); MS (ES) M+H expect 459.1, found 459.5.