Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][Si](C(C)(C)C)(C)C)=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:52]3[CH:53]=[CH:54][C:55]([OH:58])=[CH:56][CH:57]=3)[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc(O)cc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Yield: 68.4 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (42.5 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 3 H at 0° C. and then 3 H at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) affording 25.7 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(3"-(4'"-hydroxyphenyloxy)-4"-hydroxycyclohexyl)-1 '-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis were consistent with the desired structure).
Reaction SMILES: Br.[NH2:2][C@H:3]([C:7]1[O:8][C:9]([C:16]2[C:24]3[C:19](=[C:20]([Br:25])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=1)[CH:4]([CH3:6])[CH3:5].C1C=CC2N(O)N=NC=2C=1.[NH:36]([C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[C@H:37]([C:46](O)=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C.C(Cl)CCl>CCOC(C)=O.CN(C=O)C>[CH2:52]([O:51][C:49]([NH:36][C@@H:37]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[C:46]([NH:2][C@H:3]([C:7]1[O:8][C:9]([C:16]2[C:24]3[C:19](=[C:20]([Br:25])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[C:10]([C:12]([O:14][CH3:15])=[O:13])[N:11]=1)[CH:4]([CH3:6])[CH3:5])=[O:47])=[O:50])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: COC(=O)c1nc([C@@H](N)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: Br
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1nc([C@@H](NC(=O)[C@H](Cc2ccc(O)cc2)NC(=O)OCc2ccccc2)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.6 %

Procedure:
DMF (100 mL) was added to methyl 2-((S)-1-amino-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate hydrobromide (9.16 g, 19.4 mmol), HOBt (3.17 g, 23.5 mmol), and Cbz-Tyr-OH (6.44 g, 20.4 mmol) in a round-bottom flask. N,N-Diisopropylethylamine (4.22 mL, 3.13 g, 129 mmol) was added, followed by EDC (4.15 g, 21.6 mmol). After stirring for 24 h at 25° C., the solution was diluted with EtOAc (500 mL) and the mixture was washed with 1 N aqueous HCl (250 mL), saturated aqueous NaHCO3 (250 mL), and saturated aqueous NaCl (250 mL). The solution was dried (Na2SO4), decanted, and evaporated to give a tan solid. This material was dissolved in 2-PrOH (180 mL) at 90° C. Hexanes (85 mL) were added and the solution was allowed to cool to RT. After standing overnight, the mixture was cooled to 5° C. for 4 h. The solid was separated by filtration and washed with 1:1 2-PrOH/hexanes (140 mL). This material, which at this point held residual solvent, was dried on a vacuum manifold to give methyl 2-((S)-1-((S)-2-(benzyloxycarbonylamino)-3-(4-hydroxyphenyl)propanamido)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate (11.58 g, 87% yield). 1H NMR (300 MHz, DMSO-d6): consistent with proposed structure. MS: m/z=689.0 (M+1).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[O:27]1[CH2:32][CH2:31][N:30]([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([OH:36])=[O:35])[CH2:29][CH2:28]1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[O:27]1[CH2:28][CH2:29][N:30]([CH:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:34]([O:36][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:35])[CH2:31][CH2:32]1
Reactant: O=C(O)C(c1ccccc1)N1CCOCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCOCC1
Reaction time: 8 h
Yield: 23.5 %

Procedure:
PS-DCC (loading: 1.25 mmol/g; 0.93 g, 1.16 mmol) was suspended in dry THF (11.6 ml) and HOBT (0.18 g, 1.16 mmol), 2-morpholino-2-phenylacetic acid hydrochloride (0.15 g, 0.58 mmol) and (R)-quinuclidin-3-ol (0.22 g, 1.75 mmol) were sequentially added. The mixture was shaken overnight and then PS-DCC was filtered off washing with EtOAc and THF. The solution was evaporated and the residue was dissolved in EtOAc (30 ml) and washed with water and then with a sat. NaHCO3. The organic phase was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5 to 85/15) to obtain (R)-quinuclidin-3-yl 2-morpholino-2-phenylacetate (45 mg, 23.4% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH:16]2[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.O.[Li+].[OH-]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH:16]2[C:21]([OH:23])=[O:22])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A solution of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid, methyl ester (0.1 g, 0.28 mmol) in 2.4 mL of THF:methanol:water [4:1:1] was cooled in an ice bath and 2N LiOH (0.3 mL, 0.59 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After evaporating the solvent, the residue was diluted with ether and filtered. The solid was dissolved in water, neutralized with 1N HCl to pH˜3 and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give 0.06 g of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid. Yield˜69.8%. mp 40-42° C. Electrospray Mass Spec 338.1 (M—H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[C:10]1=[O:15]
Reactant: O=C1CCCCC1c1ccc(Cl)cc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 116.8 %

Procedure:
2-(2,4-Dichloro-phenyl)-cyclohexanone (50 mg, 0.21 mmol) was dissolved in chloroform (1 mL). To this solution bromine (34.5 mg, 0.22 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (79 mg) which was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2B2OC(C)(C)C(C)(C)O2)C1
Reactant: FC(F)(F)c1ccc(I)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Temperature: 130 °C
Yield: 85.9 %

Procedure:
A solution of Pd(PPh3)4 (Strem Chemicals Inc., Newburyport, Mass., 0.804 g, 0.696 mmol), 2-bromo-1-iodo-4-(trifluoromethyl)benzene (Matrix Scientific, Columbia, S.C., 3.05 g, 8.70 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 2.500 g, 6.96 mmol), and potassium carbonate (4.81 g, 34.8 mmol) in 14 mL dioxane and 6 mL water was heated to 100° C. overnight. LC/MS showed about 50% conversion, so the reaction mixture was transferred to a microwave vial, and was heated to 130° C. in a microwave reactor for 3 hours. The reaction mixture was diluted with EtOAc, washed with water then brine, the organics dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 30% EtOAc/heptane) gave tert-butyl 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.73 g, 5.98 mmol).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CS(C)=O.CCOC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: ClCCCn1nnc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of benzotriazole (303 mg, 2.54 mmol) and powdered NaOH (101 mg, 2.52 mmol) in DMSO was added 1-bromo-3-chloro propane (437 mg, 2.77 mmol). The reaction mixture was stirred for 16 h at 20° C. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O (100 mL) and saturated NaCl (100 mL), dried over MgSO4 and concentrated in vacuo. Column purification (hexanes:EtOAc 4:1) yielded 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (167 mg, 34%). The title compound was prepared according to Example 286, Step C as a yellow oil (21 mg, 42%) from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b]l[1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.88-1.98 (m, 3H), 1.99-2.18 (m, 2H), 2.20-2.41 (m, 5H), 2.51-2.60 (m, 1H), 2.64-2.71 (m, 1H), 2.89-3.00 (m, 1H), 3.03-3.13 (m, 2H), 3.21-3.27 (m, 1H), 3.47-3.60 (m, 1H), 3.76-3.88 (m, 1H), 4.73 (t, 2H, J=6.6 Hz), 6.61 (t, 1H, J=7.4 Hz), 6.84 (d, 1H, J=6.6 Hz), 6.94 (dd, 1H, J=1.1, 8.1 Hz), 7.37 (td, 1H, J=1.1, 7.4 Hz), 7.49 (td, 1H, J=1.1, 7.8 Hz), 7.57 (d, 1H, J=8.0 Hz), 8.07 (d, 1H, J=8.4 Hz) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:33]([O:34][CH3:35])[CH3:32])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 4-bromo-2-methyl-benzoic acid (1.00 g, 4.65 mmol) in methylene chloride (40 mL) at room temperature, were added N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.936 g, 4.88 mmol), triethylamine (1.49 mL, 1.07 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.544 g, 5.86 mmol). The mixture was stirred at room temperature overnight and then diluted with ethyl acetate (50 mL) and washed with 0.5 M aqueous sodium hydroxide solution (75 mL). The aqueous layer was separated, extracted with ethyl acetate (50 mL) and the organic extracts combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography over silica gel gradient eluted between 0 and 50% v/v ethyl acetate in hexanes to give 4-bromo-N-methoxy-2,N-dimethyl-benzamide (886 mg, 74%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].[CH3:9][N:10]([CH2:53][CH:54]=O)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1.[BH3-]C#N.[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[CH3:9][N:10]([CH2:53][CH2:54][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[CH2:4]1)[C:11](=[O:52])[C:12]1[CH:51]=[CH:50][CH:49]=[C:14]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:20][C:19]=2[C:30]2[CH:35]=[C:34]([C:36](=[O:48])[NH:37][C@@H:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH2:41][CH2:40][CH2:39]3)[CH:33]=[CH:32][N:31]=2)=[O:16])[CH:13]=1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CN1CCNCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CN1CCN(CCN(C)C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)N[C@H]4CCCc5ccccc54)ccn3)c2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using methylpiperazin-2-one in place of L-proline-tert-butyl ester. Into a 50-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (2 mL). This was followed by the addition of a solution of 1-methylpiperazin-2-one (18 mg, 0.16 mmol, 1.00 equiv) in ethanol (2 mL), two drop of acetic acid. To this was added NaBH3CN (20 mg, 0.32 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (22% CH3CN up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 70 mg product was obtained. This resulted in 70 mg (61%) of (S)—N1-methyl-N1-(2-(4-methyl-3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LC-MS (ES, m/z): 728 [M+H]+ H-NMR (300 MHz, DMSO, ppm): 12.25 (s, 1H), 9.18 (d, J=8.4 Hz, 1H), 8.80 (d, J=5.1 Hz, 1H), 8.29 (d, J=13.8 Hz 2H), 7.99 (t, J=6.9 Hz, 2H), 7.86 (d, J=4.8 Hz, 1H), 7.57˜7.67 (m, 3H), 7.10˜7.28 (m, 5H), 5.25 (d, J=5.4 Hz, 1H), 3.92˜3.85 (m, 4H), 3.30˜3.54 (m, 10H), 2.78˜2.95 (m, 9H), 1.99 (d, J=3.6 Hz, 2H), 1.72˜1.80 (m, 6H), 1.60 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[C@H:10]([OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](O)C1
Temperature: 25 °C
Yield: 148.3 %

Procedure:
Heat a mixture of (3R,4R)-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.02 mol, 6.0 g), 5-bromo-2-fluoronitrobenzene (0.03 mol, 6.71 g) and triethyl amine (0.058 mol, 5.88 mL) in ethyl acetate (180 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (12.35 g, crude). 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.50-1.51 (m, 1H), 2.08-2.12 (m, 1H), 2.93 (dd, 1H), 3.01 (br s, 1H), 3.55-3.61 (m, 1H), 3.62-3.68 (m, 1H), 3.68 (br s, 1H), 4.13-4.18 (m, 1H), 6.97 (d, 1H), 7.48 (dd, 1H), 8.08 (d, 1H), 8.30 (d, 1H). ES-MS m/z 316 [M−Boc]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:29].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:29].[ClH:29].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][OH:16])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(NCCNCCO)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCNCCO)cc1

Procedure:
The 2-[2-(4-nitrophenylamino)ethylamino]ethanol (1) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)CCO.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CS(C)=O
Solvent: OCCNCCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 83.2 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of diethanolamine and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 17.5 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[CH:4][CH:3]=1.IC.[H-].[Na+].[C:20]([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([CH3:20])[C:9]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC1(C)CN(c2ccc(Br)nc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)N(c2ccc(Br)nc2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
(810 mg, 3.0 mmol) 1-(6-Bromo-pyridin-3-yl)-4,4-dimethyl-imidazolidin-2-one (Example 3, step 1) was dissolved in DMF (8 ml) and cooled to 0-5° C. Iodomethane (640 mg, 280 μl, 4.5 mmol, 1.5 equiv.) and NaH (60%) (156 mg, 3.9 mmol, 1.3 equiv.) were added and the mixture was stirred for 2 hours at 0-5° C. The reaction mixture was treated with sat. NaHCO3 solution and extracted two times with EtOAc. The organic layers were extracted with water and brine, dried over Na2 SO4 and evaporated to dryness. The crude product was purified by flash chromatography on a silica gel column eluting with a heptane:ethyl acetate gradient 100:0 to 0:100. The desired 1-(6-bromo-pyridin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (800 mg, 94% yield) was obtained as a yellow solid, MS: m/e=284.1/286.0 (M+M+).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:7].C.Cl>O.C(O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.3 %

Procedure:
A solution containing 9.4 g of KCN in 20 ml of water is prepared and then it is poured dropwise over a mixture containing 20 g of 2-bromo-1-(4-bromo-phenyl)ethanone dissolved in 800 ml of 90% ethanol. After stirring for 5 hours at RT, the solid formed is filtered and then it is rinsed with ice-cold water. The solid obtained is dissolved in 400 ml of water and then activated charcoal is added, the mixture is kept stirring for 20 minutes, and then filtered on Celite®. The filtrate obtained is treated with HCl at 10% and the white precipitate formed is filtered, washed with water and then dried under vacuum. 7.63 g of the expected compound are obtained. m.p.=164° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[S:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2].[CH2:17](O)[CH3:18]>CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:17]#[CH:18])[S:9][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:5])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)c1nc(I)sc1C(=O)OCC
Solvent: CO
Product: C#Cc1nc(C(=O)OCC)c(C(=O)OCC)s1

Procedure:
4,5-Diethoxycarbonyl-2-ethynylthiazole (539 mg) was prepared from 1.16 g of 4,5-diethoxycarbonyl-2-iodothiazole in the same manner as in step b) in Example 4, except that ethanol was used as the solvent instead of methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([N:18]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:19](=[O:21])[CH3:20])[CH2:10][CH:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:40][CH2:41][O:42][C:43](Cl)=[O:44].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([N:18]([C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([N:1]4[CH2:40][CH2:41][O:42][C:43]4=[O:44])=[CH:31][CH:30]=3)[C@@H:9]([CH3:29])[CH2:10]2)[C:19](=[O:21])[CH3:20])=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCCBr
Reactant: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N3CCOC3=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[1-(4-Amino-benzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]-N-(4-chloro-phenyl)-acetamide (61 mg, 0.142 mmol) was dissolved in methylene chloride (2 mL) and was added triethylamine (0.100 mL, 0.700 mmol). 2-Bromoethylchloroformate (0.023 mL, 0.213 mmol) was added and the reaction was allowed to warm to room temperature. After 1 hour at room temperature, DMF (2 mL) and Cs2CO3 (100 mg, 0.307 mmol) were added and the mixture was stirred over night. The mixture was partitioned between methylene chloride and water; the methylene chloride layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (1/1 hexanes/ethyl acetate to 100% ethyl acetate gradient) to afford the product.