Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]1[CH2:15][N:14]2[C:10](=[N:11][C:12]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:13]=32)[N:9]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:8][CH2:7]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+].C(OCC)(=O)C>CN(C)C=O>[N:33]([CH:6]1[CH2:15][N:14]2[C:10](=[N:11][C:12]3[C:13]2=[C:16]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:17]=[CH:18][CH:19]=3)[N:9]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[CH2:8][CH2:7]1)=[N+:34]=[N-:35].[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:16]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:17]=[CH:18][CH:19]=3)[N:14]2[CH:15]=[CH:6][CH2:7][CH2:8]1
Reactant: CCN(CC)c1cccc2nc3n(c12)CC(OS(C)(=O)=O)CCN3c1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc3n(c12)C=CCCN3c1ccc(Cl)cc1Cl
Product: CCN(CC)c1cccc2nc3n(c12)CC(N=[N+]=[N-])CCN3c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 18 %
Yield: 75 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)-7-(diethylamino)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-4-yl methanesulfonate (144 mg, 0.289 mmol) and sodium azide (56.4 mg, 0.868 mmol) in N,N-dimethylformamide (1.4 mL) was stirred at 100° C. for 3 hr. Ethyl acetate was added, and the resultant mixture was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-30% ethyl acetate/n-hexane gradient mixture to give 4-azido-1-(2,4-dichlorophenyl)-N,N-diethyl-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-amine as a colorless solid (96.6 mg, 0.217 mmol, 75%) and 1-(2,4-dichlorophenyl)-N,N-diethyl-2,3-dihydro-1H-[1,3]diazepino[1,2-a]benzimidazol-7-amine (21.4 mg, 00532 mmol, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].C(O[C:27](=[NH:34])[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])C.C(O)(=O)C>C(O)C>[NH2:34]/[C:27](/[N:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17])[CH2:5][C:4]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:3]=1[O:2][CH3:1])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: COc1ccc(CNCc2ccc(OC)cc2OC)c(OC)c1
Reactant: CCOC(=N)CC(=O)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\N)N(Cc1ccc(OC)cc1OC)Cc1ccc(OC)cc1OC
Yield: 156.7 %

Procedure:
A mixture of bis(2,4-dimethoxybenzyl)amine (8 g), ethyl 3-ethoxy-3-iminopropanoate (8.02 g), acetic acid (1.44 mL) and ethanol (420 mL) was refluxed overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:27](=[O:28])[NH:26][C:25]4[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]5[CH:41]=[CH:40][C:39]([N:42]6[CH2:47][CH2:46][O:45][CH2:44][CH2:43]6)=[CH:38][CH:37]=5)[CH:31]=[CH:32][C:24]=4[NH:23][C:22]=3[CH:48]=2)=[CH:14][C:13]=1[O:49][CH3:50])(C(C)(C)C)(C)C.CO.O.[F-].C([N+](CC)(CC)CC)C>O1CCOCC1>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[C:27](=[O:28])[NH:26][C:25]4[CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]5[CH:41]=[CH:40][C:39]([N:42]6[CH2:43][CH2:44][O:45][CH2:46][CH2:47]6)=[CH:38][CH:37]=5)[CH:31]=[CH:32][C:24]=4[NH:23][C:22]=3[CH:48]=2)=[CH:14][C:13]=1[O:49][CH3:50]
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCCO[Si](C)(C)C(C)(C)C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)ccc1OCCO
Temperature: 25 °C

Procedure:
A mixture of Example 609A (23 mg, 0.033 mmol) in 1:1 MeOH:dioxane (2 mL) was treated with tetraethylammonium fluoride hydrate (49.4 mg, 0.33 mmol) at 50° C. for 24 hours. The reaction was then cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was purified by preparative HPLC to provide the title compound. MS (ESI) m/e 582 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.75 (s, 1H), 7.84 (s, 1H), 7.72 (d, J=8.1 Hz, 1H), 7.25 (d, J=1.4 Hz, 1H), 7.15-7.20 (m, 3H), 7.07 (m, 1H), 6.80-6.96 (m, 7H), 4.00-4.06 (m, 4H), 3.85 (s, 3H), 3.70-3.75 (m, 6H), 2.96-2.99 (m, 4H), 2.86 (t, J=6.4 Hz, 2H).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)=[CH:14][N:13]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:10]2=[N:11][CH:12]=1)=[NH:6])C.[CH:30]([NH:32][NH2:33])=O.CCN(CC)CC>CCO>[C:24]1([S:21]([N:13]2[C:10]3=[N:11][CH:12]=[C:7]([C:5]4[NH:6][CH:30]=[N:32][N:33]=4)[CH:8]=[C:9]3[C:15]([C:16]3[CH:20]=[CH:19][O:18][CH:17]=3)=[CH:14]2)(=[O:22])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NNC=O
Reactant: CCOC(=N)c1cnc2c(c1)c(-c1ccoc1)cn2S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3nnc[nH]3)cnc21
Temperature: 75 °C
Yield: 48.4 %

Procedure:
A mixture of 39 (300 mg, 0.70 mmol), formic hydrazide (209 mg, 3.47 mmol) and Et3N (759 μM, 6.95 mmol) in EtOH (10.4 mL) was heated at 75° C. overnight. After cooling, the solvent was evaporated and the residue purified by silicagel chromatography using 80% ethyl acetate in hexane (gradient elution) then preparative TLC (1 mm plates, EtOAc eluent) to give 40 as a white solid (132.6 mg, 76%); 1H NMR (400 MHz, CDCl3+2 drops CD3OD) δ 6.71 (m, 1H), 7.40-7.70 (m, 5H), 7.84 (s, 1H), 7.93 (t, J=1.0 Hz, 1H), 8.10-8.30 (m, 3H), 8.63 (d, J=2.0 Hz, 1H), 9.10 (bs, NH); MS (CI) m/z 391.9 (MH+), 433.1 (M+MeCN).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]3[CH2:29][CH2:28][C:27](=O)[CH2:26]3)=[CH:19][CH:18]=5)[C:8]=2[C:31]([F:34])([F:33])[F:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[NH4+:36].[C-:37]#[N:38].[Na+].N>CO.ClCCl>[NH2:36][C:27]1([C:37]#[N:38])[CH2:28][CH2:29][CH:25]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[C:14]2=[N:15][O:16][C:12]([C:9]4[C:8]([C:31]([F:34])([F:33])[F:32])=[C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[O:11][N:10]=4)=[C:13]2[CH2:24][CH2:23]3)[CH2:26]1
Reactant: [C-]#N
Reactant: [NH4+]
Reactant: O=C1CCC(c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#CC1(N)CCC(c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101 %

Procedure:
A mixture of 3-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)cyclopentanone (Preparation 121C, 230 mg, 0.495 mmol), ammonium chloride (79 mg, 1.486 mmol), sodium cyanide (72.8 mg, 1.486 mmol), 7 M methanol solution of ammonia (4.95 mL, 34.7 mmol) and dichloromethane (2 mL) was stirred at room temperature for 1 day. Additional 7 M methanol solution of ammonia (2 mL) was added and the mixture was stirred at room temperature for 2.5 days. The mixture was concentrated. The residue was partitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (3 mL). The aqueous layer was separated and extracted with ethyl acetate (2×1.5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure to give 1-amino-3-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)cyclopentanecarbonitrile (245 mg, 0.500 mmol, 100% yield) as a glassy solid. The compound had an HPLC retention time=3.51 min. (condition C); LC/MS M+1=491.2.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]=[CH:54][C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N+:60]1([O-:65])[CH2:61][CH2:62][CH2:63][CH:64]=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH:53]3[O:65][N:60]4[CH2:61][CH2:62][CH2:63][CH:64]4[CH:54]3[C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [O-][N+]1=CCCC1
Reactant: CCCCc1nc2ccc(C=CC(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc(C3ON4CCCC4C3C(=O)OCC)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 53.2 %

Procedure:
To a solution of 0.300 g of ethyl 3-[2-butyl-3,4-dihydro-4-oxo-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-6-quinazolinyl]-2-propenoate in 20 ml of toluene is added 0.293 g of 3,4-dihydro-2H-pyrrole 1-oxide and the reaction mixture heated at reflux for 6 hours. The reaction mixture is cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel by elution with 1:1 ethyl acetate-hexanes to give 0.177 g of the desired product. FAB mass spec 620 (M+H, -ph3C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: NCCc1cccnc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCCc2cccnc2)n1

Procedure:
Following the general procedure A, 2,4,6-trichloro-1,3,5-triazine was coupled with 3-(2-aminoethyl)pyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@@H:8](Cl)[CH:7]=[CH:6]1)(=[O:3])[CH3:2].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)C.O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:12]=[N+:13]=[N-:14])[CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C=C[C@H](Cl)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)O[C@@H]1C=C[C@@H](N=[N+]=[N-])CC1
Yield: 85.9 %

Procedure:
To a stirred solution of cis-1-acetoxy-4-chloro-2-cyclohexene (6.87 g, 39.4 mmol) in DMF (160 mL) was added sodium azide (5.29 g, 81.1 mmol) and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into brine (160 mL) and diluted with diethyl ether (300 mL) and water (80 mL). The phases were separated and the organic phase was washed with brine (5×50 mL). The organic phase was dried (MgSO4), and concentrated to provide 6.13 g (85%) of trans-1-acetoxy-4-azido-2-cyclohexene as a pale red oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:20]=1)[O:11][CH2:12][C:13]1(CC#N)[CH2:15][CH2:14]1.[OH-].[K+].CCO.[CH3:38][C:39]([OH:41])=[O:40]>CCOC(C)=O.C1(C)C=CC=CC=1.CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:20]=1)[O:11][CH2:12][C:13]1([CH2:38][C:39]([OH:41])=[O:40])[CH2:15][CH2:14]1
Reactant: N#CCC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Yield: 75 %

Procedure:
A mixture of the nitrile of Step 6 (13.22 g, 26.5 mmol), 8N KOH (330 mL), and EtOH (130 mL) was heated to reflux for 17 hr. 25% Aq. NH4OAc (500 mL) and AcOH (190 mL) were than added at room temperature (to give pH~6) and the product was extracted in EtOAc and dried over Na2SO4. Hash chromatography of the residue with EtOAc:toluene:AcOH 10:90:1 afforded 10.34 g (75% yield) of the title acid.
Reaction SMILES: O=[O+][O-].CC1(C)OC(=O)C(C[CH:13]([OH:16])[CH2:14][Cl:15])=CO1.CO.CSC.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>>[Cl:15][CH2:14][CH:13]([OH:16])[CH2:24][C:23]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CC1(C)OC=C(CC(O)CCl)C(=O)O1
Reactant: CCOC(C)=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: CCOC(=O)CC(O)CCl
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Ozone was introduced into a mixture of 225.5 mg (1 mmol) of (+)-2,2-dimethyl-(3-chloro-2-hydroxypropyl)-1,3-dioxin-4-one (96% ee) obtained in Example 4 and 20 ml of methanol at -78° C. for 5 hours, and 2 ml of dimethyl sulfide were added thereto, followed by stirring at the same temperature for 2 hours. The temperature was gradually returned to room temperature, and the solution was then stirred for 5 hours. Afterward, the solvent was distilled off, and the resultant residue was then dissolved in ethanol. 3 drops of concentrated sulfuric acid were added thereto, and the solution was then heated at 80° C. for 30 minutes. Next, ethanol was distilled off, and the residue was diluted with water. The solution was extracted with dichloromethane and then dried over anhydrous sodium sulfate, and the solvent was distilled off and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate=5:1), thereby obtaining 109.4 mg (yield 66%) of (+)-ethyl 4-chloro-3-hydroxybutanoate.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH2:3][CH3:4].Cl[CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:14][CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19])=[CH:10][CH:11]=1)[CH2:3][CH3:4]
Reactant: COC(=O)NCCCl
Reactant: CCC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)Oc1ccc(OCCNC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(1-methylpropoxy)phenol (9.2 mmol), methyl 2-chloroethylcarbamate (11.9 mmol), and potassium carbonate (18.4 mmol) in 20 ml of dimethylformamide (DMF) is heated at 85° for 18 hours. The reaction mixture is cooled to room temperature (RT), poured into water and extracted with ether. The combined ether extracts are washed with water until neutral, followed with brine and dried over calcium sulfate. The solvent is removed in vacuo and the residue is placed under high vacuum at 80° for ca. 2 hours to remove the excess methyl 2-chloroethylcarbamate. Purification by preparative thin layer chromatography (prep. TLC) gives methyl N-{2-[4-(1-methylpropoxy)phenoxy]ethyl}carbamate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([C:22]([OH:24])=O)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:27].F[P-](F)(F)(F)(F)F.CNC.C(N(CC)CC)C>CN(C=O)C.O>[C:18]([O:17][C:15]([NH:14][CH:13]([C:22]([N:26]([CH3:27])[CH3:25])=[O:24])[CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-N-(tert-butoxycarbonyl)alanine (10.0 g, 30.0 mmol) in DMF (100 mL) was added HATU (14.0 g, 36.0 mmol). After 2 hours, dimethylamine (4.9 g, 60 mmol) and triethylamine (15.0 g, 149 mmol) were added. After 16 hours, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile/water gradient) to give benzyl {2-[(tert-butoxycarbonyl)amino]-3-(dimethylamino)-3-oxopropyl}carbamate. MS ESI calc'd. for C18H28N3O5 [M+H]+ 366. found 366. 1H NMR (400 MHz, CD3OD) δ 7.33-7.31 (m, 5H), 5.31-5.20 (m, 2H), 4.61-4.48 (m, 1H), 2.93 (s, 3H), 2.87 (s, 3H), 2.74-2.71 (m, 1H), 2.71-2.68 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[CH3:20][O:21][C:22](=[O:31])[C@@H:23]([NH2:30])[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C.ON1C(=O)C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.NC(N)=O>C1(C)C=CC=CC=1.CN(C)C=O>[CH3:20][O:21][C:22](=[O:31])[C@@H:23]([NH:30][C:11](=[O:13])[CH:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Reactant: N#Cc1ccc(CC(C(=O)O)C2CCCCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(N)=O
Agent: O=c1c2ccccc2nnn1O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1)C1CCCCC1
Reaction time: 36 h
Yield: 76.1 %

Procedure:
A solution of 3-(4-cyano-phenyl)-2-(R,S)-cyclohexyl-propionic acid (8.8 g, 34.2 mmol, prepared as described in example 1d), (S)-amino-cyclohexyl-acetic acid methyl ester (6.27 g, 36.6 mmol), diisopropylethylamine (6.8 ml, 40.0 mmol), 3-hydroxy-3H-benzo[d][1,2,3]triazin-4-one (1.40 g, 8.6 mmol), and dimethylformamide (200 ml) was cooled to 10° C. A solution of dicyclohexyl-carbodiimide (8.26 g, 40.0 mmol) in toluene (8 ml) was added dropwise over a period of 3 hours and the reaction mixture was stirred for 36 hours. The precipitated urea was sucked off and the filtrate was evaporated in vacuo. Crystallization from n-heptane/isopropanol gave 10.68 g of the desired product, which contained 1,3-dicyclohexyl-urea. The crude material was used without further purification. MS m/z: 411 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH:34]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:35]([C:41](O)=[O:42])[CH2:36][CH2:37][C:38](=[O:40])[NH2:39].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[NH:34]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C@H:35]([C:41]([NH:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:42])[CH2:36][CH2:37][C:38](=[O:40])[NH2:39]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: C1CCOC1
Product: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 15 h

Procedure:
In 500 ml of THF is dissolved 50.0 g of H-Trp-OBzl. p-toluenesulfonate, and under ice-cooling, 15.4 ml of TEA, 28.0 g of Z-Gln-OH, 19.7 g of HONB and 22.7 g of DCC are added. The mixture is stirred for 15 hours. The precipitated DCU is filtered off, the filtrate concentrated and the residue dissolved in 300 ml of ethyl acetate. The solution is washed with saturated aqueous sodium hydrogen carbonate (150 ml×2), 10% aqueous citric acid (150 ml×2) and water (150 ml×2) in the order mentioned. The solvent is distilled off under reduced pressure, the residue dissolved in 300 ml of THF and the insolubles are filtered off. The filtrate is concentrated and precipitated with 500 ml of diethyl ether. The resultant powders are collected by filtration and recrystallized from acetonitrile. Yield 46.1 g (82.8%); [α]D23 +5.8°(c=1.0, DMF); Rf1 =0.60.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>CN(C=O)C.[Cu]I>[CH3:38][Si:39]([C:42]#[C:43][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2)([CH3:41])[CH3:40]
Reactant: O=C1NCc2cccc(I)c21
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cccc2c1C(=O)NC2
Temperature: 100 °C
Yield: 49 %

Procedure:
To a nitrogen de-gassed solution of 7-iodoisoindolin-1-one (I59) (0.233 g, 0.899 mmol) in dry DMF (6 mL) were added triethylamine (0.501 mL, 3.598 mmol) followed by triphenylphosphine (0.035 g, 0.14 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.063 g, 0.090 mmol), CuI (0.026 g, 0.14 mmol) and finally (trimethylsilyl)acetylene (0.292 mL, 1.63 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 30 then 10 minutes. The reaction mixture was concentrated in vacuo, then absorbed onto silica gel and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-46% EtOAc in dichloromethane) to give the title compound (I60) (0.120 g, 49% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.60-7.51 (m, 2H), 7.49 (dd, J=6.7, 2.0 Hz, 1H), 4.32 (s, 2H), 1.03 (t, J=7.9 Hz, 9H), 0.66 (q, J=7.9 Hz, 6H). LCMS Method C: rt 6.44 min; m/z 272.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[CH:3]=1.[CH2:9]([OH:14])[CH2:10][CH2:11][C:12]#[CH:13]>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>[OH:14][CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:4]1[CH:3]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCCCC#Cc1cccc(C#CCCCO)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
1,3-Dibromobenzene (7.48 g, 31.71 mmol), 4-pentyn-1-ol (6.40 g, 76.10 mmol), and bis(triphenylphosphine)palladium(II) dichloride (445 mg, 0.63 mmol) was stirred in triethylamine (150 mL) under nitrogen for 5 min. Copper(I) iodide (61 mg, 0.32 mmol) was added and the mixture was stirred for 18 hrs at 75° C. The mixture was cooled to room temperature and filtered through a celite pad, rinsed with ethylacetate. The combined filtrate was evaporated to dryness under reduced pressure. The resulting residue was purified by column chromatography (chloroform:methanol 20:1) to afford 7.24 g of the title compound. Yield: 94%. 1H NMR (300 MHz, CDCl3) δ 1.85 (m, 4H), 2.53 (t, J=6.9 Hz, 4H), 3.81 (t, J=6.0 Hz, 4H), 7.16-7.31 (m, 3H), 7.42 (t, J=1.2 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3) δ 16.2, 31.6, 61.9, 80.6, 90.0, 124.0, 128.3, 130.8, 134.7 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH3:9][O-:10].[Na+].C1(C)C=CC=CC=1>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:10][CH3:9])[CH:3]=1
Reactant: C[O-]
Reactant: Clc1cc(Br)ccn1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Br)ccn1

Procedure:
4-Bromo-2-chloropyridine, sodium methoxide (1.6 equiv.) and toluene (6.1 volumes) were heated to 95° C. for 40 h. Toluene (6.1 volumes) and water (3 volumes) were added and the lower aqueous phase cut away. The organic was washed with water (1.5 volumes) and then the volatiles evaporated to give the title compound as an oil. HRMS (ES, M+H) Calcd 187.9711. Found 187.9711.