Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[NH2:20][CH2:21][CH2:22][SH:23].C(N(CC)CC)C.S(=O)(=O)(O)O>CO>[S:23]1[CH2:22][CH2:21][NH:20][CH:1]1[CH:3]([NH:8][C:9](=[O:19])[C@H:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[NH:11][C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(C)=O
Reactant: NCCS
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(C)=O)C1NCCS1
Yield: 73.8 %

Procedure:
In 20 ml of methanol was dissolved 2.0 g of N-acetyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 16-(c), and 800 mg of 2-aminoethanethiol, 1.0 ml of triethylamine, and a catalytic amount of concentrated sulfuric acid were added thereto. The mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by medium-pressure column chromatography on silica gel to obtain 1.8 g of the titled compound as a colorless crystal.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH:14]([F:16])[F:15])=[CH:11][C:10]([CH3:17])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3]>C(O)(C(F)(F)F)C(F)(F)F.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:16][CH:14]([F:15])[O:13][C:12]1[C:4]([CH:1]=[CH:2][CH3:3])=[C:5]2[C:9](=[C:10]([CH3:17])[CH:11]=1)[N:8]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH:7]=[CH:6]2
Reactant: C=CCc1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC=Cc1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To solution of tert-butyl 4-allyl-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (2.05 g, 6.08 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (7.6 mL) was added Pd(OAc)2 (0.041 g, 0.182 mmol) and the reaction stirred for 45 minutes at room temperature. At this point the reaction was concentrated and purified directly by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (d, J=4.04 Hz, 1H) 6.87-7.32 (m, 3H) 6.65 (dd, J=16.17, 1.77 Hz, 1H) 6.26-6.43 (m, 1H) 1.94 (dd, J=6.69, 1.64 Hz, 3H) 1.60 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])[C@@H:20]([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:22][C@H:20]1[NH:21][C:32](=[O:34])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:7]3[C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH:10]=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[C:19]1=[O:23]
Reactant: Cc1noc2cccc(Oc3ccc(NC(=O)[C@@H](C)N)cc3)c12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1noc2cccc(Oc3ccc(N4C(=O)N[C@H](C)C4=O)cc3)c12
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
N1-{4-[(3-methyl-1,2-benzisoxazol-4-yl)oxy]phenyl}-D-alaninamide (Intermediate 14, 337 mg) was dissolved in 8.0 ml of ethyl acetate. Triethylamine (0.33 ml, 2.38 mmol) was added followed by a solution of triphosgene (161 mg, 0.54 mmol) in 2.0 ml of ethyl acetate. After 5 minutes stirring, DMAP (66 mg, 0.54 mmol) was added and the reaction mixture was stirred at room temperature for 10 minutes. After quenching with a saturated aqueous solution of NaHCO3, the reaction mixture was extracted two times with ethyl acetate. The gathered organic layers were dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with a gradient Cy-Hex/EtOAc from 100/0% to 0/100%. This afforded the title compound (160 mg).
Reaction SMILES: [CH2:1]([OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:22][O:23][C:24]1[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=1[C:26]([O:33][CH3:34])=[C:27]([O:31][CH3:32])[C:28](Cl)=[O:29].O=P(Cl)(Cl)Cl.O>N1C=CC=CC=1>[CH3:22][O:23][C:24]1[CH:38]=[CH:37][CH:36]=[CH:35][C:25]=1[C:26]([O:33][CH3:34])=[C:27]([O:31][CH3:32])[C:28]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:29]
Reactant: COC(C(=O)Cl)=C(OC)c1ccccc1OC
Reactant: CCCCCCCCCCCCCCCCCCCCO
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCCCOC(=O)C(OC)=C(OC)c1ccccc1OC
Reaction time: 8 h
Yield: 83.3 %

Procedure:
2.9 g of 1-eicosanol dissolved in 50 ml of anhydrous pyridine are placed in a 100 ml flask equipped with a stirrer, a thermometer and a dehydrating valve. To this solution there are added 2.5 g of trimethoxycinnamoyl chloride and 0.01 ml of POCl3. The reaction mixture is left alone at room temperature overnight and is then poured into 200 ml of water. After filtration, the precipitate formed is crystallized from 30 ml of methanol. After drying, 4.2 g of eicosyl trimethoxycinnamate having the following characteristics are obtained:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:12][NH2:13])=[O:11].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=O.Cl>C(Cl)Cl>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]1[O:11][C:10]([CH2:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[N:12][N:13]=1
Reactant: O=C(Cl)CCCCl
Reactant: NNC(=O)Cc1ccc(F)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Fc1ccc(Cc2nnc(CCCCl)o2)c(F)c1
Reaction time: 1 h

Procedure:
A mixture of 2-(2,4-difluorophenyl)acetohydrazide (570 mg, 3.06 mmol) and DIPEA (0.553 ml, 3.2 mmol) in dry DCM (30 ml) was added to 4-chlorobutyryl chloride (0.343 ml, 3.06 mmol) in dry DCM (5 ml) over 15 min. An immediate white precipitate formed. After stirring for 1 h, 2M HCl (20 ml) was added and the solid 2-(3-chloropropyl)-5-[(2,4-difluorophenyl)methyl]-1,3,4-oxadiazole was filtered off, washed with water and dried (726 mg).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>N1C=CC=CC=1>[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)([O:10][CH2:9][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:11])(=[O:18])=[O:17]
Reactant: CC(CO)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)Oc2ccccc2)cc1

Procedure:
(-)-2-Phenoxypropanol [α]D25 = -38.95° (c. 0.9, CHCl3) was treated with tosylchloride in pyridine to give the corresponding (-)-2-phenoxypropyl tosylate of which 1.10 g. was reacted with LiPPh2 following Example 28 to give 0.87 g. of (+)-2-phenoxypropyl diphenylphosphine having [α]D25 = +27.90° (c. 3.03, CHCl3).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)C>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: ClCCCOc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
4-Iodophenol (10 g, 45.4 mmol), 1-bromo-3-chloropropane (7 g, 50.0 mmol) and potassium carbonate (7.54 g, 54.5 mmol) were mixed in DMF, and stirred at room temperature for 15 hours. The reaction liquid was diluted with diethyl ether, washed with water and saturated saline in that order, and the organic layer was dried with sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (eluate: ethyl acetate/hexane=5/95) to obtain the entitled compound (11.1 g, 82.3%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:41])[O:9][CH2:10][CH:11]([O:34][C:35]1[CH:39]=[C:38]([CH3:40])[O:37][N:36]=1)[CH2:12][O:13][C:14]1[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:16][N:15]=1.[N-:42]=[N+:43]=[N-:44].[Na+].[CH:46]([O-])([O-])OCC>C(O)(=O)C>[N:1]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:41])[O:9][CH2:10][CH:11]([O:34][C:35]2[CH:39]=[C:38]([CH3:40])[O:37][N:36]=2)[CH2:12][O:13][C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:16][N:15]=2)[CH:46]=[N:44][N:43]=[N:42]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCc1cc(OCC(COC(=O)NCCCCCN)Oc2cc(C)on2)no1
Reactant: CCOC([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCc1cc(OCC(COC(=O)NCCCCCn2cnnn2)Oc2cc(C)on2)no1
Reaction time: 3 h

Procedure:
A mixture of 0.230 g of (2RS)-2-(5-methyl-3-isoxazolyloxy)-3-(5-pentadecyl-3-isoxazolyloxy)propyl N-(5-aminopentyl)carbamate (prepared as described in Example 27), 0.067 g of sodium azide, 0.30 ml of ethyl orthoformate and 0.45 ml of acetic acid was heated on an oil bath kept at 115° C. for 3 hours. The solvent was removed by evaporation under reduced pressure, and then the residue was subjected to column chromatography through 10 g of silica gel. 0.152 g of the title compound was obtained as a powder from the fractions eluted with mixtures of methylene chloride and methanol ranging from 5:1 to 2:1 by volume. It melted at 82°-84° C. (after reprecipitation from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: CO[CH:3](OC)[CH2:4][Br:5].Br.O.[Br:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15](Br)[N:16]=1>CN(C=O)C>[Br:5][C:4]1[N:16]=[C:11]([Br:10])[C:12]2[N:18]([CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: COC(CBr)OC
Reactant: Nc1ncc(Br)nc1Br
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cn2ccnc2c(Br)n1
Reaction time: 12 h
Yield: 81.3 %

Procedure:
A mixture of 5.0 g (30 mmol) of bromoacetaldehyde dimethyl acetal 1.0 ml of concentrated aqueous HBr solution and 4.0 ml of distilled water was brought to reflux for 1 h. After reaction, the mixture was alkalinized and extracted with ether. This organic phase was added to a solution of 1.0 g (4.0 mmol) of 3,5-dibromopyrazin-2-amine in 2 ml of DMF. The ether was removed and the mixture was stirred under a stream of nitrogen for 12 h. After reaction, the DMF was removed and the residue was dissolved in 5 ml of anhydrous ethanol and then it was brought to reflux for 1 h. The alcohol was then removed and the residue was dissolved in water, alkalinized with Na2CO3 and extracted with dichloromethane. After chromatography with alumina column (eluted with ether), 900 mg (yield: 82%) of 6,8-dibromoimidazo[1,2-a]pyrazine was obtained. ESI-MS (M+H+): 278.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:4]=1[O:14][CH3:15].[C-:16]#[N:17].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:14][C:4]1[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:16]#[N:17]
Reactant: [C-]#N
Reactant: COCCOc1cccc(CCl)c1OC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cccc(CC#N)c1OC
Temperature: 60 °C
Yield: 54.3 %

Procedure:
1-(Chloromethyl)-2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzene (0.33 g, 1.4 mmol) was dissolved in N,N-dimethylformamide (2 mL) followed by the addition potassium cyanide (0.12 g, 1.6 mmol), and the resulting mixture was heated at 60° C. for 18 hours. After cooling to room temperature, it was diluted with ethyl acetate (50 mL), washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (50% ethyl acetate/hexanes) to provide (2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.17 g, 0.76 mmol, 54% yield). 1H NMR (400 MHz, CDCl3): 7.03-7.00 (d, d, 1H), 6.95-6.89 (m, 2H), 4.16-4.14 (m, 2H), 3.94 (s, 3H), 3.79-3.77 (m, 2H), 3.70 (s, 2H), 3.44 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH2:5]([O:7][CH:8](OCC)[CH2:9][CH2:10]Cl)[CH3:6].[I-].[K+]>C(O)C>[NH2:1][C:2]1[S:3][CH2:10][CH2:9][CH:8]([O:7][CH2:5][CH3:6])[N:4]=1
Reactant: CCOC(CCCl)OCC
Reactant: NC(N)=S
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC1CCSC(N)=N1

Procedure:
A mixture of 10 g. of thiourea, 50 ml. of β-chloropropionaldehyde diethyl acetal, 75 ml. of absolute ethanol, and 2 g. of potassium iodide was refluxed for 2 days. The solvent was evaporated, and the residue was partitioned between water and ether. The aqueous phase was extracted twice more with ether, basified with sodium carbonate and extracted 4 times with chloroform. The chloroform was concentrated to dryness, and the residue was thoroughly extracted with ether. The ether extracts were evaporated to a small volume which deposited 6.88 g. of crystalline 2-amino-4,5-dihydro-4-ethoxy-6H-1,3-thiazine.
Reaction SMILES: CS(OC[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:22]=3)[O:18][N:17]=2)=[CH:11][C:10]=1[CH2:34][CH3:35])(=O)=O.[CH2:36]([CH2:38][NH2:39])[OH:37].[C:40](#N)C>>[CH:29]1([C:23]2[CH:22]=[C:21]([C:19]3[O:18][N:17]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:7][CH2:40][NH:39][CH2:38][CH2:36][OH:37])=[C:10]([CH2:34][CH3:35])[CH:11]=4)[N:20]=3)[CH:26]=[C:25]([O:27][CH3:28])[N:24]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCOS(C)(=O)=O
Reactant: NCCO
Reactant: CC#N
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OCCNCCO
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)ethyl methanesulfonate (184 mg, 0.367 mmol) and ethanolamine (112 mg, 1.83 mmol) in acetonitrile (6 mL) is stirred at 65° C. for 18 h before it is separated by prep. HPLC to give the title compound (77 mg) as a white solid; LC-MS: tR=0.92 min, [M+H]+=467.25; 1H NMR (CD3OD): δ 7.91 (s, 1H), 7.88 (s, 1H), 7.62 (s, 1H), 7.41 (s, 1H), 4.20 (t, J=5.0 Hz, 2H), 4.07 (s, 3H), 3.93 (t, J=5.1 Hz, 2H), 3.60 (t, J=4.9 Hz, 2H), 3.34-3.38 (m, 2H), 3.24-3.31 (m, 1H), 2.82 (q, J=7.5 Hz, 2H), 2.45 (s, 3H), 2.10-2.19 (m, 2H), 1.85-1.97 (m, 4H), 1.72-1.84 (m, 2H), 1.35 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[O:104]=[C:105]1[CH:109]=[CH:108][C:107](=[O:110])[N:106]1[CH2:111][CH2:112][CH2:113][CH2:114][CH2:115][C:116]([NH:118][NH:119][CH3:120])=[O:117]>CN(C=O)C>[O:110]=[C:107]1[CH:108]=[CH:109][C:105](=[O:104])[N:106]1[CH2:111][CH2:112][CH2:113][CH2:114][CH2:115][C:116]([NH:118][N:119]([C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH3:120])=[O:117]
Reactant: CNNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)N(C)NC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.9 mg (8 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 2540 μl of DMF and then admixed with 3.6 mg (9 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 3 μl of N,N-diisopropylethylamine and with 4.1 mg (12 μmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N′-methylhexanehydrazide trifluoroacetate. The mixture was stirred at RT overnight. Subsequently, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. Thus, 3.9 mg (45% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].[C:18]([O:22][C:23](=[O:38])[NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=2)[CH2:26]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:38])[NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=4)[N:5]=[CH:4][C:3]=3[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:33][N:32]=2)[CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Product: CC(C)C(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 90.6 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)-2-methylpropan-1-one (500 mg, 1.85 mmol) was reacted with (R)-tert-butyl(1-(5-aminopyridin-2-yl)piperidin-3-yl)carbamate (815 mg, 2.78 mmol) to afford the desired product (880 mg, 88%) as a red solid: ESI MS m/z 525 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>O1CCOCC1>[OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])[CH2:6][CH2:5]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: OCC(O)CN1CCNCC1
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 32 of 1-(2,3-dihydroxypropyl)piperazine and 15.7 g of 2-chloronicotinic acid in 500 ml dioxane were refluxed for 8 hours. The reaction mixture was cooled, settled, the solvent separated and removed. The residue was triturated under heating with absolute ethanol and gave 16.2 g of 2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]nicotinic acid melting at 210°-212° C. (with decomposition)
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:37]=[CH:36][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=4)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][NH:39][CH3:40].C(Cl)CCl>ClCCl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([N:39]([CH3:40])[CH3:38])=[O:33])=[CH:29][CH:28]=4)=[O:24])=[CH:36][CH:37]=3)(=[O:17])=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Reactant: CNC
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Yield: 15.2 %

Procedure:
Combine 4-{[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl}-benzoic acid (0.489 mmole) with dimethylamine (0.587 mmole), and EDC (0.733 mmole) in 5 ml of dichloromethane and stir for 15 hrs. Dilute □eaction and wash with 1 N HCl. Dry organic layer over MgSO4 and concentrate. Purify the residue via column chromatography with a mixture of ethyl acetate and dichloromethane to isolate 0.040 g (15.2%) of the title compound: MSES+ 537.95; MSES− 536.08.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:18]([NH:20][C@H:21]([C:32]#[N:33])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])=[O:19])[CH:15]([CH3:17])[CH3:16])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[F:34][CH:35]([F:53])[C@@H:36]([C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=1)[OH:37]>>[C:32]([C@H:21]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=1[F:31])[NH:20][C:18](=[O:19])[C@@H:14]([NH:13][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:41]2[CH:40]=[CH:39][C:38]([C@@H:36]([OH:37])[CH:35]([F:53])[F:34])=[CH:43][CH:42]=2)=[CH:3][CH:4]=1)[C:9]([F:12])([F:11])[F:10])[CH:15]([CH3:17])[CH3:16])#[N:33]
Reactant: CC1(C)OB(c2ccc([C@@H](O)C(F)F)cc2)OC1(C)C
Reactant: CC(C)[C@H](N[C@@H](c1ccc(Br)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(C#N)cc1F
Product: CC(C)[C@H](N[C@@H](c1ccc(-c2ccc([C@@H](O)C(F)F)cc2)cc1)C(F)(F)F)C(=O)N[C@H](C#N)Cc1ccc(C#N)cc1F

Procedure:
(S)—N—[(S)-Cyano-(4-cyano-2-fluoro-benzyl)-methyl]-2-{(S)-1-[4′-((R)-2,2-difluoro-1-hydroxy-ethyl)-biphenyl-4-yl]-2,2,2-trifluoro-ethylamino}-3-methyl-butyramide was prepared from N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-cyano-2-fluorophenyl)ethyl]-L-valinamide and (1R)-2,2-difluoro-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanol (described in U.S. Pat. No. 7,407,959, hereby incorporated by reference in its entirety.) using procedure described in step 2 of Example 10.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=O)[NH:3][CH:2]=1.[Cl:8][C:9]1[C:14](I)=[CH:13]N=CN=1.Cl.[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23])([CH3:19])[CH3:18]>>[ClH:8].[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:23])([CH3:19])[CH3:18].[CH:17]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH:23][C:4]1[C:5]([CH2:13][CH2:14][C:9]2[CH:26]=[CH:25][CH:24]=[CH:22][CH:21]=2)=[CH:6][N:1]=[CH:2][N:3]=1)([CH3:19])[CH3:18]
Reactant: O=c1ccnc[nH]1
Reactant: Clc1ncncc1I
Agent: CC(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Product: CC(C)OC(=O)[C@H](Cc1ccccc1)Nc1ncncc1CCc1ccccc1

Procedure:
L-Phenylalanine isopropyl ester hydrochloride was prepared by Method LLL. 4(3H)-Pyrimidinone (Aldrich) was sequentially converted via Methods N and O to 4-chloro—5-iodopyrimidine. L-Phenylalanine isopropyl ester hydrochloride and 4-chloro—5-iodopyrimidine were coupled via Method P and the coupled product sequentially converted via Methods OOO and X to give the title compound.