Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:32])=[C:20]([NH:22][S:23]([C:26]3[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=3)(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH3:33][S:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[F:32][C:19]1[CH:18]=[CH:17][C:16]([C:9]2[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:38][CH2:37][CH2:36][CH2:35][S:34][CH3:33])[N:7]=2)=[CH:21][C:20]=1[NH:22][S:23]([C:26]1[N:27]=[CH:28][N:29]([CH3:31])[CH:30]=1)(=[O:25])=[O:24]
Reactant: CSCCCN
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)c(-c2ccnc(Cl)n2)s1
Product: CSCCCNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3cn(C)cn3)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-methyl-1H-imidazole-4-sulfonamide (75 mg, 0.152 mmol) and [3-(methylthio)propyl]amine (86 mg, 0.817 mmol) the title compound of Step B was obtained as a golden oil (76 mg, 89% yield). MS (ESI): 561.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9](NC1CCN(C2C=CN=C(Cl)N=2)CC1)=[O:10].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]2)[N:33]=1)[C:29]#[N:30].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:40][CH:37]1[CH2:38][CH2:39][N:34]([C:32]2[CH:31]=[C:28]([C:29]#[N:30])[CH:27]=[C:26]([Cl:25])[N:33]=2)[CH2:35][CH2:36]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ccnc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: N#Cc1cc(Cl)nc(N2CCC(O)CC2)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)OC2CCN(c3cc(C#N)cc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 3, 164 mg, 0.84 mmol) was dissolved in anhydrous THF (3 ml). 2-Chloro-6-(4-hydroxypiperidin-1-yl)isonicotinonitrile (Intermediate 26), 200 mg, 0.84 mmol) was added, then DEAD (133 μl, 0.84 mmol) was added dropwise followed by triphenylphosphine (221 mg, 0.84 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, filtered and purified by semi-preparative reverse phase HPLC eluting with CH3CN/water (0.1% TFA). (135 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:15]([NH:17][CH3:18])=[O:16])=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:12]=[C:11]1[CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH3:32]C1C=CC(S(O)(=O)=O)=CC=1.O.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[C:15](=[O:16])[N:17]([CH3:32])[CH2:18][N:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[C:13]=2[N:12]=[C:11]1[CH2:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1nc(Nc2ccc(Cl)cc2Cl)c(C(=O)NC)n1COCc1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1nc2c(n1COCc1ccccc1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A solution of 1-benzyloxymethyl-4-[(2,4-dichlorophenyl)amino]-2-ethyl-N-methyl-1H-imidazole-5-carboxamide (2.70 g, 6.23 mmol) dissolved in toluene (100 mL) was treated with paraformaldehyde (8.0 g) and p-TsOH.H2O (0.67 g, 3.52 mmol). The reaction mixture was heated at reflux for 15 min. The mixture was cooled to rt, and transferred to a separatory funnel containing saturated aqueous NaHCO3 (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (40% ethyl acetate in hexanes) to afford 7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (1.6 g, 58% yield) as a colorless amorphous solid: 1H NMR (300 MHz, CDCl3) δ 7.46 (d, J=2.2 Hz, 1H), 7.34-7.29 (m, 5H), 7.19 (dd, J=8.4, 2.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 5.84 (s, 2H), 4.85 (s, 2H), 4.71 (s, 2H), 2.97 (s, 3H), 2.77 (q, J=7.7 Hz, 2H), 1.28 (t, J=7.7 Hz, 3H); HRMS (ESI) m/e 445.1212 [(M+H)+, calcd for C22H23N4O2Cl2 445.1198].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]#[N:12])[C:5]([C:9]#[N:10])=[N:6][C:7]=1Cl.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22].[CH3:25][O-:26].[Na+]>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[C:7]([O:26][CH3:25])=[N:6][C:5]([C:9]#[N:10])=[C:4]([C:11]#[N:12])[N:3]=1)(=[O:23])=[O:22]
Reactant: N#Cc1nc(N)c(Cl)nc1C#N
Reactant: C[O-]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Agent: [Na+]
Product: COc1nc(C#N)c(C#N)nc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method outlined in Example 1 using 5-amino-6-chloro-2,3-dicyanopyrazine (1.8 g) and 2,3-dichlorobenzenesulfonyl chloride (2.7 g). The adduct was reacted by the method outlined in example 31b using sodium methoxide to afford the sub-titled compound that was used directly.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][CH:10]=[C:9]1[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([O:29][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:23]=[CH:22]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccccc3)ccc2c1

Procedure:
In a similar manner as described in step 1 of Example 4, the title compound was prepared from 6-(1-benzyl-5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.250 g, 0.665 mmol), prepared in step 2 of Example 2, methyl bromoacetate (0.122 g, 0.797 mmol) and cesium carbonate (1.08 g, 3.33 mmol). The isolated tan amorphous solid (0.298 g, 100%) was used without further purification, mp 101–102° C. Elemental Analysis for C30H25NO3 Calc'd: C, 80.51; H, 5.63; N, 3.13. Found: C, 79.81; H, 5.60; N, 2.83.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([NH:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH2:29][CH3:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:11]([N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][S:27][C:21]=2[N:20]=[C:19]1[CH:28]([N:31]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:29][CH3:30])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(NCCN(C)C)c1nc2sccc2c(=O)n1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(c1nc2sccc2c(=O)n1Cc1ccccc1)N(CCN(C)C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (8 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL) was added to a solution of 3-benzyl-2-(1-{[2-(dimethylamino)ethyl]amino}propyl)thieno[2,3-d]pyrimidin-4(3H)-one (3-1, 13 mg, 0.035 mmol, 1 equiv) and N,N-diisopropylethylamine (5 mg, 0.035 mmol, 1 equiv) in dichloromethane (1 mL), and the resulting mixture was stirred under ambient conditions for 1 h. The reaction mixture was washed with saturated aqueous NaHCO3 solution, and brine, then dried (MgSO4) and concentrated. The residue was purified by flash chromatography. Elution with CH2Cl2 to 5% NH3-EtOH/CH2Cl2 gave N-[1-(3-benzyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)propyl]-4-bromo-N-[2-(dimethylamino)ethyl]benzamide (3-2) as an off-white foam. 1H NMR (500 MHz, CDCl3) δ 7.53 (m, 3H), 7.31 (m, 5H), 7.14 (m, 2H), 6.09 (d, J=15.6 Hz, 1H), 5.94 (m, 1H), 5.10 (d, J=15.6 Hz, 1H), 3.40 (m, 2H), 2.11 (m, 1H), 2.03 (m, 2H), 1.87 (m, 1H), 1.79 (s, 6H), 0.66 (t, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.C([N:18]([CH2:21][CH3:22])CC)C.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[CH2:23]([NH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:18][CH2:21][CH3:22])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1)[CH3:24]
Reactant: CCN
Reactant: O=[N+]([O-])c1c(Cl)nc(C(F)(F)F)nc1Cl
Reactant: CCN(CC)CC
Solvent: CCO
Product: CCNc1nc(C(F)(F)F)nc(NCC)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 98.5 %

Procedure:
5.25 g (0.02 mol) of 4,6-dichloro-5-nitro-2-trifluoromethyl-pyrimidine (J. Org. Chem. 26 (1961), pp. 4504-8) are dissolved in 150 ml of abs. ethanol. The solution is treated with 5 ml of triethylamine (0.05 mol) and 4.5 g (0.1 mol) of ethylamine and the mixture is stirred overnight, then evaporated to dryness. The residue is taken up in ether and washed with water. The ethereal phase is dried and concentrated to yield 5.5 g of 4,6-bis-ethylamino-5-nitro-2-trifluoromethyl-pyrimidine; m.p. 60°-65° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])C1C=CC=CC=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CCO>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[NH2:8][CH2:9][C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)CN(Cc1ccccc1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)C(F)(F)CN
Reaction time: 8 h
Yield: 94 %

Procedure:
In a round bottom flask, Ethyl 3-(dibenzylamino)-2,2-difluoropropanoate (1.72 g, 5.2 mmol) was solubilized in EtOH (25 mL) and TFA added (0.4 mL, 5.5 mmol). Under an atmosphere of nitrogen Pd(OH)2/C (170 mg of 20% Pd by wt. wet) was added. The reaction mixture was repeatedly purged with nitrogen and then left under hydrogen overnight. At this point the reaction was deemed complete by LCMS, filtered through a pad of Celite, the pad washed with EtOH and the filtrate concentrated without heating to yield a foggy syrup which starts to crystallize upon standing (1.31 g, 94% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.20 Hz, 3H) 3.72 (t, J=16.17 Hz, 2H) 4.34 (q, J=7.24 Hz, 2H). [M+H] calc'd for C5H9F2NO2, 154. found 154.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:17][S:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:15])=[O:16]
Reactant: COC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)CCCCC1(C(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 15 h
Yield: 92.3 %

Procedure:
To a solution of 1-[4-(methylsulfonyl)butyl]cyclopentanecarboxylic acid methyl ester (18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL) and the mixture was heated to 50-55° C. After 15 h, TLC analysis of the reaction mixture indicated the absence of starting material and the mixture was allowed to cool to room temperature. The solvent was removed under vacuum and the residue was diluted with water (100 mL) and extracted with diethyl ether (2×50 mL) to remove any neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×75 mL). The combined extracts were washed with brine, dried (MgSO4), filtered and the solution was concentrated in vacuo. The residual material was dried under high vacuum to afford 4.31 g (92%) of 1-[4-(methylsulfonyl)butyl]cyclopentane carboxylic acid as a low melting colorless solid. LR MS (C11H20O4S): 249 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: OB(O)c1ccccc1F
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2F)cc1
Yield: 69.4 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.048 g (69%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:14][C:15](=[O:34])[NH:16][C@@H:17]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:35]1[C:47]2[CH:46]([CH2:48][O:49][C:50]([NH:52][CH:53]([CH2:57][CH2:58][CH2:59][CH2:60][N:61]([CH2:88][C:89]3[N:90]([CH2:94][C:95]([N:97]([CH2:106][C:107]([O:109][C:110]([CH3:113])([CH3:112])[CH3:111])=[O:108])[CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])=[O:96])[CH:91]=[CH:92][N:93]=3)[CH2:62][C:63]3[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:85])([CH3:84])[CH3:83])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[CH:65]=[CH:66][N:67]=3)[C:54](O)=[O:55])=[O:51])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]=2[CH:38]=[CH:37][CH:36]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:110]([O:109][C:107](=[O:108])[CH2:106][N:97]([CH2:98][C:99](=[O:105])[O:100][C:101]([CH3:104])([CH3:103])[CH3:102])[C:95](=[O:96])[CH2:94][N:90]1[CH:91]=[CH:92][N:93]=[C:89]1[CH2:88][N:61]([CH2:62][C:63]1[N:64]([CH2:68][C:69](=[O:87])[N:70]([CH2:79][C:80](=[O:86])[O:81][C:82]([CH3:83])([CH3:84])[CH3:85])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:75])([CH3:76])[CH3:77])[CH:65]=[CH:66][N:67]=1)[CH2:60][CH2:59][CH2:58][CH2:57][C@@H:53]([C:54](=[O:55])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:14][C:15](=[O:34])[NH:16][C@H:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:52][C:50](=[O:51])[O:49][CH2:48][CH:46]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:39]2[C:47]1=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:111])([CH3:112])[CH3:113]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](CCCCN(Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A solution of (5)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (97 mg, 0.20 mmol), 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (132 mg, 0.12 mmol), EDCI (38 mg, 0.20 mmol), HOBt (26 mg, 0.20) and DIPEA (0.30 mL) in DCM (5.0 mL) was stirred at rt for 2 days. The reaction mixture was purified by biotage eluting with 1% MeOH in DCM to afford (5S,12S,16S)-tri-tert-butyl 5-(4-(bis((1-(2-(bis(2-tert-butoxy-2-oxoethyl)amino)-2-oxo ethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-1-(9H-fluoren-9-yl)-3,6,14-trioxo-2-oxa-4,7,13,15-tetraazaoctadecane-12,16,18-tricarboxylate (impure) as an oil.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18]C)=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 ml), and methanol (60 ml) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 ml of methylene chloride. The organic extract was washed with brine and concentrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification, 1H NMR (CDCl3): δ 0.89 (t, 3H); 1.21, 1.24 (s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42 (m, 1H); 5.31 (d, 1H)
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].N([O-])=O.[Na+].[CH:14]([CH:16]=[CH2:17])=[O:15]>Cl.O.CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([CH2:17][CH2:16][CH:14]=[O:15])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: C=CC=O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Cl)cc1CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a suspension of 2-amino-4-chlorotoluene (1.41 g, 10 mmol) in 24% aq. HCl (5 mL) Was added dropwise NaNO2 (710 mg, 1.03 mmol) in H2O (3 mL) over 30 min at 0° C. The resulting solution was added dropwise to a solution of acrolein (1 mL, 15 mmol) in a mixture of DMF (15 mL) and 20% aq. TiCl3 (20 mL, 26 mmol). After the addition was completed, the mixture was stirred for 30 min at room temperature and extracted with diethyl ether. The extracts was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 5:1 hexane/AcOEt to give 1.11 g of the title compound (60%): 1H NMR (CDCl3) δ9.83 (s, 1H), 7.06~7.12 (m, 3H), 2.90 (t, 2H, J=7.2 Hz), 2.74 (t, 2H, J=7.2 Hz), 2.27 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH2:12][CH2:13][CH3:14])[C@@H:10]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:24].[OH-].[Na+].S(=O)(=O)(O)[O-:28].[Na+]>C1COCC1.CO>[C:18]1([CH2:17][CH2:16][CH2:15][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:12][CH2:13][CH3:14])[C:9]([OH:24])=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)([O-])O
Reactant: CCC[C@H]1[C@@H](CCCc2ccccc2)C(=O)N1OC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC[C@H](NOC1CCCCO1)[C@@H](CCCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 36 h
Yield: 72 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-phenyl-1-propyl)-4-propylazetidin-2-one (1.22 g, 3.69 mmol) in THF-methanol (2:1, 15 mL) is added 1 N aqueous sodium hydroxide (5.5 mL). The solution is stirred at 23° C. for 36 h, is acidified to pH 3 with saturated aqueous sodium bisulfate solution, and is extracted with two 100-mL portions of EtCOAc. The combined organics are dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide (2R,3s)-2-(3-phenyl-1-propyl)-3-(2-tetrahydropyranyloxyamino)hexanoic acid as an oil (0.93 g, 72% yield).
Reaction SMILES: C(OC([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[NH:30][C:31]([NH:33][C:34]2[CH:39]=[N:38][C:37]([CH3:40])=[CH:36][N:35]=2)=[O:32])[CH2:12]1)=O)C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:40][C:37]1[N:38]=[CH:39][C:34]([NH:33][C:31]([NH:30][C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:21][CH:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:11][CH2:12]2)=[O:32])=[N:35][CH:36]=1
Reactant: Cc1ccc(OCC2Cc3ccccc3N(C(=O)OCc3ccccc3)C2)c(NC(=O)Nc2cnc(C)cn2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(OCC2CNc3ccccc3C2)c(NC(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C

Procedure:
A stirred suspension of the crude 3-{4-Methyl-2-[3-(5-methyl-pyrazin-2-yl)-ureido]-phenoxymethyl}-3,4dihydro-2H-quinoline-1-carboxylic acid benzyl ester (6.6 mg, 12 μmol) was heated in 5 mL EtOAc on a heat gun until in solution. The clear solution was cooled to rt and treated with triethylamine (3.4 μL, 24 μmol) followed by Pearlman's catalyst (20% palladium hydroxide on carbon, 9 mg). The mixture was put through a vacuum/purge cycle three times with hydrogen gas and then held under 1 atmosphere hydrogen pressure for 1 hour. The reaction was filtered through GF/F filter paper with EtOAc and concentrated to a white solid which corresponds to the desired product (4.7 mg, 100%). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.23 (s, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.04 (t, 1H), 6.97 (d, 1H), 6.81 (m, 2H), 6.67 (t, 1H),6.58 (d, 1H), 4.04 (m, 2H), 3.57 (d, 1H), 3.26 (t, 1H), 2.92 (ddd, 2H), 2.64 (m, 1H), 2.34 (s, 3H), 2.31 (s, 3H). LRMS (APCI, Positive) m/e 404.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([OH:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)[CH3:2].[C:19](#[N:23])[CH2:20][C:21]#[N:22].C(NCC)C.O>CN(C=O)C>[NH2:23][C:19]1[O:17][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:20]=1[C:21]#[N:22]
Reactant: N#CCC#N
Reactant: CCc1ccc(C(=O)C(O)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(-c2c(-c3ccccc3)oc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cool a mixture of 145 g (603 mmol) 1-(4-ethylphenyl)-2-hydroxy-2-phenylethanone and 51.8 g (784.4 mmol) malononitrile in 2.23 litres DMF to 0° C. and add 53.7 ml (518 mmol) diethylamine, with cooling. After 1 h, heat the reaction mixture to RT and stir for a further 4 h, before adding 1.5 litre water. After 30 min, pour off a large proportion of the water and replace with 750 ml of fresh water. Stir the mixture vigorously, before decanting from the sticky organic residue. Dissolve the residue in ethyl acetate, dry, and concentrate under vacuum, until the product begins to crystallize. Add 450 ml diisopropyl ether, stir and then leave to stand overnight. Filter off the crystalline precipitate with suction, wash twice with 50 ml diisopropyl ether and dry under vacuum. 98.5 g (56.6% of theor.) of the target product is obtained.