Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12](S(O)(=O)=O)=[CH:11][CH:10]=1>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][CH2:19][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a manner similar to that described in Example III, 0.68 ml of benzyl alcohol and 7 mg of p-toluenesulfonic acid are added to a solution of 350 mg of Compound Z-1(DMTD) in a mixture of 7 ml of tetrahydrofuran and 3 ml of dimethylformamide and the mixture stirred at room temperature for 24 hours. At the end the volatiles are removed in vacuo to obtain a residue which is purified on a preparative HPLC column using water/acetonitrile aseluant. The appropriate fractions are combined and lyophilized to obtain benzyl ether of Z-1(DMTD), molecular weight of 1168.
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH:4]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.S(=O)(=O)(O)O>O>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH:4]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)N1CCC(OC)(OC)C(OCc2ccccc2)C1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)N1CCC(=O)C(OCc2ccccc2)C1

Procedure:
A mixture of 94 parts of ethyl 4,4-dimethoxy-3-(phenylmethoxy)-1-piperidinecarboxylate and 2300 parts of a sulfuric acid solution 1% in water was stirred and refluxed for 2.50 hours. The reaction mixture was cooled and the product was extracted three times with dichloromethane. The combined extracts were washed with a small amount of water, dried, filtered and evaporated. The residue was taken up in methylbenzene and the latter was evaporated again. The residue was stirred in petroleum ether. The latter was separated and the solvent was evaporated, yielding 64.9 parts of ethyl 4-oxo-3-(phenylmethoxy)-1-piperidinecarboxylate as a residue (intermediate 50).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH:5][C:6](=[O:22])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Cl:32][C:33]1[CH:34]=[C:35]([N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47]Cl)[CH2:41][CH2:40]2)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([S:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:47][CH2:46][CH2:45][N:42]3[CH2:43][CH2:44][N:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=4)[CH2:40][CH2:41]3)=[CH:26][CH:25]=2)=[O:22])(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1
Reactant: ClCCCN1CCN(c2cccc(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccc(OCCCN3CCN(c4cccc(Cl)c4)CC3)cc2)C(=O)O)cc1

Procedure:
The methyl ester was prepared via O-alkylation of N-(toluene-4-sulfonyl)-L-prolyl-L-tyrosine methyl ester with 1-(3-chlorophenyl)-4-(3-chloro-propyl)piperazine in refluxing 2-butanone in the presence of potassium carbonate and sodium iodide. The title compound was prepared using the procedure described in Method 7 as a solid, mp=116-8° C.
Reaction SMILES: [I-].C[N+]1[CH:7]=[CH:6][N:5]([C:8](/[N:10]=[C:11]2\[S:12][C:13]([CH3:26])=[CH:14][N:15]\2[C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[O:9])[CH:4]=1.N1CCC[CH2:28]1.CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[CH3:26][C:13]1[S:12]/[C:11](=[N:10]\[C:8]([N:5]2[CH2:6][CH2:7][CH2:28][CH2:4]2)=[O:9])/[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:14]=1
Reactant: C1CCNC1
Reactant: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc(C(F)(F)F)cc2)/c(=N/C(=O)N2CCCC2)s1
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-1-({[(2Z)-5-methyl-3-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2(3H)-ylidene]amino}carbonyl)-1H-imidazol-3-ium iodide (0.1 g, 0.2 mmol, Example 18B) and pyrrolidine (1.2 equivalents) in anhydrous acetonitrile (3 mL) was added Hunig's base (33 mg, 1.2 equivalents), and the resultant solution was heated at 60° C. for 3 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (25 mL) and washed with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was chromatographed over silica using dichloromethane to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 2-methylthiazole-4-carboxylate (17.0 g, 99.3 mmol) was dissolved in 150 ml of methanol and 2N NaOH (150 ml, 300 mmol) was added. The reaction mixture was stirred for 2 hours at room temperature. Methanol was evaporated and the residue was acidified with 2N HCl to pH 2. The aqueous layer was extracted two times with ethyl acetate. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (13.0 g, 91%) was used without any further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:31][CH3:32])[C:22]=1[O:23][Si](C(C)(C)C)(C)C)/[CH:6]=[CH:7]/[C:8]1[CH:12]=[C:11]([OH:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=1.[Si](OC(C1C=NN(C2C=CC=CN=2)C=1O)=CC1C=CC=CC=1)(C(C)(C)C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([O:31][CH3:32])[C:22]=1[OH:23])[CH:6]=[CH:7][C:8]1[CH:12]=[C:11]([OH:13])[N:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]=1
Reactant: COc1cc(/C=C/c2cc(O)n(-c3ccccn3)n2)cc(OC)c1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC(=Cc1ccccc1)c1cnn(-c2ccccn2)c1O
Product: COc1cc(C=Cc2cc(O)n(-c3ccccn3)n2)cc(OC)c1O
Yield: 94 %

Procedure:
The title compound was prepared in the same manner as in Example C-11, except that 1.201 mmol of Compound 9i prepared in Example C-9 was used in place of Compound 9g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:23](=[O:24])[CH2:22][C:21](=[O:25])[NH:20][C:19]3[C:26]4[C:31]([CH:32]=[CH:33][C:18]2=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:13][CH:12]=1.CN1C=CN=C1C(Cl)=O>>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:23](=[O:24])[CH2:22][C:21](=[O:25])[NH:20][C:19]3[C:26]4[C:31]([CH:32]=[CH:33][C:18]2=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:13][CH:12]=1)=[O:9]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cn1ccnc1C(=O)O
Agent: Cn1ccnc1C(=O)Cl
Product: Cn1ccnc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 13.4 %

Procedure:
1-Methyl-1H-imidazole-2-carboxylic acid (40 mg, 0.317 mmol) was made into acid chloride in a conventional manner. By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and 1-methyl-1H-imidazole-2-carboxylic acid chloride mentioned above, the title compound (9 mg, yield 13%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([N+:36]([O-:38])=[O:37])[CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cc([N+](=O)[O-])ccc5n4)cc3CC[C@@H]12
Yield: 53.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (96 mg, 1.14 mmol), 2-chloro-6-nitroquinoline (96 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 88 mg (53%) of the title compound as a tan solid. mp 195°-196°. FDMS: m/e=433. α[D]589 =+64.56 (c =0.78, chloroform).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH:25](=O)[CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: CCCCC=O
Solvent: CC(=O)N(C)C
Product: CCCCC=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Yield: 69.7 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with pentanal (0.5 g, 5.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 130° C. for 40 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.081 g, 70%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH:13][C:12](=[O:11])[CH3:17]
Reactant: O=Cc1ccccc1F
Reactant: COc1ccccc1C=CC(C)=O
Product: CC(=O)C=Cc1ccccc1F

Procedure:
The title compound was prepared from 2-fluoro-benzaldehyde (6.2 g, 50.0 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:18][N:19]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (36 mg, 0.13 mmol, CAS RN 1271-19-8) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol) and DIPEA (40 μL, 0.23 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (23 mg, 41%). MS (ESI): m/z=439.0 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@@H:17]([OH:21])[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.C([O:34][C@@H:35]1[C@@:63]2(C)[C:39](=[CH:40][CH2:41][C@@H:42]3[C@@H:62]2CC[C@@]2(C)[C@H]3CC[C@@H]2[C@H](C)CCC(OC(=O)C)C(C)C)C[C@@H](OC(=O)C)C1)(=O)C>>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH:8]=[C:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][C@@H:17]([O:21][C:2](=[O:1])[C:27]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:26]=2)[CH:18]([CH3:20])[CH3:19])[CH2:5][C@@H:4]([O:30][C:35](=[O:34])[C:63]2[CH:62]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:3]1
Reactant: CC(=O)OC(CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Reactant: CC(C)[C@H](O)CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)[C@@H](CC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(=O)c5ccccc5)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C)OC(=O)c1ccccc1

Procedure:
The 1α,3β,24(R)-trihydroxy-cholesta-5,7-diene was benzoylated in quite the same way as in Example 22, (A) to form 1α-hydroxy-3β,24(R)-dibenzoyloxy-cholesta-5,7-diene.
Reaction SMILES: ClC1C=CC=CC=1CN1C(CC(O)=O)=CN=C1SCCC.ClC1C=CC=CC=1CN1C(/C=C(\CC2SC=CC=2)/C(O)=O)=CN=C1SCCC.[CH2:50]([C:54]1[N:55]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[Cl:78])[C:56](/[C:59](/C)=C(\C2C=CN=CC=2)/C(O)=O)=[CH:57][N:58]=1)[CH2:51][CH2:52][CH3:53].[CH2:79]([CH:86]([C:92]1[S:93][CH:94]=[CH:95][CH:96]=1)[CH2:87][C:88]([O:90]C)=[O:89])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:50]([C:54]1[N:55]([CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][C:73]=2[Cl:78])[C:56](/[CH:59]=[C:87](\[CH:86]([C:92]2[S:93][CH:94]=[CH:95][CH:96]=2)[CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)/[C:88]([OH:90])=[O:89])=[CH:57][N:58]=1)[CH2:51][CH2:52][CH3:53]
Reactant: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Reactant: COC(=O)CC(Cc1ccccc1)c1cccs1
Agent: CCCSc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Agent: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(/C=C(/C(=O)O)C(Cc2ccccc2)c2cccs2)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared using the procedure of Example 1 (i, ii, iii, iv [Method B]) replacing methyl 3-(2-thienyl)propanoate with methyl 3-benzyl-3-(2-thienyl)propanoate [prepared following the procedure described in Tetra. 44 (7) 2055 (1988)]; mp 200°-202° C.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([O:23]CC)=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl>>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[S:19][C:18]([CH2:20][C:21]([OH:23])=[O:22])=[N:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cc1nnc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)s1
Agent: Cl
Product: Nc1ccc(S(=O)(=O)Nc2nnc(CC(=O)O)s2)cc1
Yield: 82.1 %

Procedure:
Distilled water (3.0 mL) and 10% aqueous NaOH (1.5 mL) were added to compound 118E (300 mg, 0.78 mmol) and the mixture was heated under reflux for 2 h. The pH of the solution was then adjusted to 4.0 by addition of 1.0 M HCl, the resulting precipitate was isolated by filtration, washed with cold water, and dried to give 201 mg (0.64 mmol, 82%) of the product as a solid, mp 209-210° C.; 1H NMR (600 MHz, DMSO-d6) δ 3.59 (s, 2H), 6.52 (d, 2H, J=8.1 Hz), 7.42 (d, 2H, J=8.9 Hz); 13C NMR (75 MHz, DMSO-d6) δ 36.6, 113.3, 127.8, 128.4, 152.4, 153.3, 167.7, 170.4; MS (LCQ, ESI+) Calcd for C10H11N4O4S2 315.0, found 315.0 (M+H)+; HRMS (ESI+, m/z) Calcd for C10H11N4O4S2 315.0222, found 315.0220 (M+H)+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][CH:11]([CH3:40])[CH2:12][C@H:13]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][N:32]=1)[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[CH:16][CH:15]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.C(=O)(O)[O-].[Na+]>[CH3:10][CH:11]([CH3:40])[CH2:12][C@H:13]([NH:30][C:31]1[N:32]=[CH:33][C:34]([C:35]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:36])=[CH:38][CH:39]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][N:21]=2)=[CH:18][CH:19]=1
Reactant: CC(C)C[C@H](Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cn3)cc2)nc1
Temperature: 40 °C
Yield: 86 %

Procedure:
To a mixture of ethyl 3-aminopropionate hydrochloride (41.1 g, 268 mmol), (S)-6-[(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)amino]nicotinic acid (57.51 g, 133.9 mmol), hydroxybenzotriazole hydrate (20.5 g, 134 mmol), and triethylamine (103 ml, 737 mmol) in dichloromethane (1.34 L) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38.9 g, 201 mmol) at ambient temperature. The reaction was heated to 40° C. for 12 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (1.5 L) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2×500 ml) and the combined organic layers were washed with brine (1 L), then dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified via ISCO MPLC (SiO2, 0-100% ethyl acetate in heptane) to yield the product (60.9 g, 86%) as a white foam. 1H NMR (400 MHz, CDCl3, δ): 8.93 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.95-8.02 (m, 3H), 7.81 (d, J=8.6 Hz, 1H), 7.78 (dd, J=9.1, 2.4 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 6.73 (t, J=5.7 Hz, 1H), 6.29 (d, J=8.8 Hz, 1H), 5.81-5.91 (m, 1H), 4.76 (q, J=6.8 Hz, 1H), 4.10-4.16 (m, 2H), 3.67 (q, J=6.1 Hz, 2H), 2.60 (t, J=5.9 Hz, 2H), 1.77-1.87 (m, 1H), 1.65-1.77 (m, 2H), 1.23-1.28 (m, 3H), 1.01 (d, J=6.1 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H). MS (M+1): 529.3.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]1[O:22][CH2:21]1>C1COCC1.O.C(Cl)Cl>[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH2:20][CH2:21][OH:22]
Reactant: C1CO1
Reactant: Fc1cccnc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Solvent: O
Product: OCCc1ccncc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
n-Butyl lithium (1.8 M in hexanes, 35 mL, 64.4 mmol) was charged to a round bottom flask and diluted with THF (25 mL). The solution was cooled to 0° C., and a solution of N,N-diisopropylamine (9.0 mL, 65 mmol) in THF (25 mL) was slowly added. The mixture was stirred at 0° C. for 20 min and was cooled to −78° C. A solution of 3-fluoropyridine (20 g, 206 mmol) was added dropwise (temperature of mixture kept below −70° C.), resulting in the formation of a red precipitate. The mixture was stirred at −78° C. for 4 h. Ethylene oxide (4.6 M in THF, 67.2 mL, 309 mmol) was slowly added, and the mixture allowed to warm to room temperature overnight. The mixture was diluted with water and CH2Cl2. The layers were separated, and the water layer extracted with CH2Cl2. The organic layers were combined, washed with brine, dried (Na2SO4), filtered, and concentrated to provide a dark brown oil. The residue was purified by chromatography (SiO2, 19:1-6:1 CH2Cl2:CMA) to provide 3-fluoro-4-(2-hydroxyethyl)pyridine (6.7 g, 23%) as a tan oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH:21][O:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]1[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].C1N=CN(C(N2C=NC=C2)=O)C=1.C(=O)(O)O.[NH2:61][C:62]([NH2:64])=[NH:63]>CN(C=O)C>[NH2:63][C:62](=[N:61][C:27]([C:26]1[CH:25]=[C:24]([CH:32]=[CH:31][CH:30]=1)[CH2:23][O:22][NH:21][C:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:33])[N:10]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]2[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20])=[O:28])[NH2:64]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(=O)O)c2)C1c1ccc(Cl)cc1Cl
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(=O)N=C(N)N)c2)C1c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A mixture of 590 mg of 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}benzoic acid, 217 mg of CDI, and 9 ml of DMF was stirred at 50° C. for 1 hour, and 241 mg of guanidine carbonate was then added thereto, followed by stifling at the same temperature for 3 hours. The reaction solution was left to be cooled and the solvent was then evaporated under reduced pressure. The residue was diluted with ethyl acetate, and washed with a saturated aqueous sodium hydrogen carbonate solution and then with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform-methanol) and recrystallized from acetonitrile to obtain 348 mg of (3RS,4RS)-N-({3-[(diaminomethylene)carbamoyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl]-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:12][CH:13]1[CH2:15][O:14]1>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:12][CH:13]2[CH2:15][O:14]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(NCC2CO2)n1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 6-bromopyridin-2-amine (1 g, 5.81 mmol) in DMF (15 mL) was added NaH (696 mg, 17.4 mmol), 2-(bromomethyl)oxirane (790 mg, 5.81 mmol) at 0° C. The mixture was stirred at 0° C. for 4 hours then quenched with water (50 mL), extracted with EA (30 mL×3). The combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was directly for the next step. LCMS (m/z): 279.1/280.1 [M+H]+/[M+2H]+
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:13])[CH2:6]P(OC)(OC)=O.[CH3:14][C:15]1([C:20]2([CH:23]=O)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17][O:16]1>C1COCC1>[CH3:3][O:4][C:5](=[O:13])/[CH:6]=[CH:23]/[C:20]1([C:15]2([CH3:14])[O:16][CH2:17][CH2:18][O:19]2)[CH2:21][CH2:22]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC1(C2(C=O)CC2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/C1(C2(C)OCCO2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3 g of sodium hydride suspension (60% in paraffin oil) is introduced into 750 ml of THF, cooled under nitrogen to 0° C., and 10.9 g of dimethylphosphonoacetic acid methyl ester is added. Then, 7.5 g of aldehyde 7 is added in drops to 15 ml of THF, and it is stirred at room temperature for 2 hours. It is now quenched carefully with sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate, and the solvent is removed. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 9.5 g of title compound 93 accumulates as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][CH2:9][C:10]1[O:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1nnc(CN)o1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
In an alternative procedure, compound 8 (33.3 g, 0.12 mol) is added portionwise to a 0° C. commercially available solution of hydrogen chloride in 1,4-dioxan (Aldrich, 4 M, 750 ml.) Compound 8 slowly dissolves to afford a clear yellow solution. After stirring for approximately 30 minutes, the reaction mixture turns cloudy. The starting material is consumed in about two hours, as determined by TLC on silica using methylene chloride:ethyl acetate (9:1) as the eluent. The reaction mixture is filtered and a colorless solid product is obtained. The solid is washed exhaustively with ether (1L) to afford 19.2 g (76%) of compound 9.