Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:38]([CH:40]2[CH2:42][CH2:41]2)=[O:39])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:36]=[CH:35][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:38]([CH:40]2[CH2:41][CH2:42]2)=[O:39])[C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:34])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)=[O:20])[C@@H:11]([CH3:37])[CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)C3CC3)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1C[C@@H](N(C(=O)C2CC2)c2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(OCCC(C)(C)C(=O)O)cc1
Temperature: 40 °C
Yield: 86.9 %

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(cyclopropylcarbonyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoate (100 mg, 0.17 mmol, 1 equ.) was dissolved in methanol/tetrahydrofuran (2/1) (1 ml). A solution of sodium hydroxide (21 mg, 0.51 mmol, 3 eq.) in water (0.5 ml) was added and reaction mixture heated to 40° C. for 2 h. The mixture was concentrated and the residue was acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the crude acid. Purification by silica gel chromatography (methylene chloride/methanol 98/2) gave pure 4-(4-{[(2S,4R)-4-[(4-chlorophenyl)(cyclopropylcarbonyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2,2-dimethylbutanoic acid (85 mg, 87%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:29][CH2:30][C:31]([NH:33][C@H:34]1[CH2:39][CH2:38][C@@H:37]([N:40]([CH:48]([CH3:50])[CH3:49])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][C@H:35]1[CH2:51][OH:52])=[O:32]>C1COCC1.O>[OH:52][CH2:51][C@H:35]1[C@@H:34]([NH:33][C:31](=[O:32])[CH2:30][NH:29][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)[CH2:39][CH2:38][C@@H:37]([N:40]([CH:48]([CH3:50])[CH3:49])[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])[CH2:36]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CN)[C@H](CO)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)N(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)[C@H](CO)C1
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
A solution of 3-Trifluoromethyl-benzoic acid (0.55 g, 0.0029 mol) in THF was cooled in an ice bath and treated with N-methylmorpholine (0.3 g, 0.003 mol) and then drop-wise with isobutyl chloroformate (0.39 g, 0.0029 mol). The resulting mixture was stirred for 5 min and then treated with a solution of tert-butyl(1R,3R,4S)-4-(2-aminoacetamido)-3-(hydroxymethyl)cyclohexyl-(isopropyl)carbamate (2.8 g, 0.01 mol) in THF. The resulting mixture was stirred for 30 minutes and then diluted with water and extracted into CH2Cl2. The extract was washed with dilute NaOH, water, and brine and then concentrated under vacuum. The residue was chromatographed on silica gel (elution 55% ethyl acetate/hexane, then 100% ethyl acetate) to give 1.4 g of tert-butyl(1R,3R,4S)-3-(hydroxymethyl)-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexyl(isopropyl)carbamate as a white solid. MS found: (M+H)+=516.3.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:16])([F:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24](O)=[O:25])(=[O:19])[CH3:18].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[C:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][N:29]=1)[C:24]([NH:14][CH2:13][C:9]1[CH:8]=[C:7]([O:6][CH2:5][C:4]([F:3])([F:15])[F:16])[CH:12]=[CH:11][N:10]=1)=[O:25])(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1cc(C(=O)O)ccn1
Reactant: NCc1cc(OCC(F)(F)F)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1cc(C(=O)NCc2cc(OCC(F)(F)F)ccn2)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
To a mixture of (4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanamine dihydrochloride (20 mg, 0.070 mmol, Amine-2), 2-acetamidoisonicotinic acid (15 mg, 0.084 mmol) and N,N-diisopropylethylamine (0.049 mL, 0.28 mmol) in N,N-dimethylformamide (0.5 mL) is added a solution of HBTU (40 mg, 0.11 mmol) in N,N-dimethylformamide (0.5 mL) at room temperature. After stirring at room temperature for 2 hours, the mixture is poured into water (2 mL) and extracted with ethyl acetate (3 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on NH-silica gel eluting with ethyl acetate and then by preparative LC-MS to give 9.8 mg (38% yield) of the title compound.
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15](NC(OC(C)(C)C)=O)[C:14](=[O:32])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:33][C:34]3[C:43]4[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=4)[N:37]=[C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:35]=3)[CH2:12]1)[C:8](=[O:52])[NH:7]2)=[O:5])C.[Li+].[OH-:54]>C1COCC1.O.CO>[C:6]([O:54][C@@H:15]1[C:14](=[O:32])[N:13]2[C@:9]([N:7]=[C:8]=[O:52])([CH2:10][C@@H:11]([O:33][C:34]3[C:43]4[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=4)[N:37]=[C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:35]=3)[CH2:12]2)[C:8](=[O:52])[NH:7][C@@:6]2([C:4]([OH:3])=[O:5])[C@@H:22]([CH2:23]2)[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:23])([CH3:22])[CH3:4]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Reactant: [OH-]
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: COc1ccc2c(O[C@H]3CN4C(=O)[C@@H](OC(C)(C)C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@]4(N=C=O)C3)cc(-c3ccccc3)nc2c1
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(O[C@H]3CN4C(=O)[C@@H](OC(C)(C)C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@]4(N=C=O)C3)cc(-c3ccccc3)nc2c1

Procedure:
Following the experimental and purification procedure of Step 1i, (1S,4R,6S,13S,17R)-7-cis-13-tert-butoxycarbonylamino-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo [13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (290 mg, 0.406 mmol) was reacted with 100 mg (2.5 mmol) of LiOH in 23.9 mL of 14.4:7.7:1.8 of THF/H2O/MeOH to afford (1S,4R,6S,13S,17R)-7-cis-13-tert-butoxy-carbonylamino-17-(7-methoxy-2-phenylquin-olin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (279 mg, 100%): 1H NMR (300 MHz, CD3OD) δ 0.97-1.05 (m, 2H), 1.14 (s, 9H), 1.20-1.55 (m, 5H), 1.60-1.73 (m, 2H), 1.85 (brs, 1H), 2.06-2.22 (m, 1H), 2.29 (brs, 1H), 2.52-2.73 (m, 2H), 3.93 (s, 3H), 4.14-4.19 (m, 1H), 4.26 (d, J=9.5 Hz, 1H), 4.56-4.67 (m, 2H), 5.47-5.53 (m, 2H), 5.71-5.78 (m, 1H), 7.08 (dd, J=9.1, 2.2 Hz, 1H), 7.22 (s, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.45-7.56 (m, 3H), 8.02, 8.04 (2s, 2H), 8.09 (d, J=9.1 Hz, 1H). LC-MS (Method E-retention time: 1.60), MS m/z 685 (M++1). Step 7j: Preparation of Compound 7, Example 7 (1S,4R,65,13S,17R)-7-cis-[4-Cyclopropanesulfonylamino-carbonyl-17-(7-methoxy-2-phenylquinolin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-en-13-yl]carbamic acid tert-butyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=[O:31])=[CH:4][CH:3]=1.[C:38](Cl)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[C:9]([C:38](=[O:40])[CH3:39])=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:36][CH:37]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Product: CC(=O)c1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc12

Procedure:
The title compound was prepared according to the conditions described in Step B and Step C of Example 47, from methyl 3-[N-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy) indol-2-yl]-2,2-dimethylpropanoate (prepared in Step A of Example 47) but using acetyl chloride in place of trimethylacetyl chloride in Step B.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O.C1C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:10][CH2:11][CH2:12][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(CCCCl)c1ccc(Cl)cc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: O
Product: Cl
Product: O=S(CCCN1CCCCC1)c1ccc(Cl)cc1

Procedure:
A mixture of 2.46 g. of 1-(p-chlorophenylsulfinyl)-3-chloropropane, 0.9 g. of piperidine, 0.53 g. of sodium carbonate in 30 ml. of dimethylformamide is heated for 3 hours at a temperature of 80° - 87°C. After the reaction mixture has been cooled, a mixture of benzene and water is added thereto. The aqueous layer is separated and extracted with benzene. The organic layers are combined, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The oily residue is dissolved in ether and treated with ethanolic hydrogen chloride under cooling. The precipitate is collected by filtration and dried to give 1-[γ-(p-chlorophenylsulfinyl)-propyl]piperidine hydrochloride, m.p.: 170° - 174°C. Recrystallization from benzene gives white crystals, m.p.: 176° - 177°C.
Reaction SMILES: F[C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[CH3:15][OH:16].C[O-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:16][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1
Reactant: CO
Reactant: COC(=O)c1cc2ccsc2cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc2ccsc2cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In 35 ml of N,N-dimethylformamide is dissolved 7.00 g of methyl 6-fluorobenzo[b]thiophene-5-carboxylate, to which is added 7.1 mL of a 28% methanol solution of sodium methoxide. The mixture is stirred at 80° C. for 4 hours. Water and ethyl acetate are added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: hexane:ethyl acetate=20:1 to 3:1) to obtain 6.30 g of methyl 6-methoxybenzo[b]thiophene-5-carboxylate as an oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH:7]=1.[S:13]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](B(O)O)=[CH:24]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[CH:7]=[C:2]([C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:23]([S:13]([C:16]4[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=4)(=[O:15])=[O:14])[CH:24]=3)[CH:3]=[N:4][CH:5]=2)=[CH:9]1
Reactant: Brc1cncc(-c2ccsc2)c1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B(O)O)c3ccccc32)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: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(-c4ccsc4)c3)c3ccccc32)cc1

Procedure:
A deoxygenated solution of 3-bromo-5-thiophen-3-yl-pyridine (250 mg, 1.04 mmol, 1 equiv), 1-tosyl-3-indoleboronic acid (430 mg, 1.36 mmol, 1.31 equiv, prepared according to Zheng, Q; Yang, Y; Martin, A. R. Heterocycles 1994, 37, 1761), Pd(PPh3)4 (60 mg, 0.052 mmol, 0.050 equiv), and 2.0 M Na2CO3 (1.0 mL, 2.0 mmol, 1.9 equiv) in dioxane (10 ml) was heated under argon at reflux for 20 h. The reaction mixture was allowed to cool, then partitioned between water (100 mL) and ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (40% ethyl acetate in hexane) to afford 3-(5-thiophen-3-yl-pyridin-3-yl)-1-(toluene-4-sulfonyl)-indole as a white foam.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25].CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:28])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: CCCN=C=O
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 40 °C
Yield: 21.5 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and propylisocyanate (0.26 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (2×150 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient over 15 min). The product fractions were combined, concentrated and triturated in Et2OCH2Cl2 (50 mL) for 18 h. The product was isolated by filtration dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea as a white solid (0.24 g, 29% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 1.63 min (98.92%); mp: 166-168° C.; 1H NMR (DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H, CH3), 1.31-1.46 (m, 2H, CH2), 2.03-2.08 (m, 1H, CHH), 2.45-2.62 (m, 2H, CHH, CHH), 2.82-3.01 (m, 3H, CHH, CH2), 4.36 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.3, 12.6 Hz, 1H, CH), 6.10 (t, J=5.7 Hz, 1H, NH), 6.53 (t, J=6.0 Hz, 1H, NH), 7.71-7.89 (m, 3H, Ar), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.31, 22.01, 23.16, 30.94, 41.20, 42.74, 48.98, 121.54, 123.39, 129.51, 131.53, 133.07, 149.53, 158.03, 167.06, 167.24, 169.84, 172.74; LCMS: MH=373; Anal Calcd for C18H20N4O5+0.1H2O: C, 57.78; H, 5.44; N, 14.97. Found: C, 57.52; H, 5.37; N, 14.76.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:3]=1[NH2:4].ClC1C=CC([C:20](=[O:34])[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])=CC=1N.[CH2:35]([O:37][C:38](=[O:47])[CH:39]=[C:40](OCC)[O:41][CH2:42][CH3:43])[CH3:36]>>[CH2:35]([O:37][C:38](=[O:47])[CH:39]=[C:40]([NH:4][C:3]1[CH:5]=[C:6]([NH:9][C:20](=[O:34])[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])[CH:7]=[CH:8][C:2]=1[Cl:1])[O:41][CH2:42][CH3:43])[CH3:36]
Reactant: CCCCCCCCCCCCCC(=O)c1ccc(Cl)c(N)c1
Reactant: CCOC(=O)C=C(OCC)OCC
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC(=CC(=O)OCC)OCC)c1

Procedure:
Using the same procedure as Method (a) of Synthesis Example 1, in place of 2-chloro-5-nitroaniline, 152 g of 2-chloro-5-tetradecanoylaniline was reacted with 94 g of β,β-diethoxyacrylic acid ethyl ester at 130°-150°C for 3 hours to give β-(2-chloro-5-tetradecanoylaminoanilino)-β-ethoxyacrylic acid ethyl ester. The product was, without being isolated and purified, mixed with 106 g of 2,4,6-trichlorophenylhydrazine and 500 ml of acetic acid and the mixture was refluxed for 2 hours. After distilling off the acetic acid from the reaction product mixture under a reduced pressure, a mixture of 300 ml of acetonitrile and 300 ml of ethanol was added to the reaction product followed by heating to dissolve the product therein and the solution was, then, allowed to cool to form precipitates, which were collected by filtration and recrystallized from a mixture of 150 ml of acetonitrile and 150 ml of ethanol to give 87 g of the desired product having a melting point of 115°-118°C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([OH:31])[CH2:26]1.Cl>CO>[CH:12]([OH:19])=[O:31].[OH:31][CH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([NH:24][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:26]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCC(O)C1
Agent: Cl
Solvent: CO
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NC3CCCC(O)C3)n2n1)c1cccnc1
Product: O=CO
Temperature: 120 °C

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50.0 mg; 0.14 mmol; 1.00 eq) and 3-aminocyclohexanol (Betapharma, 84 mg; 0.73 mmol; 5.00 eq), heated at 120° C. HCl (1.5 M) in MeOH (2 mL) was added to the solid residue and the salt was precipitated by addition of Et2O, filtered and dried under vacuum, purified by Mass Directed AutoPrep and lyophilized to give the title compound as a mixture of cis:trans isomers as a white solid (11 mg, 18%). HPLC, Rt: 1.72 min. (purity 48.9%, isomer A), 1.87 min. (purity 46.6%, isomer B). LC/MS, M+(ESI): 420.9, M−(ESI): 418.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=2)=[O:22])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 97.2 %

Procedure:
To a solution of p-toluidine (0.44 g, 4.1 mmol) in 10 ml of CH2Cl2 (pre-cooled to 0° C.) are added Et3N (1.14 ml, 2 eq.) and 4-chloro-3-trifluoromethyl-benzoyl chloride (1 g, 4.1 mmol) in 5 ml of CH2Cl2. The mixture is slowly warmed to room temperature and continued to stir at room temperature for an hour. The mixture is diluted with 50 ml of CH2Cl2, washed with 1N HCl solution, and brine. The organic layer is separated, dried over MgSO4, filtered, and concentrated. The residue is purified by column chromatography (EtOAc/Hexanes, 2:3) to give 1.25 g (97%) of 4-chloro-N-p-tolyl-3-trifluoromethyl-benzamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1F.[C:12]1([NH2:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(F)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
A mixture of 1,2-difluoro-3-nitrobenzene (690 μL, 6.29 mmol), phenylamine (600 μL, 6.60 mmol) and potassium carbonate (1.74 g, 12.57 mmol) in DMSO (3 mL) was stirred at RT for 3 h and then heated to 90° C. for 4 h. After cooling to RT, the reaction mixture was partitioned between EtOAc and water. The organic layer was then washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% EtOAc in cyclohexane) followed by (Si—PCC, gradient 0-50% DCM in cyclohexane) affording (2-Fluoro-6-nitrophenyl)phenylamine as a orange/red oil (563 mg, 39%). 1H NMR (CDCl3, 400 MHz): δ 8.70 (1H, s), 8.00 (1H, d, J=8.66 Hz), 7.36-7.23 (3H, m), 7.09 (1H, t, J=7.41 Hz), 7.03-6.89 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11]>ClCCl.[O-2].[Mn+2]>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]=[O:11]
Reactant: COc1ccc(CO)c(N)c1
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(C=O)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A mixture of (2-amino-4-methoxyphenyl)methanol (20 g, 131.0 mmol) and manganese oxide (68 g, 786.0 mmol) in dichloromethane (300 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=6:1) to give the title compound (7 g, 35%) as a yellow solid. MS (ES+) C8H9NO2 requires: 151. found: 152 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][CH:22]([CH2:25][C:26](=O)[CH:27]=[CH2:28])[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[OH:30][CH2:31][CH2:32][NH:33][NH2:34].O>O1CCCC1>[OH:30][CH2:31][CH2:32][N:33]1[CH2:28][CH2:27][C:26]([CH2:25][CH:22]2[S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)=[N:34]1
Reactant: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: NNCCO
Solvent: O
Solvent: C1CCOC1
Product: CN(c1cccc2cc(C3=NCC(CC4=NN(CCO)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 57.9 %

Procedure:
A solution of N-methyl-N-{2-[5-(2-oxobut-3-en-1-yl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (223 mg) and 2-hydroxyethylhydrazine (60 mg) in tetrahydrofuran (5 mL) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (146 mg, yield 58%) as a white amorphous solid from a fraction eluted with ethyl acetate. MS: 504 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]2[S:11][CH:12]=[CH:13][CH:7]2[CH2:6]1.[Cl:18][CH2:19][C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([C:12]1[S:11][CH:8]2[CH:7]([CH2:6][N:5]([CH2:4][C:3]3[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=3[Cl:1])[CH2:10][CH2:9]2)[CH:13]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: Clc1ccccc1CN1CCC2SC=CC2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCl)C1=CC2CN(Cc3ccccc3Cl)CCC2S1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To 10.0 g (33.3 mmol) 5-(2-chloro-benzyl)-3a,4,5,6,7,7a-hexahydro-thieno[3,2-c]pyridine is added 3.18 mL (40.0 mmol) chloro-acetyl chloride and then 8.88 g (66.6 mmol) aluminium(III)-chloride. The reaction mixture is stirred 1 h at 70° C. and then a water-ice mixture is added followed by DCM. The formed precipitate is collected and dried.