Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][S:37]([NH2:40])(=[O:39])=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([NH:34][CH2:35][CH2:36][S:37](=[O:39])(=[O:38])[NH2:40])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: NCCS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NS(=O)(=O)CCNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 24.6 %

Procedure:
4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (500 mg, 1.042 mmol), 2-aminoethanesulfonamide (142 mg, 1.146 mmol), HATU (594 mg, 1.563 mmol), and Hunig's Base (0.910 mL, 5.21 mmol) were stirred in DCM (Volume: 5 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-(2-sulfamoylethyl)benzamide (150 mg). 1H NMR (400 MHz, MeOD) δ ppm 1.31-1.42 (m, 4H), 3.34-3.40 (m, 2H), 3.79-3.89 (m, 2H), 4.86-4.92 (m, 2H), 7.20-7.33 (m, 4H), 7.58-7.71 (m, 3H), 7.76-7.89 (m, 1H); LC-MS (Condition A), MS m/z (M++H) 585.9.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[CH2:26]([NH:29][C:30]([NH2:32])=[O:31])[C:27]#[CH:28]>CN(C=O)C.I[Cu].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>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]#[C:27][CH2:26][NH:29][C:30]([NH2:32])=[O:31])=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: C#CCNC(N)=O
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3nc(C#CCNC(N)=O)cnc3N)[nH]c2c1
Yield: 82 %

Procedure:
5-Bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (50 mg, 0.1644 mmol), Et3N (166.4 mg, 229.2 μL, 1.644 mmol), iodocopper (31.3 mg, 0.1644 mmol), Pd(PPh3)4 (9.5 mg, 0.0082 mmol) and the relevant prop-2-ynylurea (24.2 mg, 0.2466 mmol) in DMF (2 mL) were heated at 100° C. for 30 minutes under microwave conditions. The reaction mixture was purified directly by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (43.3 mg, 82% Yield). 1H NMR (400.0 MHz, DMSO) δ 2.45 (3H, s), 4.7 (2H, s), 6.1 (1H, s), 7.1-7.15 (1H, m), 7.4 (1H, vbr s), 7.6 (1H, vbr s), 7.85 (2H, s), 8.65 (1H, s), 9.5-9.7 (2H, m), 10.6 (1H, br s); MS (ES+) 332.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.O>[C:16]1(=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:26]3[CH:27]=[CH:28][O:24][CH:25]=3)=[CH:3][CH:4]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Oc1ccc(C(=C2CCCCCCC2)c2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(C(=C2CCCCCCC2)c2ccc(-c3ccoc3)cc2)cc1
Yield: 76 %

Procedure:
The procedure described for 202 was used. A round-bottomed flask was charged with 4-[(4-bromophenyl)(cyclooctylidene)methyl]phenol (9) (0.150 g, 0.404 mmol), PdCl2(PPh3)2, (0.028 g, 0.40 mmol), 3-furanylboronic acid (0.090 g, 0.80 mmol), Na2CO3 (0.086 g, 0.808 mmol), and THF/H2O (4:1, 5 mL). The reaction mixture was refluxed for 10 h. Upon usual work-up and purification by flash silica gel chromatography provided 0.110 g (76%) of compound 204 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.10 (s, 1H), 7.70 (s, 1H), 7.50 (d, J=6.00 Hz, 2H), 7.11 (d, J=6.00 Hz, 2H), 6.94 (d, J=6.3 Hz, 2H), 6.89 (s, 1H), 6.67 (d, J=6.3 Hz, 2H), 2.19 (br s, 4H), 1.60 (br s, 2H), 1.50-1.45 (m, 8H). LCMS (ESI): m/z 359 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(Cl)Cl.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:33]1([CH2:32][CH2:31][NH:39][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCCc2ccccc2)c1
Reaction time: 18 h

Procedure:
Made in the same manner as EXAMPLE 62 using 2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (37.2 mg), CH2Cl2 (2 mL), triethylamine (72 μL), phenethylamine (39 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg) and 4-dimethylaminopyridine (˜1 mg). Run for 18 h then concentrated under reduced pressure and purified by silica gel chromatography (98:2 CH2Cl2:MeOH) to yield 21.6 mg of the title compound. 1H NMR (500 MHz, CDCl3 partial): δ 8.48 (br s, 1H); 8.40 (d, J=5.5 Hz, 1H); 7.84 (m, 2H); 7.56 (m, 2H); 7.42 (t, J=7.7 Hz, 1H); 6.80 (d, J=5.5 Hz,1H); 6.10 )br s, 1H); 5.69 (br s, 1H); 5.23 (br s, 1H); 3.72 (m, 2H); 2.94 (t, J=7.0 Hz, 2H); 1.65 (d, J=6.9 Hz, 3H). Mass Spectrum (ESI): m/e 463.2 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([CH3:33])[CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:31]([O:30][C:28](=[O:29])[CH:22]([CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH:21]([CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)[CH3:33])[CH3:32]
Reactant: CCOC(=O)C(CSC(C)=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CSC(C)=O)C(C)C1CCNCC1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
TFA (2 mL) was added to a solution of 4-(3-acetylsulfanyl-2-ethoxycarbonyl-1-methyl-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.439 mmol) in methylene chloride (10 mL). The reaction was stirred for 90 min and concentrated under reduced pressure. The crude product was purified using HPLC (10→50% acetonitrile in water, 0.1% TFA) to give 2-acetylsulfanylmethyl-3-piperidin4-yl-butyric acid ethyl ester (101 mg, 54%) as the TFA salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:40])([CH3:39])[C:35](=O)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.FC(F)(F)C(O)=O>C(O)C>[CH2:1]([O:8][C:9]1[C:10]2[CH2:29][C@:28]3([CH3:42])[C@@H:30]([CH3:41])[CH2:31][CH2:32][C@H:33]4[C:34]([CH3:39])([CH3:40])[C:35](=[N:43][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[CH2:36][CH2:37][C@@:27]34[O:26][C:11]=2[C:12]2[CH2:13][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:15](=[O:18])[C:16]=2[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=O)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reactant: NN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: C[C@H]1CC[C@H]2C(C)(C)C(=NN3CCOCC3)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
To a solution of Compound (37) (573 mg, 1.00 mmol) in 60 ml of ethanol were added 306 mg (3.00 mmol) of N-aminomorpholine and 328 μl (3.51 mmol) of trifluoroacetic acid. The reaction was allowed to proceed for 72 hours. The reaction mixture was then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 100 g; n-hexane:ethyl acetate=7:3) to give 265 mg (40%) of Compound (60).
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14][O:15][CH2:16][CH3:17])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)C[OH:36]>>[NH:1]([C:8]1[C:13]([CH2:14][O:15][CH2:16][CH2:17][OH:36])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Agent: Cl
Product: CN(C)CC(O)COc1ccc(Nc2ncc(COCCO)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 70 mg, 0. 16 mmol) was dissolved in ethylene glycol (2 ml). Ethereal hydrogen chloride (1.0M; 0.32 ml, 0.32 mmol) was added, and the solution was heated at 100° C. for 20 hours. Volatile material was removed by evaporation and the residue was triturated with diethyl ether, giving the product as a dihydrochloride salt (43 mg). NMR (CDCl3): 2.34 (s, 6H), 2.3-2.6 (m, 2H), 3.63 (t, 2H), 3.73 (s, 1H), 3.86 (t, 2H), 3.96 (d, 2H), 4.08 (m, 1H), 4.54 (s, 2H), 6.86 (d, 2H), 6.88 (s, 1H), 7.08 (t, 1H), 7.30 (dd, 2H), 7.43 (d, 2H), 7.58 (d, 2H), 7.88 (m, 2H); MS (MH+): 454.3.
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:41])[C:35]#[C:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:30][CH:29]=1>C(#N)C>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([C:35]2[C:36]([CH2:37][CH2:38][CH2:39][CH3:40])=[N:14][N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=23)=[O:41])=[CH:32][CH:33]=1
Reactant: N[n+]1ccccc1
Reactant: CCCCC#CC(=O)c1ccc(Br)cc1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nn2ccccc2c1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2.5 g of N-aminopyridinium mesitylene sulfonate (prepared by Synthesis, 1977 page 1, TAMURA, et al.), 25 ml of acetonitrile and 3.5 g of potassium carbonate was stirred for 15 minutes at ambient temperature and then the 2.27 g of the product of Step A in solution in 25 ml of acetonitrile were added.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:16])[O:9][C:10]([C:12]([F:15])([F:14])[F:13])=[N:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)[CH:20]=[CH:21][CH3:22])C>>[F:13][C:12]([F:15])([F:14])[C:10]1[C:21]([CH3:22])=[CH:20][C:5]2[C:6](=[C:7]([C:8]([OH:9])=[O:16])[C:2]([Cl:1])=[CH:3][CH:4]=2)[N:11]=1
Reactant: CC=CN(CC)CC
Reactant: O=c1oc(C(F)(F)F)nc2cccc(Cl)c12
Product: Cc1cc2ccc(Cl)c(C(=O)O)c2nc1C(F)(F)F
Yield: 41 %

Procedure:
2-trifluoromethyl-3-methyl-7-chloroquinoline-8-carboxylic acid of melting point 186°-188° C. is prepared, in a yield of 41%, from 5-chloro-2-trifluoromethyl-3,1-benzoxazin-4-one and 1-diethylaminoprop-1-ene, using a method similar to that described in Example 3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])[CH3:2].[N+](=[CH2:19])=[N-]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([CH:5]1[CH2:19][CH:6]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[F:15])=[O:16])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)/C=C/c1ccc(OC)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1c1ccc(OC)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
(E)-3-(2-Fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester (0.3 g, 1.34 mmol) obtained in Step A was dissolved in THF (10 mL), and diazomethane solution (21.4 mL, 5.36 mmol, 0.25M ether) was added thereto. After the reactant was cooled to 0˜5° C., palladium(II) acetate (45 mg, 0.2 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 5 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title compound (0.16 g, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:16](=O)[CH2:17][CH3:18])[C:12](=O)[CH2:13][CH3:14].Cl.[C:27]([CH2:32][NH:33][NH2:34])([O:29][CH2:30][CH3:31])=[O:28].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:16]([CH2:17][CH3:18])=[N:34][N:33]([CH2:32][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:12]=1[CH2:13][CH3:14]
Reactant: CCC(=O)C(CCCCCCOc1ccc(OC)cc1Cl)C(=O)CC
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1nc(CC)c(CCCCCCOc2ccc(OC)cc2Cl)c1CC
Yield: 74.1 %

Procedure:
A mixture of 18.45 g of 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-heptanedione, 7.73 g of carbethoxymethylhydrazine hydrochloride and 5 g of triethylamine in 100 ml of absolute ethanol was heated at reflux for 8 hours. The product was isolated and distilled to give 16.7 g of ethyl 4-[6-(2-chloro-4-methoxyphenoxy)hexyl]-3,5-diethyl-1H-pyrazol-1-acetate as a pale yellow oil, b.p. 205°-210° C. (0.05 mm); MIC=6-12 microg/ml (herpes 1 and 2).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=O)[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:14]([C:15](=[S:33])[CH:16]=2)=[CH:13][CH:12]=[CH:11][C:10]=3[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:3][CH2:2]1
Reactant: O=c1cc(N2CCOCC2)oc2c(-c3ccccc3)cccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: S=c1cc(N2CCOCC2)oc2c(-c3ccccc3)cccc12
Temperature: 130 °C
Yield: 135.1 %

Procedure:
A 2 mL conical microwave vial was charged with a magnetic stirring bar, 2-morpholino-8-phenyl-4H-chromen-4-one (LY294002) (150 mg, 488 μmol), Lawesson's reagent (118 mg, 293 μmol), and toluene (2 mL). The reaction mixture was sealed, and the reaction mixture was magnetically stirred and heated via microwave irradiation to 130° C. for 20 minutes. The final mixture was poured onto water (approximately 30 mL), extracted with dichloromethane (3×5 mL), the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification via column chromatography (silica gel; hexanes/ethyl acetate (1:1), then 100% ethyl acetate) afforded pure 2-morpholino-8-phenyl-4H-chromene-4-thione (68) (128 mg, 81% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:14]=[C:13]([O:12][CH3:11])[C:18]=1[O:19][CH3:20]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]ccc3c2)cc(OC)c1OC
Yield: 83.6 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.54 g, 7.83 mmol), 3,4,5-trimethoxyphenylboronic acid (1.83 g, 8.61 mmol) and dichlorobis(triphenylphosphine)palladium (II) (275 mg, 0.39 mmol) were combined in CH3CN (10 ml) and 1 M Na2CO3 (10 ml) and reacted in a microwave reactor for 5 min at 150° C. EtOAc was added and the mixture was washed with water, brine, dried, evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to yield 1.86 g (84%) of the title compound. 1H NMR (CDCl3, 300 MHz): δ 9.9 (bs, 1H), 8.54 (d, J=2.1 Hz, 1H), 8.11 (d. J=2.1 Hz, 1H), 7.41 (t, J=2.1 Hz, 1H), 6.82 (s, 2H), 6.58 (t, J=1.5 Hz, 1H), 3.96 (s, 6H), 3.92 (s, 3H).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30][CH2:29][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:27][CH2:26][N:25]([CH2:56][C:57]([OH:59])=[O:58])[CH2:24][CH2:23]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:62][C:63]([N:65]([CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[O:64]>C1(C)C=CC=CC=1>[C:12]1([CH2:18][O:19][C:20](=[O:60])[CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH2:56][C:57]([O:59][CH2:62][C:63]([N:65]([CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:84][CH2:85][CH2:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH3:101])=[O:64])=[O:58])[CH2:26][CH2:27][N:28]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[CH2:29][CH2:30][N:31]([CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:32][CH2:33]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)CBr
Reactant: O=C(O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COC(=O)CN1CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CCN(CC(=O)OCc2ccccc2)CC1
Yield: 68 %

Procedure:
DBU (820 μL; 5.5 mmol) was added to a suspension of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tris(phenylmethyl)ester (prepared according to Step E3 of Example 17) (3.71 g; 5.5 mmol) in toluene (350 mL) obtaining a clear solution, then 2-bromo-N,N-dioctadecylacetamide (prepared according to Example 5, Step A) (3.9 g; 6.05 mmol) dissolved in toluene (50 mL) was added dropwise. After 2 h the reaction mixture was filtered and the solvent was evaporated. The crude was suspended in CH3CN (50 mL) and the insoluble was filtered off with a paper filter. The solution was evaporated obtaining the desired product (4.63 g; 3.74 mmol). Yield 68%. The 13C-NMR, MS and IR spectra were consistent with the structure.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH2:14][CH:10]([C:11]([OH:13])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:18]1([NH:17][C:11]([CH:10]2[CH2:14][CH2:15][CH2:16][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9]2)=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of N-Boc-nipecotic acid 33 (102 mg, 0.445 mmol) and aniline (41 μL, 1.0 eq.) in 2 mL of dry CH2Cl2 was added DCC-resin (430 mg). The reaction mixture was shaken at room temperature overnight. Filtration and removal of the solvent gave oily crude product, which was purified by flash column chromatography (silica gel, hexane:ethyl acetate) to afford 1-Boc-piperidine-3-carboxylic acid phenyl amide 34 as a colorless oil (120 mg, 89%).
Reaction SMILES: [Mg].Br[C:3]([O:16][C:17](C1C=CC=CC=1)(Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1C=CC=C[CH:11]=1)[C:4]1C=CC=[CH:6][CH:5]=1.[CH:31]12[O:37][CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36]2>C1COCC1.C(OCC)(=O)C.[Cu]Cl>[CH2:17]([O:16][C:3]1[CH:4]=[CH:5][CH:6]=[CH:11][C:10]=1[C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1CCC2OC2C1
Reactant: BrC(OC(Br)(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Cu]
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A 1 L round bottom flask equipped with a mechanical stirrer, addition funnel, condenser, and nitrogen inlet is charged with 6.6 g (0.27 mol) of magnesium turnings and 25 ml of dry tetrahydrofuran. To this stirred mixture a solution of 50 g (0.27 mol) of bromophenyl benzylether in 50 ml of dry THF is added dropwise. The reaction needs to be heated (30°-40° C.) at first to initiate it but then the heating mantel is removed and the temperature maintained by the rate of addition. Once the addition is complete the reaction is held at 45°-50° C. for 2 hours, then 300 ml of dry THF is added. The solution is cooled to -30° C. and 1.2 g (0.012 mol) of copper (I) chloride is added. The resulting mixture is stirred for 10 minutes and then a solution of 26 g (0.265 mol) of cyclohexene oxide in 30 ml of THF is added dropwise over 1 hour. Upon completion of the addition the reaction is allowed to warm to 0° C. and stirred for 2 hours, then diluted with 300 ml of ethyl acetate and quenched by addition of 150 ml of saturated aqueous ammonium sulfate solution. The organic phase is separated and washed with another 75 ml of ammonium sulfate solution. The combined aqueous phases are extracted with 100 ml of ethyl acetate. The organic phases are combined, dried with magnesium sulfate, and evaporated under reduced pressure to yield 65 g of trans-2-(2'-benzyloxyphenyl)cyclohexanol as an amber oil, which is used directly in the next step.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1([C:29](=[O:31])[CH3:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:26]5[CH2:27][CH2:28][N:23]([C:29](=[O:31])[CH3:30])[CH2:24][CH2:25]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(=O)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(piperazin-1-yl)ethanone (1.2 equiv) to give 179 (13.5 mg, M+1 424.1)