Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:32]1C2C(=CC=CC=2)CC[CH:33]1C(O)=O.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:27][CH2:26][C@H:25]([N:11]([CH2:10][CH:9]2[CH2:33][CH2:32][C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH2:8]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)C1CCc2ccccc2C1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CC2CCc3ccccc3C2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17]3)=[C:9]([NH:31][CH2:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:8]=2)[CH2:3]1.[CH:46]1[N:50]=[CH:49][N:48]([C:51](N2C=NC=C2)=[O:52])[CH:47]=1>C(Cl)Cl>[CH3:24][C:22]1([CH3:25])[O:23][C@@H:19]2[C@@H:18]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])[CH2:17][C@@H:16]([N:13]3[CH:12]=[N:11][C:10]4[C:14]3=[N:15][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:51]([N:48]5[CH:47]=[CH:46][N:50]=[CH:49]5)=[O:52])[CH2:3]3)=[N:8][C:9]=4[NH:31][CH2:32][CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:20]2[O:21]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)n5ccnc5)C4)nc32)[C@@H]2OC(C)(C)O[C@@H]21

Procedure:
A mixture comprising N-{(3aR,4S,6R,6aS)-6-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,2-dimethyl-tetrahydro-cyclopenta[1,3]dioxol-4-yl}-propionamide (see preparation of intermediates) (0.24 g, 0.39 mmol) and CDI (0.275 g, 1.7 mmol) in DCM is stirred at room temperature for 3 hours. Purification of the resulting mixture by chromatography on silica eluting with 0-5% MeOH in DCM yields the titled compound as a yellow oil. The compound exists as a mixture of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole which are equally suitable as precursors to ureas.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11](=[O:32])[CH:12](P(OCC)(OCC)=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:9])([CH3:8])[CH3:7].[C:33]([O:37][C:38](=[O:48])[NH:39][C:40]1[CH:45]=[C:44]([CH:46]=O)[CH:43]=[CH:42][N:41]=1)([CH3:36])([CH3:35])[CH3:34].O>C1COCC1>[C:6]([O:10][C:11](=[O:32])[C:12](=[CH:46][C:44]1[CH:43]=[CH:42][N:41]=[C:40]([NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:48])[CH:45]=1)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1cc(C=O)ccn1
Reactant: CCOP(=O)(OCC)C(CC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C=C(CC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Butyllithium (1.6 M in hexane, 14.8 ml, 23.7 mmol) was added dropwise to a solution of 2-(diethoxy-phosphoryl)-succinic acid 4-benzyl ester 1-tert-butyl ester (9.50 g, 23.7 mmol in THF (75 mL) at 0° C. under nitrogen. After stirring at 0° C. for 1 h, the solution was transferred to a solution of (4-Formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3.70 g, 16.6 mmol) in THF (75 mL). The resulting reaction mixture was stirred at 0° C. for 1 h before being allowed to warm to 25° C., and the mixture was stirred overnight. Water (400 mL) was added and the product extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried and concentrated. Flash chromatography (hexane/EtOAc, 4:1) gave 2-(2-tert-Butoxycarbonylamino-pyridin-4-ylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester 4.30 g (55%).
Reaction SMILES: [OH:1][N:2]1[CH:6]=[C:5]([I:7])[CH:4]=[N:3]1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[I:7][C:5]1[CH:4]=[N:3][N:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1
Reactant: On1cc(I)cn1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1cc(I)cn1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-4-iodopyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (98%, oil).
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:33])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][CH2:22]NC(OC(C)(C)C)=O)[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:32])[C:11]1=[O:12])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])[O-].[K+].[K+].[C:50](#[N:52])C>>[C:1]([O:4][C@H:5]([CH3:33])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]3[CH2:21][CH2:22][CH2:50][NH:52][C:16]3=[N:15][C:14]=2[N:13]([CH3:32])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CC#N
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(Br)n2CCNC(=O)OC(C)(C)C)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc3n2CCCN3)n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
(R)-1-(5-acetoxyhexyl)-8-bromo-7-(2-(N-tert-butoxycarbonylamino)ethyl)-3-methylxanthine (6.10 g, 11.2 mmol) was added to a solution of trifluoroacetic acid (50 ml) and dichloromethane (50 ml) and stirred at room temperature for 3 hours. Concentration under reduced pressure provided an oil to which was added acetonitrile (30 ml) followed by potassium carbonate (13.8 g, 100 mmol). The mixture was stirred at 650° C. for 3 hours and filtered to remove solids. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate-methanol (4:1) to provide (R)-3-(5-acetoxyhexyl)-1-methyl-6,7,8,9-tetrahydro-pyrimido[2,1-f]purine-2,4(1H,3H)-dione (3.58 g, 88% yield) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[NH:24]([C:26]([O:28][CH3:29])=[O:27])[NH2:25].O>CO>[Cl:1][CH:2]1[C:10](=[C:11]=[N:25][NH:24][C:26]([O:28][CH3:29])=[O:27])[C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]1[C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: COC(=O)NN
Reactant: O=Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Solvent: CO
Solvent: O
Product: COC(=O)NN=C=C1c2cc(Cl)c(Cl)cc2N([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)C1Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(β-D-ribofuranosyl)indole (4.3, 122 mg, 0.32 mmol) was dissolved in MeOH (10 mL) to which was added methyl hydrazinocarboxylate (115 mg, 1.3 mmol). The resulting solution was heated on a 60 C oil bath for 16 h, then cooled to room temperature and poured into 100 mL of water, and the solvent evaporated to approx 50 mL. The resulting suspension was cooled to 4 C, then filtered and the solids rinsed with cold water (25 mL). The solids were recrystallized from boiling EtOAc/hexane to yield 123 mg (85%) of 4.31 as a pale pink crystalline solid: mp 217-219 C; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 11.17 (b, 1H, D2O exch.), 8.54 (s, 1H), 8.42 (s, 1H), 8.22 (b, 1H), 5.92 (d, 1H), 5.42-5.37 (m, 2H, D2O exch.), 5.25 (d, 1H, D2O exch.), 4.43 (q, 1H), 4.15 (d, 1H), 3.98 (d, 1H), 3.72 (b, 5H). 13C-NMR (125 MHz, DMSO-d6): δ 153.88, 133.17, 129.33, 126.08, 124.96, 124.06, 122.17, 115.34, 108.59, 88.76, 86.03, 71.30, 69.73, 69.62, 61.07, 52.04. HRMS (ES) m/z calcd. for C16H16Cl3N3O6.Na 474.0002. found 473.9999. Anal calcd for C16H16Cl3N3O6.¼H2O: C, 42.03; H, 3.64; N, 9.19. Found: C, 42.11; H, 3.92; N, 9.18.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.C(OCC)(=O)C>[CH2:1]([O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCCCOc1ccccc1CO

Procedure:
12.4 g (90.5 mmol) of butyl bromide, 11.2 g (90.5 mmol) of 2-hydroxybenzyl alcohol and 12.5 g (90.5 mmol) of potassium carbonate in 270 ml of 2-propanol are heated at reflux overnight. The suspension is cooled, taken up in ethyl acetate and washed with 1N aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl.[Pd](Cl)Cl.C(#N)C.C(#N)C>[C:22]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:5][CH:4]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCN(c2cccc3ccc([Sn](C)(C)C)cc23)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2cccc3ccc(C(=O)c4ccccc4)cc23)CC1
Temperature: 25 °C

Procedure:
7-Trimethylstannyl-1-(4-methyl-1-piperazinyl)-naphthalene (0.1 g, 0.27 mmol), benzoyl chloride (0.031 mL, 0.27 mmol) and bis (acetonitrile) palladium chloride (0.007 g, 0.027 mmol) were combined in chloroform (5 mL) and heated to 60° to 65° C. for 15 minutes. The reaction was cooled to room temperature and saturated aqueous ammonium chloride (10 mL) and chloroform (10 mL) were added, Phases were separated and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to a milky oil. The oil was purified by flash chromatography on silica gel (1×6 inches), the product eluting with 5% methanol/ethyl acetate as a yellow oil (0.07 g, 79%). The oil was crystallized from ether to obtain a bright yellow solid: mp 124°-124.5° C. Analysis calculated for C22H22N2O: C, 79.97; H, 6.71; N, 8.48. Found: C, 79.74; H, 6.69; N, 8.46.
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])O.[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[CH:11][CH:12]=4)=[CH:8][CH:7]=1)=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3>O>[CH:6]1[C:15]2[C:16]3[C:25]([C:13]4[C:14]=2[C:9]([CH:10]=[C:11]([S:1]([OH:3])(=[O:5])=[O:4])[CH:12]=4)=[CH:8][C:7]=1[S:1]([OH:5])(=[O:4])=[O:3])=[N:24][C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]=3
Reactant: c1cc2c3c(cccc3c1)-c1nc3ccccc3nc1-2
Reactant: O=S(=O)(O)O
Solvent: O
Product: O=S(=O)(O)c1cc2c3c(cc(S(=O)(=O)O)cc3c1)-c1nc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
As represented by the following reaction pathway, after 30% fuming sulfuric acid (2.1-liter) was added to 300 g of acenaphtho[1,2-b]quinoxaline obtained by synthesis example 1 and the mixture was stirred at room temperature for 24 hours, the resultant was heated to 130° C. and stirred for 32 hours for reaction. While keeping the obtained solution at 40° C. to 50° C., 4.5-liter of ion exchange water was added for dilution, and the resultant was further stirred for 3 hours. The precipitate was filtered and recrystallized with sulfuric acid to obtain acenaphtho[1,2-b]quinoxaline-2,5-disulfonic acid as represented by the following formula (c).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.[Cu](I)I>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: Brc1ccccn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1Nc1ccccn1
Temperature: 160 °C
Yield: 26.9 %

Procedure:
Under the atmosphere of nitrogen gas, 15.0 g (109 mmol) of 2-nitroaniline, 17.2 g (109 mmol) of 2-bromopyridine, 2.06 g (10.9 mmol) of copper iodide and 30 g (218 mmol) of potassium carbonate were stirred with heating at the temperature of 160° C. for 9 hours. The reacted solution was cooled down to room temperature, diluted with ethyl acetate and filtered. After concentrating the filtrate, it was refined with silicagel column chromatography, and 6.30 g of 2-nitro-N-pyridyl aniline was obtained (yield: 27%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[C:4]([CH3:29])[N:3]=1.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=1>>[Cl:40][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][NH:30][C:2]2[N:3]=[C:4]([CH3:29])[CH:5]=[C:6]([C:8]3[CH:28]=[CH:27][CH:26]=[C:10]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]4[CH3:25])[CH:9]=3)[N:7]=2)[CH:38]=[CH:37][C:36]=1[OH:39]
Reactant: Cc1cc(-c2cccc(CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c2)nc(Cl)n1
Reactant: NCCc1ccc(O)c(Cl)c1
Product: Cc1cc(-c2cccc(CN3CCNC[C@@H]3C)c2)nc(NCCc2ccc(O)c(Cl)c2)n1

Procedure:
Intermediate 150 from above was coupled with 4-(2-aminoethyl)-2-chlorophenol following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 452. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.6 (d, 1H) 8.3 (d, 1H) 7.9 (d, 1H) 7.7 (t, 1H), 7.5 (s, 1H), 7.2 (s, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 4.12-3.9 (m, 5H) 3.8-3.47 (m, 6H), 2.9 (t, 2H), 2.6 (s, 3H), 1.6 (d, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][S:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:46])(=[O:45])[N:43](COCC[Si](C)(C)C)[C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:1]1([CH2:7][CH2:8][S:9][C:10]2[N:15]=[N:14][C:13]([C:16]3[CH:57]=[CH:56][C:19]([CH2:20][C:21]4[N:22]([C:34]5[CH:35]=[C:36]([N:40]6[S:44](=[O:46])(=[O:45])[NH:43][C:42](=[O:55])[CH2:41]6)[CH:37]=[CH:38][CH:39]=5)[CH:23]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=5[Cl:33])[N:25]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(SCCC5CCCCC5)nn4)cc3)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(SCCC5CCCCC5)nn4)cc3)c2)S(=O)(=O)N1

Procedure:
5-{3-[2-{4-[6-(2-Cyclohexyl-ethylsulfanyl)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (17 mg, 0.02 mmol) was treated as described in general procedure W using tetrabutylammonium fluoride (26 mg, 0.1 mmol) to give 5-{3-[2-{-4-[6-(2-cyclohexyl-ethylsulfanyl)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH2:35])[CH2:27][CH2:26]1.Cl>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:31]/[CH:32]=[CH:33]/[CH2:34][NH:35][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:16][CH:15]=2)[CH2:29][CH2:30]1
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Agent: Cl
Product: COc1ccccc1N1CCN(C/C=C/CNC(=O)c2ccc(-c3ccccn3)cc2)CC1
Yield: 65 %

Procedure:
Prepared from 4-pyridin-2-yl-benzoic acid hydrochloride and 4-(4-(2-methoxyphenyl)-piperazin-1-yl)-trans-but-2-enyl amine according to the general procedure. Yield: 65%. Mp. (hydrochloride): 168-170° C. 1H NMR (400 MHz, CDCl3): δ 2.70 (s, 4H), 3.12 (s, 6H), 3.86 (s, 3H), 4.13 (m, 2H), 5.78-5.85 (m, 2H), 6.43 (m, 1H), 6.85-7.02 (m, 4H), 7.27 (s, 2H), 7.77 (s, 2H), 7.90 (d, J 7.5, 2H), 8.06 (d, J 8.1, 2H), 8.72 (d, J 3.1, 1H). 13C NMR (101 MHz, CDCl3): δ 41.0, 50.9, 53.7, 55.8, 60.7, 111.6, 118.7, 121.3, 121.4, 123.2, 123.5, 127.5, 127.9, 129.1, 130.5, 135.0, 137.4, 141.6, 142.7, 150.3, 152.7, 156.7, 167.4. Anal. (O27H30N4O2.3HCl.4H2O) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=[CH:8][C:6]=2[N:7]=1.[NH2:26][CH2:27][C@@H:28]([OH:30])[CH3:29]>>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([NH:26][CH2:27][C@@H:28]([OH:30])[CH3:29])=[O:15])=[CH:8][C:6]=2[N:7]=1
Reactant: C[C@H](O)CN
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Product: C[C@H](O)CNC(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with (S)-(+)-1-amino-2-propanol via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide. 3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-((S)-2-hydroxypropyl)benzamide (56 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 24.8 mg of 336. MS (Q1) 515.2 (M)+
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:17])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-phenylpentanoic acid (0.14 g, 0.81 mmol) in anhydrous dichloromethane (5 mL) was added two drops of N,N-dimethylformamide, followed by the addition of oxalyl chloride (0.11 g, 0.89 mmol). The reaction was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to dryness to afford 5-phenylpentanoyl chloride (0.16 g, 0.81 mmol) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]([NH2:41])(=[NH:40])[CH3:39]>>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH:41][C:38](=[NH:40])[CH3:39])=[O:16])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: CC(=N)N
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=N)NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2

Procedure:
9-Bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid 28, triphenylphosphine, and acetamidine were reacted to give 29.
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:7]2=[CH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:17](Br)[C:18]1C=CC=C[CH:19]=1>>[CH2:1]([N:5]1[C:10](=[O:11])[CH:9]=[C:8]2[C:12]([CH3:16])([CH3:15])[CH2:13][NH:14][C:7]2=[CH:6]1)[C:2]1[CH:4]=[CH:19][CH:18]=[CH:17][CH:3]=1
Reactant: CC(C)Cn1cc2c(cc1=O)C(C)(C)CN2
Reactant: BrCc1ccccc1
Product: CC1(C)CNc2cn(Cc3ccccc3)c(=O)cc21

Procedure:
Prepared in an analogous method to 6-isobutyl-3,3-dimethyl-1,2,3,6-tetrahydro-pyrrolo[2,3-c]pyridin-5-one using benzyl bromide instead of 3-bromo-2-methylpropene and omitting the hydrogenation step (see Preparations 128 and 130).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[C:22]([N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:37][CH:34]2[CH2:33][CH2:32][N:31]([C:22]3[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:24][N:23]=3)[CH2:36][CH2:35]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 78.4 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (200 mg, 0.667 mmol) was dissolved in dry DMF (2 mL) under nitrogen atmosphere. 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (188 mg, 0.674 mmol) was added followed by TEA (68 mg, 0.667 mmol) and the reaction mixture was heated in a microwave reactor at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (284 mg, 77.6%). 1H NMR (500 MHz, CDCl3): δ 1.46-1.54 (m, 2H), 1.73-1.79 (m, 1H), 2.51 (t, 2H), 3.12-3.19 (m, 1H), 3.79-3.82 (m, 2H), 5.28 (d, 1H), 7.44-7.46 (m, 3H), 7.53-7.55 (m, 2H), 7.72 (s, 1H), 8.33 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 27.82, 32.36, 47.43, 50.27, 61.80, 107.32, 120.35 (q, J=33.4 Hz), 121.28, 123.48 (q, J=271.3 Hz), 125.36, 128.94, 130.17, 131.85, 134.16, 136.15, 143.10, 159.87, 160.06; Mass Spectrum: M+H+ 543.1.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9].[C-:16]#[N:17].[Na+]>CS(C)=O.O>[C:16]([CH2:3][C:4]1[N:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])#[N:17]
Reactant: [C-]#N
Reactant: Cc1[nH]c(-c2ccccc2)nc1CCl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1[nH]c(-c2ccccc2)nc1CC#N
Reaction time: 2 h

Procedure:
A solution of 48.6 g (0.2 mole) of 4-chloromethyl-5-methyl-2-phenylimidazole hydrochloride [see Cornforth & Huang, J. Chem. Soc., 731 (1948)] in 200 ml of DMSO is added (over 20 minutes) to a rapidly stirred solution of sodium cyanide, prepared by dissolving 29.4 g (0.6 mole) of sodium cyanide in 70 ml of water and adding 200 ml of DMSO, at 0° to 5° C. [slightly modified procedure of W. Schultze, J. Prakt. Chem. 19, 91-100 (1922)]. The reaction mixture is stirred in the cold for 2 hours and then poured onto a slight excess of cracked ice which causes a semicrystalline gum to separate (Crop A). The gum is quickly filtered off and to the filtrate is added sufficient aqueous sodium carbonate (10%) to give a volume of 2 liters. The mixture is allowed to stand overnight during which time a second crop (about 12-13 g) crystallizes (Crop B). Extraction of the mother liquor with ethyl acetate gives an aditional (about 2-3 g) yield (Crop C). Crop A is recrystallized from benzene-Norite B. Crop C is recrystallized from benzene. The resulting crystals are combined with Crop B. Repeated recrystallizations from benzene gives a pure product of 4-cyanomethyl-5-methyl-2-phenylimidazole, m.p., 132°-140° C. Treatment with a mineral acid, e.g., sulfuric, hydrobromic and the like, affords the corresponding acid addition salts.