Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCC(NC(C2SC=CC=2NC2C=CN=C3NC=CC=23)=O)C1)=O)(C)(C)C.[C:31]([N:38]1[CH2:43][CH2:42][CH2:41][CH:40]([NH2:44])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].[NH:45]1[C:49]2=[N:50][CH:51]=[CH:52][C:53]([NH:54][C:55]3[S:56][CH:57]=[CH:58][C:59]=3[C:60](O)=[O:61])=[C:48]2[CH:47]=[CH:46]1>>[C:34]([O:33][C:31]([N:38]1[CH2:43][CH2:42][CH2:41][CH:40]([NH:44][C:60]([C:59]2[CH:58]=[CH:57][S:56][C:55]=2[NH:54][C:53]2[CH:52]=[CH:51][N:50]=[C:49]3[NH:45][CH:46]=[CH:47][C:48]=23)=[O:61])[CH2:39]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: O=C(O)c1ccsc1Nc1ccnc2[nH]ccc12
Agent: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccsc2Nc2ccnc3[nH]ccc23)C1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 1-BOC-3-aminopiperidine instead of 1-BOC-3-aminopyrrolidine and 2-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-3-carboxylic acid instead of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid. LCMS (ESI) 442 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (1H, br. s.) 11.64 (1H, s) 8.13 (1H, d, J=5.42 Hz) 7.99 (1H, d, J=6.30 Hz) 7.53 (1H, d, J=5.91 Hz) 7.35 (1H, dd, J=3.44, 2.46 Hz) 6.96 (1H, d, J=5.42 Hz) 6.90 (1H, d, J=5.81 Hz) 6.44 (1H, dd, J=3.47, 2.00 Hz) 3.82 (1H, td, J=8.59, 4.93 Hz) 2.78 (1H, br. s.) 1.82-1.94 (1H, m) 1.66-1.77 (1H, m) 1.53 (1H, d, J=11.42 Hz) 1.31-1.45 (10H, m)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:22])=[C:16]3[C:21]=2[CH2:20][NH:19][CH2:18][CH2:17]3)=[C:8]([O:23][CH2:24][CH3:25])[CH:7]=1)[CH3:2].C(N(C(C)C)C(C)C)C.[F:36][C:37]1[CH:54]=[CH:53][C:40]([CH2:41][O:42][C:43](=O)[O:44]N2C(=O)CCC2=O)=[CH:39][CH:38]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:36][C:37]1[CH:38]=[CH:39][C:40]([CH2:41][O:42][C:43]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[C:12]([C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])=[CH:7][C:8]=4[O:23][CH2:24][CH3:25])[CH:13]=[CH:14][C:15]=3[F:22])[CH2:20]2)=[O:44])=[CH:53][CH:54]=1
Reactant: O=C(OCc1ccc(F)cc1)ON1C(=O)CCC1=O
Reactant: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CNCC3)c(OCC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CN(C(=O)OCc2ccc(F)cc2)CC3)c(OCC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3-ethoxy-4-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-phenyl]-acetic acid ethyl ester (1.49 g, 4.2 mmol, 1.00 eq.) and N-ethyldiisopropylamine (3.56 mL, 20.8 mmol, 5.00 eq.) in DCM (50 mL), carbonic acid 2,5-dioxo-pyrrolidin-1-yl ester 4-fluoro-benzyl ester (1.17 g, 4.4 mmol, 1.05 eq.) was added. The mixture was stirred at r.t. for 18 hours. The solution was diluted with sat. aq. NaHCO3 soln. (100 mL). The layers were separated. The aq. phase was extracted with DCM (2×). The comb. org. phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 100 fractions of 45 mL, Heptane 100% to Heptane+40% AcOEt) to yield the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:13][N:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[N:14]([CH3:13])[CH3:26])=[CH:18][CH:19]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (6.01 g, 25.9 mmol, 1.0 Eq.), 4-(dimethylcarbamoyl)phenylboronic acid (5.00 g, 25.9 mmol, 1.0 Eq.), Na2CO3 (5.49 g, 51.8 mmol, 2.0 Eq.) and Pd(PPh3)4 (2.99 g, 2.59 mmol, 0.1 Eq.) in acetonitrile (30 mL) and water (30 mL) were heated at 90° C. for 16 hours. After cooling to ambient temperature the precipitate was removed by filtration. The aqueous filtrate was acidified to pH4 by addition of 1M HCl and then extracted with dichloromethane (3×20 mL), dried over MgSO4 and concentrated in vacuo to give the sub-title product as a yellow solid (2.42 g, 65% Yield). 1H NMR (400.0 MHz, DMSO) δ 2.95 (3H, br s), 3.00 (3H, br s), 7.49-7.51 (2H, m), 7.58 (2H, br s), 8.15 92H, d), 8.95 (1H, s), 13.25 (1H, br s) ppm; MS (ES+) 287.13.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH3:17][O:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=O>>[CH3:17][O:18][C:19]1[C:20]([C:21]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: COc1ncccc1C(=O)O
Product: COc1ncccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 53 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-methoxynicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 163 mg, 53%) which was obtained as a white solid. MS: m/e=335.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:12])[CH2:11][CH2:10][CH2:9]1.C([Li])CCC.C(NC(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cccnc1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OC1(c2ccncc2Br)CCC1
Yield: 55.6 %

Procedure:
3-bromopyridine (1 g, 6.329 mmol) was reacted with cylcobutanone (0.93 mL, 6.369 mmol), n-butyl lithium (4.02 mL, 7.64 mmol) and diisopropyl amine (0.99 mL, 7.005 mmol) in dry THF to afford the crude product. Purification by column chromatography on silica gel (40% ethyl acetate in hexane) afforded 802 mg of the product (55% yield). LCMS Purity: 79%, m/z=227.9 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][C:5]([NH2:6])=[C:4]([F:15])[CH:3]=1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:8]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:7][C:5]([N:6]2[C:19](=[O:20])[C:18]3[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=3[C:16]2=[O:21])=[C:4]([F:15])[CH:3]=1
Reactant: Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Yield: 65 %

Procedure:
A solution of 4-chloro-5-cyclopentyloxy-2-fluoroaniline (0.50 g, 2.18 mmol) and 3,4,5,6-tetrahydrophthalic anhydride (0.398 g, 2.61 mmol) in acetic acids solution (3.0 mL) was stirred under reflux for 3 h. After completion of the reaction, water (20 mL) was added to the resulting reaction mixture and extraction was conducted with ethyl acetate (20 mL×3). The organic layers were dried with anhydrous magnesium sulfate and the solvent was distilled off under vacuum. The resulting pale yellow oil was separated and purified by silica gel column chromatography (ethyl acetate/hexane=1/8), giving N-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-3,4,5,6-tetrahydrophthalimide as a colorless clear oil (0.513 g, 1.41 mmol; yield=65%). This could be obtained as white solids upon addition of ethanol and subsequent recrystallization. MP: 69.0°-75.2° C. 1H-NMR(CDCl3,TMS,ppm): δ1.32-2.10(12H,m), 2.40(4H,m), 4.68(1H,m), 6.75(1H,d,JHF =7.0Hz), 7.20(1H, d,JHF =9.0Hz). IR (neat, cm-1): 1725, 1505, 1430, 1385, 1200.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][NH2:11].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][N:11]1[CH2:21][C:16]2[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]1=[O:13]
Reactant: COC(=O)c1ccccc1CBr
Reactant: NCCCc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2CN1CCCc1ccccc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
A mixture of 3-(2-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(2-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (275 mg, 51%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (89), 146 (100), 119 (29), 109 (25) and 91 (40).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:11][C:10]([SH:12])=[N:9][N:8]=2)=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:12][C:10]3[O:11][C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[N:8][N:9]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1nnc(-c2ccncc2)o1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nnc(-c4ccncc4)o3)C(=O)O)cc2)cc1

Procedure:
Example 39 is prepared from 5-(4-pyridinyl)-1,3,4-oxadiazole-2-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.[H-].[Na+].[CH3:13]N(C=O)C>>[CH3:13][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: CN(C)C=O
Reactant: Oc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 96 %

Procedure:
To a solution of sesamol (10.0 g, 0.072 mol) in DMF (50 ml) was added sodium hydride (2.08 g, 0.087 mol) at room temperature under argon. After stirring for 1 h, the mixture was treated with iodometharc (13.5 ml. 0.216 mol) and stirred for another 18 h. Upon the removal of the solvent the residue was extracted with ethyl acetate and washed with water, dried (Na2SO4) and concentrated to afford the title compound as a dark brown oil (10.5 g, 96%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[N:25]1[C:33]([SH:34])=[C:32]2[C:28]([N:29]=[CH:30][NH:31]2)=[N:27][CH:26]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:34][C:33]3[N:25]=[CH:26][N:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[N:29]4)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ncnc2nc[nH]c12
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ncnc4nc[nH]c34)s2)c(C(=O)C2CCCC2)c1
Yield: 25.9 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(7H-purin-6-ylsulfanyl)-thiazol-2-yl]-urea(124 mg, 28%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclo pentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 7H-purine-6-thiol (304 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH:13]1[CH2:16][CH:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:16][CH:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:14]2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CN(c2ncc(C(F)(F)F)cc2Cl)C1
Temperature: 150 °C
Yield: 34.8 %

Procedure:
2,3-Dichloro-5-(trifluoromethyl)pyridine (1.50 g, 6.94 mmol), tert-butyl azetidin-3-ylcarbamate (1.67 g, 9.72 mmol) and K2CO3 (2.88 g, 20.83 mmol) were dissolved in dry DMF (13 mL) under nitrogen atmosphere. The reaction mixture was heated in a microwave reactor at 150° C. for 15 mins. The reaction mixture was filtered and diluted with EtOAc, washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography (ISOLUTE SI (20 g), eluated with DCM, DCM/MeOH (99:1)) affording the title compound (0.85 g, 34.8%). 1H NMR (500 MHz, CDCl3): δ 1.48 (s, 9H), 4.10-4.14 (m, 2H), 4.57 (bs, 1H), 4.65 (t, 2H), 5.00 (bs, 1H), 7.61 (s, 1H), 8.28 (s, 1H); 13C NMR (125 MHz, CDCl3): δ 28.56, 41.67, 60.34, 80.45, 115.51, 117.44 (q, JC-F=33.2 Hz), 123.83 (m, JC-F=271.4 Hz), 135.06, 143.75, 155.18, 157.35; Mass Spectrum: M−H+ 350.
Reaction SMILES: [C:1]([C@:3]([NH:14][C@H:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([NH2:18])=[O:17])([CH3:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)#[N:2].C(Cl)Cl.[OH:28]S(O)(=O)=O.N>CCOC(C)=O>[C:16]([C@H:15]([NH:14][C@@:3]([CH3:13])([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[C:1]([NH2:2])=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:17])[NH2:18]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C[C@@](C)(C#N)N[C@@H](C(N)=O)c2ccccc2)cc1
Agent: N
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@](C)(N[C@@H](C(N)=O)c2ccccc2)C(N)=O)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a 500 mL flask were added nitrile 2 (10.0 g, 30.95 mmol) and CH2Cl2 (130 mL). The solution was cooled to −10° C. and H2SO4 (10 mL) was added dropwise over 15 min. The mixture was stirred for 2 h at 0° C. Ice (200 g) was added and the mixture was stirred for 1 h. The mixture was basified with 32% aq NH3 to pH 8-9, EtOAc (400 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (2×250 mL). The combined organic phases were dried over MgSO4 and were concentrated to provide 3 (11.1 g (9.99 g theoretical, the sample contains 10% w/w of EtOAc by NMR) 94%, 92.9% chemical purity, 97% de by HPLC/MS) as a white solid. HPLC/MS tR=3.04 min; m/z=342.1 (M+1)
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[CH2:24]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[N:35]=[C:36]1[N:40]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:39](=[O:48])[CH2:38][S:37]1)[CH3:25]>>[CH2:24]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[N:35]=[C:36]1[N:40]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:39](=[O:48])[C:38](=[C:14]2[N:13]([CH3:12])[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15]2)[S:37]1)[CH3:25]
Reactant: CSc1sc2c([n+]1C)CCCC2
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1cccnc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1cccnc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 4-ethylamino-3-(4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino)benzonitrile. MS(ESI): 503 (MH+).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=O)(=O)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:20].C(O)(=O)C>O>[CH2:2]([C:1]1[O:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:20]=1)[CH3:3]
Reactant: [NH4+]
Reactant: CCC(=O)OCC(=O)c1ccc(O)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc(-c2ccc(O)cc2)co1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.9 %

Procedure:
A mixture of 6.2 parts of 2-(4-hydroxyphenyl)-2-oxoethyl propanoate, 2.7 parts of ammonium acetate and 52.5 parts of acetic acid was stirred for 6 hours at reflux temperature. An additional 2.7 parts of ammonium acetate were added and stirring was continued for 5 hours at reflux temperature and overnight at room temperature. The reaction mixture was poured into water and the precipitate was filtered off, yielding a first fraction of product. The aqueous layer was extracted with methylbenzene. The extract was dried, filtered and then combined with the first product fraction. The whole was dried, filtered and evaporated, yielding 3.8 parts (66.9%) of 4-(2-ethyl-4-oxazolyl)-phenol (interm. 12).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C([O-])(C)(C)C.[K+].ClCCl>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:18][C:17]1[CH:19]=[CH:20][C:14]([O:13][C:12]([F:11])([F:21])[F:22])=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1Nc1ccc(OC(F)(F)F)cc1
Temperature: 110 °C

Procedure:
To 374 μL of 2-fluoro-nitrobenzene in 2 mL of DMSO are added 962 μL of 4-trifluoromethoxyaniline (2 equivalents) and 636 mg of potassium tert-butanolate (1.6 equivalents). The whole is heated to 110° C. for 3 hrs. Once the reaction is completed, the medium taken up in a minimum of dichloromethane is hydrolyzed and then extracted. The organic phase is successively washed with water and then with a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated under reduced pressure. A silica gel chromatography of the residue (cyclohexane and then cyclohexane/ethyl acetate: 99/1) allows 575 mg of the desired product to be isolated.
Reaction SMILES: Br.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH2:21])[S:19][CH:20]=2)=[CH:12][C:11]=1[O:22][CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24]1(C)[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([NH:21][S:30]([C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)(=[O:32])=[O:31])[S:19][CH:20]=2)=[CH:12][C:11]=1[O:22][CH3:23])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(-c2csc(N)n2)ccc1OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(-c2csc(NS(=O)(=O)c3ccccc3)n2)ccc1OCc1ccccc1
Yield: 60.8 %

Procedure:
A mixture of 0.5 g of 4-(4-benzyloxy-3-methoxy-phenyl)-thiazol-2-ylamine hydrobromide with 0.27 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored solution was poured into 50 ml of 1N hydrochloric acid and extracted three times with 50 ml of methylene chloride each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was chromatographed on 40 g of Kieselgel 60 with diethyl ether/hexane (2:1) as the eluent. Concentration of the product-containing fractions yielded 0.35 g of N-[4-(4-benzyloxy-3-methoxy-phenyl)-thiazol-2-yl]-benzenesulfonamide as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH3:9][C:10]1[Te:11][C:12]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=2[N+:14]=1[CH3:15].[CH2:21]([O:23][CH:24](OCC)OCC)[CH3:22].C(OCC)C>C1C(O)=CC=CC=1C>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[CH2:21]([O:23][CH:24]=[CH:9][C:10]1[Te:11][C:12]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=2[N+:14]=1[CH3:15])[CH3:22]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc2[te]c(C)[n+](C)c2c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: Cc1cccc(O)c1
Product: CCOC=Cc1[te]c2ccc(C)cc2[n+]1C
Temperature: 140 °C

Procedure:
2,3,5-Trimethylbenzotellurazolium trifluoromethanesulfonate (Example 33) (0.84 g, 0.002 mole) was dissolved in m-cresol (1 ml). Triethoxymethane (0.89 g, 0.006 mole) was added, and the reaction mixture was heated in a 140° C. oil bath for five minutes. After cooling, diethyl ether (25 ml) was added with stirring. The solid was isolated by filtration, washed with diethyl ether, and dried at 40° C. under vacuum. Yield 0.85 g (89% of theory). The nuclear magnetic resonance spectra of the sample were in agreement with that expected for the structural formula.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(CCCBr)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCCn2ccnc2)cc1
Temperature: 50 °C
Reaction time: 60 h
Yield: 44.3 %

Procedure:
Imidazole (1.3 g) was dissolved in. THF (15.5 ml), potassium carbonate (5.3 g) was added to the mixture, and a solution of 1-(3-bromopropyl)-4-nitrobenzene (3.1 g) in THF (15.5 ml) was added dropwise to the mixture. The mixture was stirred for 60 hours at 50° C., and cooled to room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 1-[3-(4-nitrophenyl)propyl]imidazole (1.3 g).
Reaction SMILES: [CH:1]1([N:7]([CH:32]([CH3:34])[CH3:33])[C:8](=[O:31])[C:9]2[CH:14]=[CH:13][C:12]([CH:15](O)[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)=[C:11]([O:29][CH3:30])[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CCO.S(=O)(=O)(O)O.[Pd].C(OCC)(=O)C>[CH:1]1([N:7]([CH:32]([CH3:34])[CH3:33])[C:8](=[O:31])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=3)=[C:11]([O:29][CH3:30])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1C(O)c1cc(OC)c(OC)c(OC)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N(C(C)C)C2CCCCC2)ccc1Cc1cc(OC)c(OC)c(OC)c1

Procedure:
The compound of Example 45 (800 mg, 1.81 mmol) in EtOH (20 mL) containing concentrated sulfuric acid (4 drops) is hydrogenated at 60 psi and room temperature using 5% Pd/C as catalyst. The catalyst is filtered and the filtrate concentrated in vacuo to give the crude product. The crude product is dissolved in ethyl acetate and washed twice with aqueous NaHO3 solution and then with saturated aqueous NaCl solution. After drying (Na2SO4) the organic layer is filtered and concentrated in vacuo. Purification to give the title compound is carried out by chromatography of the residue on silica gel using mixtures of ethyl acetate and hexane as the eluents.
Reaction SMILES: [CH2:1]([CH:8]1[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BrH:17].BrBr>O>[Br:17][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]1=[O:14]
Reactant: Br
Reactant: O=C1NC(=O)C(Cc2ccccc2)C(=O)N1
Agent: BrBr
Solvent: O
Product: O=C1NC(=O)C(Br)(Cc2ccccc2)C(=O)N1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-benzylbarbituric Acid (1.7 g) in 15 ml of water, cooled to 0-5° C. 1 ml of 48% hydrobromic acid are added followed by the addition dropwise of 0.437 ml of bromine into the reaction mixture. After 1 hour under stirring at a temperature below 10° C. the solid which formed is separated by filtration and washed with water. 2.17 g of the product are obtained, m.p. 164-166° C.