Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9]Cl.Cl>[Zn].O>[OH:8][C:5]1[C:6](=[O:7])[CH:1]=[C:2]([CH3:9])[O:3][CH:4]=1
Reactant: O=c1cc(CCl)occ1O
Agent: Cl
Agent: [Zn]
Solvent: O
Product: Cc1cc(=O)c(O)co1
Temperature: 50 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
Chloro-kojic Acid (20.0 g; 125 mmol)—an inhibitor of tyrosinase with an EC50 of 6.8 μM—was added in portions to HPLC grade water (60 mL) and heated with an oil bath to ˜50° C. Zinc dust (16.2 grams) was carefully added in portions (5 min). An addition funnel was then attached. The reaction temperature was then increased to ˜70° C. and concentrated HCl (37 mL) was added drop-wise over 60 min; the reaction was vigorously stirred for an additional 3 hours. Next, excess zinc was removed via hot Büchner filtration. Standard extraction and purification methods afforded allomaltol (10.3 g; 81.7 mmol; 65% yield); see Liu, Z. D. et al, Bioorg. Med. Chem. 2001, 9, 563-573. Allomaltol was found to be a more potent inhibitor of tyrosinase than kojic acid with an EC50 of 3.4 μM. 1H NMR (DMSO-d5) δ 9.3-8.3 (br s, 1H; 5-OH); 7.97 (s, 1H; 6-H); 6.23 (s, 1H; 3-H); 2.24 (s, 3H; 2-CH3).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[SH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]O.Cl>ClCCl>[S:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][O:6][CH:5]1[C:4]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: OCc1ccccc1S
Reactant: COc1cc(C=O)cc(O)c1OC
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C2OCc3ccccc3S2)cc(O)c1OC

Procedure:
Following the same procedure as outlined in Example 1 step b), 3-hydroxy-4,5-dimethoxybenzaldehyde (1.08 g, 5.95 mmol) and (2-mercaptophenyl)methanol (1 g, 7.14 mmol) in dichloromethane (30 ml) %% ere treated with hydrogen chloride gas. After workup and chromatography, as in example 1 step b), the subtitle compound was obtained (1.06 g, 59%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 3.88 (s, 3H); 3.89 (s, 3H); 5.04-5.14 (m, 2H); 5.85 (s, 1H); 6.01 (s, 1H); 6.72 (d, J=2 Hz, 1H); 6.76 (d, J=2 Hz, 1H); 6.98-7.04 (m, 1H); 7.05-7.19 (m, 3H); 13C NMR (75 MHz, CDCl3, ppm) δ 56.1; 61.1; 70.5; 82.9; 102.4; 106.7; 125.1; 126.0; 127.48; 127.5; 129.8; 132.9; 134.2; 136.1; 149.4; 152.8; MS calculated for C16H16O4S+H 305 observed 305.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(/C=C/c2c(Cc3ccccc3)sc3ccccc23)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1

Procedure:
At ambient temperature, a mixture of cis and trans-2-benzyl-3-[2-(4-methoxy-phenyl)-viny]-benzo[b]thiophene in EtOAc and 10% palladium on carbon was stirred under H2 (atmospheric conditions). The reaction was filtered and the filtrate concentrated to give the title compound as a white solid, mp 68-70° C. 1H NMR; consistent. mass spectrum (EI) m/z 358 (M+). Anal. Calcd. for C24H22OS: C, 80.41; H, 6.19; N, 0.00. Found: C, 80.20; H, 6.18; N, 0.03.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]4[N:44]([N:48]=[C:49]([C:51](O)=[O:52])[CH:50]=4)[CH:45]=[CH:46][CH:47]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:54]1[CH2:58][CH2:57][C@@H:56]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:55]1.CN(C=O)C>CCOC(C)=O>[C:62]([O:61][C:60](=[O:66])[NH:59][C@@H:56]1[CH2:57][CH2:58][N:54]([C:51]([C:49]2[CH:50]=[C:43]3[C:42]([C:40](=[O:41])[NH:39][CH2:38][C:28]45[CH2:37][CH:32]6[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]6)[CH2:29]4)[CH2:35]5)=[CH:47][CH:46]=[CH:45][N:44]3[N:48]=2)=[O:52])[CH2:55]1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)c2cc3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccn3n2)C1
Reaction time: 20 h

Procedure:
BOP (680 mg, 1.5 mmol) is added to a mixture of 4-[(adamantan-1-ylmethyl)carbamoyl]-pyrazolo[1,5-a]pyridine-2-carboxylic acid (417 mg, 1.18 mmol), tert-butyl (R)-pyrrolidin-3-ylcarbamate (242 mg, 1.30 mmol), iPr2Net (620 μL, 3.6 mmol) and DMF (12 mL) under N2. The reaction vessel is sealed and the solution is left to stir for 20 h. EtOAc (50 mL) is added. The solution is washed with H2O (2×50 mL) and brine (50 mL). The organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (2% MeOH in CH2Cl2) affords (R)-(1-{4-[(adamantan-1-ylmethyl)carbamoyl]pyrazolo[1,5-a]-pyridine-2-carbonyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester as a tan solid. MeOH (6.8 mL) and 4 M HCl in dioxane (1.7 mL) are added. After 20 h, the volatiles are removed under reduced pressure to afford a light tan solid. 15% Aqueous K2CO3 (50 mL) is added. The solution is extracted with EtOAc (5×50 mL). The combined organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (1% NH4OH in 9:1 CH2Cl2:MeOH) affords the title compound as a tan foam. 1H NMR (300 MHz, CDCl3) δ: 8.48 (ddd, 1H), 7.62 (dd, 1H), 7.22 (dd, 1H), 6.87 (t, 1H), 6.50 (bt, 1H), 3.42-4.20 (m, 5H), 3.20 (d, 2H), 2.14 (septet, 1H), 1.96-2.04 (m, 3H), 1.55-1.88 (m, 12H). LC-MS m/z (M+H+): 422.3; RT=1.2 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][N:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN1CC=C(c2c[nH]c3ncccc23)CC1
Reactant: O=C(Cl)c1ccccc1
Product: CN1CC=C(c2cn(C(=O)c3ccccc3)c3ncccc23)CC1

Procedure:
(6.7 mg, 18%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (25.0 mg, 0.12 mmol) and benzoyl chloride (28 μL, 0.24 mmol); HRMS-FAB+ for C20H19N3O: calculated MH+: 318.16064. Found: 318.16191.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2.[F:24][C:25]([F:37])([F:36])[O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][C:27]([O:26][C:25]([F:24])([F:36])[F:37])=[CH:32][CH:31]=4)=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc(C)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccc(C)cc1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
A mixture of ethyl 5-bromo-1-(4-methylbenzyl)-1H-indole-2-Carboxylate (5.8 g, 15.54 mmol), 4-(trifluoromethoxy)phenylboronic acid (8.2 g, 38.85 mmol), potassium carbonate (5.4 g, 38.85 mmol), [1′1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with methylene (1:1) (4.41 g, 5.44 mmol) in dioxane-water (10:1, 154 mL) was stirred at 70° C. for two days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and brine, and then concentrated to an oil. This residue was crystallized from ethyl ether to afford the title compound as an off-white solid, m.p. 77–78° C. Mass spectrum (ESI, [M+H]+) m/z 454. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.78 (d, 2H, J=8.70 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.61 (dd, 1H, J=8.70 and 1.68 Hz), 7.44 (s, 1H), 7.42–7.41 (m, 3H), 7.06 (d, 2H, J=7.94 Hz), 6.94 (d, 2H, J=8.09 Hz), 5.83 (s, 2H), 4.29 (q, 2H), 2.21 (s, 3H), and 1.30 ppm (t, 3H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C([Mg]Br)C.[O:10]([C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH:20]=[C:21]1[CH2:25][CH2:24][N:23]=[CH:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCCCCC.C1COCC1>[CH2:1]([CH:22]1[C:21](=[CH:20][C:19]2[CH:26]=[CH:27][CH:28]=[C:17]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:18]=2)[CH2:25][CH2:24][NH:23]1)[CH2:2][CH2:3][CH3:4]
Reactant: [Li]CCCC
Reactant: C1=NCCC1=Cc1cccc(Oc2ccccc2)c1
Agent: CC[Mg]Br
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC1NCCC1=Cc1cccc(Oc2ccccc2)c1
Yield: 44 %

Procedure:
In a similar manner as Example 62 except for using 18 ml of a solution of 1.6M n-butyllithium in hexane instead of 10 ml of the solution of 3N ethyl magnesiumbromide in THF for reacting with 3-(m-phenoxybenzylidene)-1-pyrroline, 3.2 g (yield 44%) of 2-n-butyl-3-(m-phenoxybenzylidene)-pyrrolidine was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1ccc(Br)cc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)ccc1C(C)=O
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(4-bromo-2-hydroxyphenyl)-1-ethanone (28.8 g, 134 mmol), potassium carbonate (48.6 g, 352 mmol) in DMF (63 ml) was added methyl iodide (25 g, 176 mmol), and the mixture was stirred for 20 hours. The mixture was poured into water. The whole was extracted with diethylether. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31.5 g, 99% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([SH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.O.C(OCC)(=O)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[F:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(S)CC1
Reactant: Fc1ccccc1CBr
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(SCc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
After dissolving 1.70 g of 1-(tert-butoxycarbonyl)-4-mercaptopiperidine in a mixture of 8 ml ethanol/8 ml 2N sodium hydroxide, 1.05 ml of 2-fluorobenzyl bromide was added and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.72 g, 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(N)C>C(Cl)(Cl)(Cl)Cl.C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][S:12]([NH:11][C:10]([CH3:16])([CH3:15])[C:9]#[CH:17])(=[O:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCN
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C#CC(C)(C)NS(=O)(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 5-(4-Chloro-phenyl)-3,3,4-trimethyl-2,3-dihydro-isothiazole 1,1-dioxide, 1.5 g (5.5 mmol) in 150 mL of carbon tetrachloride was added 1.5 g (8.25 mmol) of N-bromosuccinimide and 0.13 g of 2,2′-azobis(2-methyl-propionitrile). The mixture was heated to reflux for 4 h then cooled to ambient temperature. Chloroform was added and the solution was washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. To a solution of the residue in 75 mL of absolute ethanol was added 3.6 mL (55.0 mmol) of ethylamine (70% solution in water). The reaction mixture was stirred 24 h at ambient temperature then concentrated to dryness. The residue was purified by chromatography on silica gel with methanol/chloroform as eluant to yield 0.21 g (12%) of the desired product, shown below, as a tan oil. 1H-NMR is consistent with structure; MS (ion spray) 313.0 (M−1); Anal. Calc'd for C14H19ClN2O2S.0.1CHCl3: C, 51.83; H, 5.89; N, 8.57. Found: C, 51.58; H, 6.38; N, 8.04.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4](=O)[C:3]=1[C:14]#[N:15].[OH2:16].[NH2:17][NH2:18]>CO>[NH2:15][C:14]1[C:3]2[C:2](=[O:16])[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH3:12])[C:4]=2[NH:18][N:17]=1
Reactant: O
Reactant: CCn1c(Cl)c(C#N)c(=O)n(CC)c1=O
Reactant: NN
Solvent: CO
Product: CCn1c(=O)c2c(N)n[nH]c2n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-chloro-5-cyano-1,3-diethylpyrimidine-2,4(1H, 3H)-dione(5 g) and hydrazine monohydrate (2.2 ml) in methanol (220 ml) was stirred for 10 minutes at room temperature. The reaction mixture was concentrated to dryness under reduced pressure, and the concentrate was crystallized from aqueous methanol to obtain colorless needles(4.3 g), m.p. 246°-248° C.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:8]([C:9](=[O:33])[NH:10][CH:11]([CH2:27][C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@@H:8]3[O:7][C@H:6]3[C:4]([OH:5])=[O:3])=[O:33])[CH2:27][C:28]3[N:29]=[CH:30][NH:31][CH:32]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)NC(Cc1c[nH]cn1)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nc(-c2ccc(F)cc2)cs1)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1O[C@H]1C(=O)O
Yield: 45.4 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18d (200 mg, 0.42 mmol); LiOH (12 mg, 0.50 mmol); THF/MeOH/H2O (2.5 mL: 1.5 mL: 1.5 mL); yielded 30b as a white solid (85 mg, 45.2%). 1H NMR (DMSO-d6, 400 MHz): δ 12.52 (bs, 1H); 8.85-8.75 (dd, 2H, J=6.9 Hz; J=43.1 Hz); 7.94-7.91 (t, 2H); 7.80 (s, 1H); 7.62 (s, 1H); 7.28-7.24 (t, 2H); 6.93 (s, 1H): 4.80-4.76 (q, 1H); 3.65-3.64 (d, 1H, J=4.40 Hz); 3.46-3.42 (d, 1H, J=14.0 Hz); 3.09-2.96 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 169.5, 168.8, 165.9, 162.9, 160.5, 157.6, 147.8, 134.6, 132.1, 130.7, 127.6, 116.4, 115.5 (d, J=21.4 Hz), 108.0, 52.9, 52.7, 52.6, 51.9, 28.6. ESI-HRMS (m/z): [M+H+] calcd. for C19H16FN5O5S: 446.0928, observed: 446.0939; HPLC method 2: Rt=15.8 min, purity=97.2%.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9](=[O:18])[C:8]2=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([N+:20]([O-:22])=[O:21])=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9](=[O:18])[C:8]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2ccc(Cl)cc2n(C2CCCCC2)c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc([N+](=O)[O-])c(Cl)cc2n(C2CCCCC2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
A solution of 3.1 g (11 mmol) 1-cyclohexyl-7-chlorquinoxaline-2,3(1H,4H)-dione in 100 ml concentrated sulfuric acid (95-97%) was ice-cooled and then added 1.1 g (11 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min. and then at 25° C. for 17 h. The reaction mixture was poured into 500 ml ice-water. The precipitate was filtered off and washed with water to give 3.0 g (82%) 1-cyclohexyl-6-nitro-7-chlorquinoxaline-2,3(1H,4H)-dione. M.p. (DSC): decomp. 1H-NMR (DMSO-d6): 12.2 (1H, broad s), 7.9 (2H, s), 4.0-1.0 (11H, m).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]2[C:5](=[C:6]([CH3:17])[CH:7]=[CH:8][C:9]=2[CH3:16])[N:4]=1)[NH2:2].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([NH:2][NH:1][C:3]2[CH:12]=[C:11]([CH:13]([CH3:14])[CH3:15])[C:10]3[C:5](=[C:6]([CH3:17])[CH:7]=[CH:8][C:9]=3[CH3:16])[N:4]=2)=[O:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(C)c2c(C(C)C)cc(NN)nc12
Product: Cc1ccc(C)c2c(C(C)C)cc(NNC(=O)Nc3cc(Cl)cc(Cl)c3)nc12

Procedure:
A solution of 2-hydrazinyl-4-isopropyl-5,8-dimethylquinoline (100 mg, 0.44 mmol) and 82 mg (1.0 eq) of 3,5-dichlorophenyl isocyanate was reacted as outlined in Scheme 1 above to give the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.74 Hz, 6 H) 2.42 (s, 3 H) 2.74 (s, 3 H) 3.88-4.06 (m, 1 H) 6.89 (s, 1 H) 6.94 (d, J=7.33 Hz, 1 H) 7.07 (t, J=1.90 Hz, 1 H) 7.22 (d, J=7.03 Hz, 1 H) 7.65 (br. s., 2 H) 8.27 (br. s., 1 H) 8.58 (s, 1 H) 9.24 (br. s., 1 H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][C:39]5[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:54])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([C:39]5[N:40]([CH3:44])[CH:41]=[CH:42][N:43]=5)=[O:54])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Sc4nccn4C)cc2)CCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)c4nccn4C)cc2)CCN3CC(C)C)cc1
Yield: 40 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-methylimidazol-2-yl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (355 mg) in dichloromethane (15 ml) at −78° C. The reaction vessel was removed from a dry ice-acetone bath, and sodium thiosulfate solution was added to the reaction vessel with strongly stirring. The mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and saturated brine, dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[1-methylimidazol-2-yl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (246 mg) (Compound 160) as yellow amorphous.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[S:14]C=NC=1C(O)=O.CC1N=C(N)C=CC=1.FC1C(F)=CC=CC=1N>>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]=[C:10]=[S:14])[C:2]=1[F:1]
Reactant: O=C(O)c1ncsc1Nc1cccc(F)c1F
Agent: Cc1cccc(N)n1
Agent: Nc1cccc(F)c1F
Product: Fc1cccc(N=C=S)c1F

Procedure:
The title compound, MS (ISP): m/e=347.3 (M+H+), was prepared as for example 1, steps A to C. Step A was performed using 1,2-difluoro-3-isothiocyanato-benzene and yielded 5-(2,3-difluoro-phenylamino)-thiazole-4-carboxylic acid ethyl ester. This was hydrolized in step B to 5-(2,3-difluoro-phenylamino)-thiazole-4-carboxylic acid, which was reacted with 6-methyl-pyridin-2-ylamine in step C. 1,2-Difluoro-3-isothiocyanato-benzene was prepared as in example 96, starting from 2,3-difluoro-phenylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[OH-].[K+].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:7])[NH:4][N:3]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1n[nH]c(C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
To a solution of 3,5-dimethylpyrazole (86.5 g, 0.90 mol) in concentrated sulfuric acid (170 ml), conc nitric acid (103 ml, d=1.423) was added with stirring and icecooling. After one hour concentrated sulfuric acid (100 ml) was added slowly with stirring resulting in a temperature rise to 70°-80° C. After stirring overnight at 30°-35° C., the mixture was poured into ice (1.5 l) and neutralized with potassium hydroxide. Extraction with methylene chloride (3×350 ml), drying of the organic phase (Na2SO4) and evaporation gave off-white crystals which were dried in vacuo at 70°. Yield 106.2 g=83.6%, m.p. 125°.
Reaction SMILES: S1C2CCC(C([O-])=O)NC=2N=C1.[N:13]([CH2:16][CH2:17][CH2:18][C:19]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]([C:24](=[S:26])[NH2:25])[N:22]=[C:21]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[F:34])[S:20]1)=[N+]=[N-].Br[CH:42]1[C:47](=O)[CH2:46][CH2:45][N:44]([C:49](OC(C)(C)C)=O)[CH2:43]1.CCN(C(C)C)C(C)C>C(O)C>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:21]1[S:20][C:19]([CH2:18][CH2:17][CH2:16][NH2:13])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:23]([C:24]2[S:26][C:42]3[CH2:43][N:44]([CH3:49])[CH2:45][CH2:46][C:47]=3[N:25]=2)[N:22]=1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Agent: O=C([O-])C1CCc2scnc2N1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN)c3ccccc3)sc2C1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Preparation of tert-butyl 24243-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-e]pyridine-5(4H)-carboxylate: To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hrs. The cooled mixture was partitioned between saturated NaHCO3 solution (30 mL) and EtOAc (30 mL) and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam (0.313 g, 73%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6]([CH3:12])[N:5]=[C:4]([SH:13])[N:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:10][C:9](=[O:11])[CH2:8][C:7]1[C:2]([OH:1])=[N:3][C:4]([SH:13])=[N:5][C:6]=1[CH3:12]
Reactant: CO
Reactant: Cc1nc(S)nc(O)c1CC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(C)nc(S)nc1O
Yield: 79 %

Procedure:
A solution of (4-hydroxy-2-mercapto-6-methyl-5-pyrimidinyl)-acetic acid (190 g, 0.95 mol) and concentrated sulfuric acid (50 ml) in methanol (1.51) is refluxed for 18 hours. The suspension is cooled and filtered to give methyl(4-hydroxy-2-mercapto-6-methyl-5-pyrimidinyl)-acetate (160 g, 79%).