Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=C[CH:11]=2)[C:6](=O)[C:5]1=O)CC.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26].BrCCN1CCCCC1>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([CH2:11][CH2:12][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:20](=[O:25])[C:19]2=[O:26]
Reactant: CCCN1C(=O)C(=O)c2ccccc21
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: BrCCN1CCCCC1
Product: O=C1C(=O)N(CCN2CCCCC2)c2ccc(Cl)cc21

Procedure:
Was prepared in an analogous manner to 1-propylindoline-2,3-dione using commercially available 5-chloroisatin (purchased from Fisher Scientific) and 1-(2-bromoethyl)piperidine (purchased from Fisher Scientific). 1H-NMR δ 7.55 (m, 2H), 6.95 (d, 1H), 3.84 (t, 2H), 2.58 (t, 2H), 2.46 (bs, 4H), 1.54 (m, 4H), 1.43 (m, 2H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([CH:18]([S:31][C:32]2[NH:36][N:35]=[N:34][N:33]=2)[N:19]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:20]2(=[O:22])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)Cl>CCOCC>[C:12]1([CH:18]([S:31]([C:32]2[NH:36][N:35]=[N:34][N:33]=2)=[O:9])[N:19]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:20]2(=[O:22])=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1C(Sc1nnn[nH]1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1c2ccccc2S(=O)(=O)N1C(c1ccccc1)S(=O)c1nnn[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 199.3 %

Procedure:
A mixture of m-chloroperbenzoic acid (0.43 g, 9,.67 mmol) and 2-(1-phenyl-1H-tetrazol-5-ylthiomethyl) saccharin (1 g, 2.67 mmol) in MDC was stirred at room temperature for 24 hours. TLC (95:5 CH2Cl2 : ether) revealed the presence of starting sulfide. Additional peracid (0.2 g) was added and the mixture stirred for an additional 2 days. The reaction mixture was washed with sodium bicarbonate solution, dried (Na2SO4) and freed of solvent under vacuum. Chromatography (silica gel-95:5 CH2Cl2 :ether) afforded a foam that was crystallized from ether to afford 0.52 g of 2-(1-phenyl-1H-tetrazol-5-ylsulfinylmethyl) saccharin as a white solid, mp 161°-162° C. 1H nmr (90 MHz, CDCl3):5.5-6.0 (2H, q). FDMS: m/e 196 (M+ -PMT), 389 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(OCC)(=O)C.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 22 %

Procedure:
0-t-Butyl-N,N-diisopropyl-isourea (3.65 gm, 20 mmol) was added to a solution of 4-hydroxy-3-nitrobenzene-acetic acid (3.61 gm, 18.3 mmol) in t-butanol (18 mL) and stirred for 24 hours. Ethyl acetate (100 mL) was added and the solution washed successively with water 3×25 mL), 1N sodium bicarbonate solution 3×25 mL), and saturated salt solution (25 mL). The product was isolated as a yellow oil (1.02 gm, 22% yield) and used without further purification: 1H-NMR δ (CDCl3) 1.44 (9H, s), 3.52 (2H, s), 7.08 (2H, d, J=8 Hz), 7.51 (1H, dd, J=8, 3 Hz), 8.00 (1H, d, J=3 Hz).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=2)=[CH:10]1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:19]([C:17]1[S:18][C:14]([C:11]2[CH:12]=[CH:13][S:9][CH:10]=2)=[CH:15][CH:16]=1)(=[O:20])=[O:21]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2ccsc2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccsc3)s2)c1Br
Yield: 40 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(3-thienyl)thiophene-2-sulfonyl chloride in 40% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) give a solid.
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].[CH:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][N:18]=[C:13]3[S:12][C:11]=2[C:19]([OH:21])=O)[CH2:9][CH2:8][CH2:7]1>C(OCC)C>[CH:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][N:18]=[C:13]3[S:12][C:11]=2[C:19]([Cl:5])=[O:21])[CH2:9][CH2:8][CH2:7]1
Reactant: Cl
Reactant: O=C(O)C1=C(C2CCC2)N2CCCN=C2S1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C1=C(C2CCC2)N2CCCN=C2S1
Yield: 115.6 %

Procedure:
To 20 ml of thionyl chloride was suspended 5.0 g of 3-cyclobutyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid obtained in Example 1, followed by reflux under heating for 30 minutes. Under cooling, an anhydrous diethylether was added dropwise to the reaction mixture to precipitate. The crystals were collected by filtration and washed with anhydrous diethylether to yield 5.4 g of 3-cyclobutyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonyl chloride as a pale yellow crystals. To the mixture of 60 ml of pyridine and 20 ml of dimethyl formamide was suspended 2.7 g of the crystal. To the mixture was added 1.5 g of 3,5-dichloroaniline and 60 mg of dimethylaminopyridine, followed by stirring at 70° C. for 17 hours. The solvent was removed under reduced pressure to obtain a residue. Addition of water to the residue caused precipitation of the crystals and the crystals were collected by filtration. After washing with cold methanol, the crystals were suspended to saturated hydrogenchloride ethanol solution. After washing with diethylether, the crystals were collected by filtration to obtain 1.2 g of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[N:16]([O-])=O.[Na+].O.O.Cl[Sn]Cl>C(O)(=O)C.O.Cl>[NH:13]([C:12]1[CH:14]=[CH:15][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:10][CH:11]=1)[NH2:16]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(Cc2ccc(NN)cc2)CC1
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
To a stirred solution of 4-[(4-methylpiperazin-1-yl)methyl]aniline (3.2 g, 15.57 mmol) in acetic acid: concentrated HCl (32:32 mL) at 10° C. was added NaNO2 (1.30 g, 18.78 mmol) in water (16 mL) and stirred for 10 min. Freshly prepared SnCl2.2H2O (11.75 g, 51.97 mmol) in concentrated HCl (32 mL) was added at 10° C. The temperature of the reaction mixture was allowed to rise to room temperature and maintained there for 4 hr. After filtering the reaction mixture, the precipitate was washed with water and the solid obtained was dried under reduced pressure to obtain 1-(4-hydrazinobenzyl)-4-methylpiperazine (3.4 g). 1H NMR (CD3OD, 200 MHz) δ: 7.66 (2H, d, J=8.4 Hz), 7.13 (2H, d, J=8.4 Hz), 4.46 (2H, s), 3.72 (8H, bm), 3.11 (3H, s);
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH:41]1[CH:46]=[CH:45][C:44](N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=[CH:43][CH:42]=1>C(Cl)Cl>[C:18]1([N:13]2[C:12]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: c1ccc(-c2c3c(nn2-c2ccccc2)CCNCC3)cc1

Procedure:
2-Phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. To a stirred solution of the above compound (1.79 g) in 35 mL of CH2Cl2 was added 3.0 mL of i-Pr2NEt and 3.05 g of N-phenyltrifluoromethanesulfonimide. The mixture was heated at reflux for 24 h and then was concentrated in vacuo. Chromatography on SiO2 (0 to 75% EtOAc/hexanes) afforded 1.88 g of the desired compound. MS (ESI): exact mass calculated for C19H22F3N3O5S, 461.12. found, m/z 407.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15](B(O)O)=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:2]3[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: Oc1ncccc1Br
Reactant: Cn1ncc2cc(B(O)O)ccc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2cc(-c3ccc[nH]c3=O)ccc21
Temperature: 90 °C

Procedure:
The suspension of 3-bromo-2-hydroxypyridine (80 mg, 0.46 mmol), 1-methyl-1H-indazol-5-ylboronic acid (121 mg, 0.69 mmol) and sodium carbonate (146 mg, 1.38 mmol) in DMF (2.0 mL) and H2O (0.4 mL) was degassed with N2 for 5 minutes. To the mixture was added bis(triphenylphosphine)palladium (II) dichloride (67 mg, 0.09 mmol), and the resulting mixture was heated at 90° C. for 2 h. The reaction mixture was filtered and purified by reverse phase HPLC (Gemini, 5 to 100% ACN/H2O+0.1% TFA) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H12N3O: 226.25; Found: 226.2.
Reaction SMILES: IC.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([OH:17])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([O:17][CH3:27])=[O:16])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
Iodomethane (554 mg) was added to a suspension of (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionoic acid (1.1 g) and potassium carbonate (539 mg) in N,N-dimethylformamide (7 mL). The mixture was stirred for 2 hours at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give methyl (S)-2-(benzyloxycarbonylamino)-3-(tert-butoxycarbonylamino)propionate (1.2 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Product: COc1ccc2c(Cl)nccc2c1
Yield: 86 %

Procedure:
1-Chloro-6-methoxy-isoquinoline was prepared according to the following procedure. To a solution of 3-methoxy cinnamic acid (25 g, 140.3 mmol) and triethylamine (39.1 mL, 280.6 mmol) in THF (200 mL) was added ethyl chloroformate (20 ml, 210 mmol) dropwise at 0° C. After stirring at this temperature for 1 hour, aqueous NaN3 (14.7 g, 226 mmol in 80 mL H2O) was added dropwise and the reaction mixture was stirred for 16 hours at ambient temperature. Water (220 mL) was added to the mixture and the volatiles were removed in vacuo. The resulting slurry was extracted with toluene (3×110 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated. The dried solution was added dropwise to a heated solution of diphenylmethane (120 mL) and tributylamine (68 mL) at 190° C. The toluene was distilled off during the addition. After complete addition, the reaction temperature was raised to 210° C. for 2 hours. Upon cooling via an ice bath, the precipitated product was collected by filtration, washed with hexanes, and dried to yield the desired product as an off-white solid (14.04 g, 57%): LCMS found 176.1 [M+H]+. 6-Methoxy-2H-isoquinolin-1-one (14.04 g, 80.15 mmol) in POCl3 (30.5 ml) was heated to gentle reflux for 1 hour and the mixture was then concentrated in vacuo. The residue was poured into ice water and brought to pH 10 by the addition of 10 M NaOH. The resulting mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford 13.31 g (86%) of the desired 1-chloro-6-methoxy-isoquinoline intermediate as a white solid. LCMS found 194.19 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([OH:27])[C:21]=4[C:28]=3[CH3:29])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[CH2:32]([O:27][CH:22]1[C:21]2[C:28]([CH3:29])=[C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=4)[CH2:16][CH2:15]3)[C:18]([CH3:31])=[C:19]([CH3:30])[C:20]=2[O:24][C:23]1([CH3:26])[CH3:25])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(OCc3ccccc3)C(C)(C)O4)CC2)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Sodium hydride (60%, 0.06 g, 1.5 mmol) was added to a solution of 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol (0.30 g, 0.75 mmol) obtained in Reference Example 18 in DMF (5 ml) under ice cooling. The mixture was stirred for 30 minutes, and then benzyl bromide (0.14 g, 0.84 mmol) was added. After stirring for 30 minutes under ice cooling, the mixture was stirred for 30 minutes at room temperature. The resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 0.23 g (yield 62%) of the title compound via recrystallization (diisopropyl ether-methanol). mp. 98–99° C.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10](I)=[N:11][CH:12]=1.CN([CH:17]=[O:18])C>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:17]=[O:18])=[N:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(I)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)cn1
Temperature: -15 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
Isopropyl magnesium chloride (11.5 mL, 2 M in THF, 23 mmol) was added dropwise to a cold (−15° C.) solution of 5-chloro-2-iodo-pyridine (5 g, 20.9 mmol) in THF (35 mL). The mixture was stirred for 1 h at −15° C. DMF (2.3 g, 31.3 mmol) was added dropwise keeping the internal temperature below 0° C. The mixture was allowed to warm to rt, stirred for 1 h, cooled to 0° C., quenched by addition of a saturated aqueous solution of ammonium chloride, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5) to provide 1.1 g of the title compound. tR: 0.39 min (LC-MS 2); ESI-MS: 142 [M+H]+ (LC-MS 2); Rf=0.22 (hexane/EtOAc, 4:1).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[C:5]1[C:15]([F:18])([F:17])[F:16])[C:2]#[CH:3].O1CCCC1.[BH4-].[K+]>O>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][OH:14])=[C:5]1[C:15]([F:18])([F:16])[F:17])[C:2]#[CH:3]
Reactant: C#CCn1c(C(F)(F)F)c(C=O)c2ccccc21
Agent: [BH4-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCn1c(C(F)(F)F)c(CO)c2ccccc21
Yield: 100.3 %

Procedure:
5.54 g of 1-(2-propynyl)-2-trifluoromethyl-3-formyl-(1H)-indol, 120 ml of tetrahydrofuran and 20 ml of water were mixed together at +5° and 2 g of potassium borohydride were added in small fractions. The mixture was concentrated to a small volume by distillation under reduced pressure and ethyl ether was added. The organic phase was washed with salted water and concentrated to dryness by distillation under reduced pressure to obtain 5.6 g of 1-(2-propynyl)-2-trifluoromethyl-(1H)-indol-3-yl methanol melting at 90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:35])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[C:29]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:28]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1ccc(Cl)cc1Oc1ccccc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4Oc4ccccc4)cc3)cc2C1=O
Yield: 96 %

Procedure:
The compound of example 43 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-chloro-2-phenoxy phenyl isocyanate.
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1.[CH2:11]([C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[C:20]([N:23]3[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]3=[O:30])[CH:21]=[CH:22][C:15]=2[N:14]=1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>O.C1COCC1>[F:1][CH:2]([F:10])[C:3]1[N:4]=[C:5]([CH2:8][O:9][C:26]2[CH:27]=[CH:28][N:23]([C:20]3[CH:21]=[CH:22][C:15]4[N:14]=[C:13]([CH2:11][CH3:12])[N:17]([CH3:18])[C:16]=4[CH:19]=3)[C:24](=[O:30])[CH:25]=2)[S:6][CH:7]=1
Reactant: OCc1nc(C(F)F)cs1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4nc(C(F)F)cs4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.1 %

Procedure:
A mixture of (4-(difluoromethyl)-1,3-thiazol-2-yl)methanol (61.3 mg), 1-(2-ethyl-1-methyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), triphenylphosphine (146 mg), bis(2-methoxyethyl) azodicarboxylate (130 mg) and THF (3 ml) was stirred at room temperature for 3 h. The mixture was diluted with water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated in vacuo and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (10.1 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[NH2:14][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:24](=[O:26])[CH3:25])[CH2:12][CH2:13]2)=[N:7][C:2]=1[Br:1]
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 0.5 h

Procedure:
To 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (50 mg, 0.194 mmol) in DCM (4 mL) in ice bath was added DIEA (0.136 mL, 0.778 mmol) and acetyl chloride (0.017 mL, 0.233 mmol). The reaction mixture was stirred at in ice bath 30 min. The reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with brine. Dried over sodium sulfate, filtered and evaporated. Proceed for next step. LCMS (m/z): 299.1/301.1 (MH+), 0.508 min. 1H NMR (400 MHz, CD3OD) δ ppm 7.81-7.69 (m, 2 H), 7.62-7.45 (m, 2H), 7.37-7.09 (m, 6H), 6.5 (dd, J=8.61, 2.35 Hz, 1H), 6.50 (dd, J=13.50, 2.15 Hz, 1H), 5.17-5.01 (m, 1H), 4.55 (d, J=13.30 Hz, 1H), 3.94 (d, J=13.69 Hz, 1H), 3.83-3.63 (m, 2H), 2.88 (tt, J=11.84, 3.62 Hz, 1H), 2.67 (td, J=12.91, 2.35 Hz, 1H), 2.03 (s, 3H), 1.96-1.79 (m, 2H), 1.78-1.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[N+]=[N-])=[CH:4][C:3]=1[S:13](=[O:20])(=[O:19])[N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].[ClH:21]>COCCOCCOC>[CH2:15]([N:14]([CH2:17][CH3:18])[S:13]([C:3]1[CH:4]=[C:5]([C:8](=[O:12])[CH2:9][Cl:21])[CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:20])=[O:19])[CH3:16]
Reactant: Cl
Reactant: CCN(CC)S(=O)(=O)c1cc(C(=O)C=[N+]=[N-])ccc1Cl
Solvent: COCCOCCOC
Product: CCN(CC)S(=O)(=O)c1cc(C(=O)CCl)ccc1Cl

Procedure:
12 g of 4'-chloro-3'-diethylsulfamoyl-diazoacetophenone were reacted as prescribed in Example 66b) with concentrated HCl in diethyleneglycol dimethyl ether and worked up. Colorless crystals, melting point: 63° - 65° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[OH:12]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[OH:12][C:7]12[CH2:9][CH:3]3[CH2:4][CH:5]([CH2:10][CH:1]([C:2]3=[O:11])[CH2:8]1)[CH2:6]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Solvent: CC(=O)O
Product: O=C1C2CC3CC1CC(O)(C3)C2
Yield: 48 %

Procedure:
A mixture of 0.1 mol of 2-adamantanone, 10 mmol of N-hydroxyphthalimide, 0.33 mmol of acetylacetonatovanadium V(AA)3, 0.17 mmol of acetylacetonatomanganese Mn(AA)2, and 250 ml of acetic acid was stirred at 85° C. in an oxygen atmosphere (1 atm) for 10 hours. The resulting reaction mixture was concentrated and was then extracted with ethyl acetate. A portion of an organic layer was concentrated and was then cooled for crystallization to yield 5-hydroxy-2-adamantanone (yield: 48%). The conversion rate from 2-adamantanone was 74%.
Reaction SMILES: I[C:2]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=[CH:4][S:3]1.[CH2:12]([O:14][P:15]([C:20]1[CH:24]=[C:23]([Sn](CCCC)(CCCC)CCCC)[S:22][C:21]=1[C:38]1[S:39][C:40]([Sn](CCCC)(CCCC)CCCC)=[CH:41][C:42]=1[P:43]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44])([O:17][CH2:18][CH3:19])=[O:16])[CH3:13].[F-].[K+]>CN(C=O)C>[CH2:46]([O:45][P:43]([C:42]1[CH:41]=[C:40]([C:4]2[S:3][C:2]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[CH:6][CH:5]=2)[S:39][C:38]=1[C:21]1[S:22][C:23]([C:4]2[S:3][C:2]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[CH:6][CH:5]=2)=[CH:24][C:20]=1[P:15]([O:17][CH2:18][CH3:19])([O:14][CH2:12][CH3:13])=[O:16])([O:48][CH2:49][CH3:50])=[O:44])[CH3:47]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(P(=O)(OCC)OCC)c(-c2sc([Sn](CCCC)(CCCC)CCCC)cc2P(=O)(OCC)OCC)s1
Reactant: IC1(c2cccs2)CC=CS1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(-c2ccc(-c3cccs3)s2)sc1-c1sc(-c2ccc(-c3cccs3)s2)cc1P(=O)(OCC)OCC
Yield: 42 %

Procedure:
At room temperature, 0.0065 g (0.0056 mmols) of commercially available tetrakistriphenylphosphine palladium and 0.0818 g (0.28 mmols) of 2-iodobithiophene were dissolved in DMF. Thereafter, 0.1345 g (0.14 mmols) of 3,3′-bis(diethoxyphosphoryl)-5,5′-bis(tributylstannyl)-[2,2′]-bithiophene was added at room temperature. The reaction mixture was heated and stirred under reflux for 5 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 2 hours. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate:hexane=1:5 and ethyl acetate:hexane=1:1) to obtain the specified substance in the form of a yellow solid at a yield of 0.0451 g (yield: 42%).