Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O>N1C=CC=CC=1>[CH2:7]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: Nc1nncs1
Reactant: CCCCCCc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-hexylbenzenesulfonyl chloride (5.48 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.72 g, 11.4 mmol, 58% yield) as a solid, mp 125-126° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=7 Hz), 1.28 (m, 6H), 1.58 (m, 2H), 2.63 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.83 (d, 2H, J=8 Hz), 8.24 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 28.9, 31.1, 31.6, 35.9, 126.5, 129.0, 138.1, 142.6, 148.6, 167.4; MS (Q-TOF) Calcd for C14H20N3O2S2 326.0997. found 326.0931 (M+H)+. Calcd for C14H19N3NaO2S2 348.0816. found 348.0816 (M+Na)+.
Reaction SMILES: [C:1]([CH:9]1[CH2:13][N:12]([NH:14][C:15]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:20]=[C:19](SC)[CH:18]=2)=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:33][S:34]([O-:36])=O.[K+].[CH3:38]O>O>[C:1]([CH:9]1[CH2:13][N:12]([NH:14][C:15]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:20]=[C:19]([S:34]([CH3:38])(=[O:36])=[O:33])[CH:18]=2)=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-n2nc(SC)cc2C(=O)NN2CCC(C(=O)c3ccccc3)C2)cc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: COc1ccc(-n2nc(S(C)(=O)=O)cc2C(=O)NN2CCC(C(=O)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93 %

Procedure:
N-(4-benzoylpyrrolidino)-1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazole-5-carboxamide (200 mg, 0.46 mmol) was dissolved in MeOH (6 mL). A solution of Oxone (561 mg, 0.91 mmol) in H2O (3 mL) was added, and the resulting mixture stirred at room temperature under Ar for 17 hours. The reaction was diluted with H2O and extracted twice with CHCl3. The combined organic extracts were dried over Na2SO4, filtered, and evaporated. The crude product was purified by preparative HPLC on a C-18 reversed-phase column (10-70% MeCN/H2O/0.05% TFA) to yield a white powder (200 mg, 93%). 1H NMR (CDCl3): δ8.98 (s, 1H), 7.52 (s, 1H), 7.39 (m, 6H), 6.95 (d, 2H, J=8.8), 3.84 (s, 3H), 3.65 (t, 2H, J=6.6 ), 3.41 (t, 2H, J=6.2 ), 3.28 (s, 3H), 1.93 (m, 4H).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[CH3:13][C@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].S1C=CC=C1>C1(C)C=CC=CC=1.[Rh]>[C:15]1([CH:14]([NH:21][CH:5]2[CH:6]3[CH2:11][C:2]4([OH:1])[CH2:9][CH:8]([CH2:10][CH:4]2[CH2:3]4)[CH2:7]3)[CH3:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: [Rh]
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: c1ccsc1
Product: CC(NC1C2CC3CC1CC(O)(C3)C2)c1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Commercially available 5-hydroxyadamantan-2-one (0.1 mol), L(-)-Alpha-methyl-benzyl amine (0.105 mol), aluminium isopropoxide (0.1 mol) and Rhodium on active carbon (20 mol %) were suspended in 500 ml of toluene, 20 ml of the 4% thiophene solution were added. The reaction mixture was stirred at 50° C. for 24 h.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].FC1C=C(C2C3CN([C:49](OC(C)(C)C)=[O:50])CCC=3NN=2)C=CC=1F.N[C@@H](C(C)(C)C)C(NCCO)=O>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=3[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:31])([CH3:1])[CH3:30])[C:4]([NH:6][CH2:7][CH2:49][OH:50])=[O:5])=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC(C)(C)[C@H](N)C(=O)NCCO
Product: CN1CCc2c(c(-c3ccc(F)c(F)c3)nn2C(=O)N[C@H](C(=O)NCCO)C(C)(C)C)C1

Procedure:
Compound 98 was prepared according to the procedure for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15, and replacing tert-leucine methylamide with intermediate 23. LCMS (+ESI) m/z=450.3 [M+H]+. 1H NMR (CDCl3) δ 7.89 (d, J=9.1 Hz, 1H), 7.52 (t, J=4 Hz, 1H), 7.40 (br, 1H), 7.23 (q, J=8.9 Hz, 1H), 4.20 (d, J=9.1 Hz, 1H), 3.69 (s, 2H), 3.56 (s, 2H), 3.42 (s, 2H), 3.16 (s, 2H), 2.74 (t, J=5.5 Hz, 2H), 2.52 (s, 3H), 1.06 (s, 9H). Purity: 96%.
Reaction SMILES: [CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH:8]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[CH3:26][NH2:27].C(Cl)Cl>C1COCC1>[CH:1]1([C@H:6]([OH:21])[C@H:7]([N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:8][NH:27][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC[C@H]([C@@H](O)C1CCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2S,3S)-3-cyclopentyl-3-hydroxy-2-(1,3-dioxoisoindolin-2-yl)propanal (1.339 g, 4.7 mmol) in dry THF (20 mL) was cooled to 0° C. Acetic acid (2.5 mL, 44 mmol), methylamine (33% in EtOH, 2.5 mL, 20 mmol), and NaHB(OAc) 3 (4.4937 g, 21.3 mmol) were added sequentially in single portions. The ice bath was removed and the mixture was stirred for 2 h at rt. The solvent was stripped and the crude 2-((1S,2R)-1-cyclopentyl-1-hydroxy-3-(methylamino)propan-2-yl)isoindoline-1,3-dione was used directly in the next step. LC-MS (3 min) tR=1.07, m/z=303 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:43][O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](/[CH:24]=[CH:25]/[C:26]([NH:43][O:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][O:46]4)=[O:27])[CH:19]=3)[O:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)O)ccc1O2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)NOC3CCCCO3)ccc1O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
A solution of (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (387 mg, 1 mmol) in DCM (15 ml) was cooled down to 0° C. EDC (383 mg, 2 mmol) and HOBT (135 mg, 1 mmol) were added, and the mixture was stirred at RT for 1 h. NH2OTHP (146 mg, 1.25 mmol) in DCM (1 ml) was added dropwise and the mixture was stirred at RT. After 4 h, the reaction mixture was washed with a saturated NaHCO3 solution and brine, dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography (eluent:DCM/MeOH 98:2) to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (464 mg) as a light yellow oil.
Reaction SMILES: C(O)C.[Cl-].[NH4+].[O:6]=[C:7]1[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[CH:18]=[C:19]([Cl:25])[C:20]([N+:22]([O-])=O)=[CH:21][C:9]=2[S:8]1>[Fe].O>[O:6]=[C:7]1[N:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[CH:18]=[C:19]([Cl:25])[C:20]([NH2:22])=[CH:21][C:9]=2[S:8]1
Reactant: CCOC(=O)Cn1c(=O)sc2cc([N+](=O)[O-])c(Cl)cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cn1c(=O)sc2cc(N)c(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
To a mixture of ethanol (10 liters) and water (1 liter) were added ammonium chloride (25 g) and iron metal (300 g). To the mixture was added ethyl 2-oxo-5-chloro-6-nitro-3-benzothiazolineacetate (434.6 g) under mild reflux. After refluxing with stirring for 4 hours, the resultant mixture was filtered under warm condition. The filter cake was washed with ethanol. The combined filtrate and washings were concentrated under reduced pressure and cooled to ambient temperature to give crystals, which were separated by filtration to give crystalline ethyl 2-oxo-5-chloro-6-amino-3-benzothiazolineacetate (347.8 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[Na+]>C(#N)C>[C:18]([O:21][CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cc(COC(C)=O)nc(C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.62 g, 5.17 mmol, from Step A) was dissolved in acetonitrile (15 mL) and sodium acetate (2.8 g, 34 mmol) was added. The mixture was heated to 80° C. for 4 hours, then allowed to stand at room temperature overnight. Acetonitrile was removed in vacuo. The residue was partitioned between water and ethyl acetate and the aqueous layer was extracted with two further portions of ethyl acetate. The combined extracts were washed with water, then brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with a gradient from 0-60% EtOAc/hexanes afforded purified product (0.95 g, 63%). H NMR (300 MHz, CDCl3): δ 8.15 (s, 1H), 5.36 (s, 2H), 4.53 (q, 2H), 2.25 (s, 3H), 1.46 (t, 3H); LCMS (M+H)+: 293.0.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[CH:22]=[C:21]2[C:12]([NH:13][C:14]3[C:19]([S:20]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]2C=[CH:24][CH:25]=[CH:26][C:10]=12>N1C=CC=CC=1>[C:5]([O:4][C:1]1[CH:22]=[C:21]2[C:12]([NH:13][C:14]3[C:19]([S:20]2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]2[CH:10]=[CH:26][CH:25]=[CH:24][C:2]=12)(=[O:7])[CH3:6]
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reaction time: 0.25 h

Procedure:
Acetic anhydride (2 ml) was added to a solution of 5-hydroxy-12H-benzo[a]phenothiazine (1) (1.4 gm) in pyridine (10 ml) and stirred for 15 minutes. The reaction mixture was concentrated under vacuum and ice-water was added to the residue. The resulting precipitate was filtered, air-dried and washed with ethyl acetate to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21]([C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])#[CH:22].C(OCC)(=O)C>C(#N)C.[Cu]I>[CH:25]([C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=1[C:21]#[C:22][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:26]
Reactant: C#Cc1ccccc1C=O
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccc(C#Cc2ccccc2C=O)cc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A mixture of 4-bromo-N,N-dimethylbenzenesulfonamide (610 mg, 2.31 mmol) bis(triphenylphosphine)palladium(II) chloride (Pd(PPh3)2Cl2) (33 mg, 0.05 mmol), copper (I) iodide (5 mg, 0.03 mmol) and triethylamine (3 mL) was degassed with argon. To the above mixture was added a degassed solution of 2-ethynyl-benzaldehyde (300 mg, 2.31 mmol) in acetonitrile (3 mL). The resulting mixture was heated at 80° C. for 3 hours under argon, and then cooled to room temperature, treated with ethyl acetate, and then washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (RediSep® Flash column, 230-400 mesh, 5-40% ethyl acetate in hexane) gave 4-(2-formyl-phenylethynyl)-N,N-dimethyl-benzenesulfonamide (454 mg, 63%) as a brown oil. MS (ESI+) cald. for C17H15NO3S [(M+H)+] 313, obsd. 314.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[N:6]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:9]=1)([OH:3])=[O:2].O1C2C=CC(C3C=C(C(OC)=O)C(=O)NN=3)=CC=2CC1.[F:44][C:45]1C=CC(CCl)=[CH:47][CH:46]=1>>[C:1]([C:4]1[C:5](=[O:23])[N:6]([CH2:19][C:20]2[CH:47]=[CH:46][C:45]([F:44])=[CH:21][CH:22]=2)[N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:9]=1)([OH:3])=[O:2]
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Agent: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Yield: 54.7 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride, to thereby yield the title compound as a yellow powder (yield: 54.7%).
Reaction SMILES: [S:1]([CH2:5][CH2:6][C:7]#[CH:8])([CH3:4])(=[O:3])=[O:2].I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:1]([CH2:5][CH2:6][C:7]#[C:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: C#CCCS(C)(=O)=O
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCC#Cc1ccccc1
Reaction time: 20 h
Yield: 52.7 %

Procedure:
A mixture of 1-mesylbut-3-yne (758 mg, 5.10 mmol), iodobenzene (1.25 g, 6.00 mmol), copper(I) iodide (40 mg), PdCl2(PPh3)2 (70 mg) in 12 mL of Et3N is stirred under N2 for 20 hr. The mixture is filtered and washed with Et3N (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a pale yellow oil (560 mg, 50%) 1H NMR (CDCl3) 2.91 (t, J=6.6 Hz, 2 H), 4.39 (t, J=6.6 Hz, 2 H), 7.30 (m, 3 H), 7.38 (m, 2 H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[S:15]1[C:19]([C:20]2[C:21]([O:30][CH3:31])=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=2)[CH:25]=O)=[CH:18][C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]1=2>>[S:15]1[C:19]([C:20]2[C:21]([O:30][CH3:31])=[CH:22][C:23]([O:28][CH3:29])=[C:24](/[CH:25]=[CH:2]/[C:1]([C:4]3[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:8][CH:9]=3)=[O:3])[CH:27]=2)=[CH:18][C:17]2[CH:32]=[CH:33][CH:34]=[CH:35][C:16]1=2
Reactant: CC(=O)c1ccc(SCC(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(SCC(=O)O)cc1

Procedure:
The title compound was prepared by condensing (4-acetylphenylthio)acetic acid (Ex-23B) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A) in a similar manner as described in Ex-22. Yellow solid, mp 136–138° C. (dec.). 1H-NMR (DMSO-d6) δ 8.35 (s, 1H), 8.08 (d, J=7.4 Hz, 2H), 8.03 (d, J=16.3 Hz, 1H), 7.93–7.87 (m, 3H), 7.82 (d, J=7.0 Hz, 1H), 7.42 (d, J=7.9 Hz, 2H), 7.37–7.27 (m, 2H), 6.85 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.93 (s, 2H). MS m/z=491 ([M+H]+, 100%).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH3:22][O:23][CH:24]([CH3:27])[CH2:25][NH2:26].C(#N)C>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:26][CH2:25][CH:24]([O:23][CH3:22])[CH3:27]
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: COC(C)CN
Agent: Br
Solvent: CCO
Solvent: CC#N
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCC(C)OC)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 5 g of 2-methoxypropyl amine in 100 ml of ethanol and worked up. Colorless crystalline solid substance, melting point: 148° C. (acetonitrile/active charcoal).
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH:13]C(=O)[O-])([CH3:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1.[Si](I)(C)(C)C.CO.O>C(#N)C>[F:17][CH:2]([F:1])[O:3][C:4]1[N:9]=[C:8]([C:10]([NH2:13])([CH3:11])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(NC(=O)[O-])c1cccc(OC(F)F)n1
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CC#N
Solvent: CO
Product: CC(C)(N)c1cccc(OC(F)F)n1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-ylcarbamate (12.4 g, 48 mmol) in acetonitrile (50 mL) was added TMSI (10 mL). The reaction was stirred 30 min and then poured into methanol (100 mL) and water (5 mL). The mixture was concentrated, dissolved in ethyl acetate (200 mL), and then washed with 1N NaOH (2×30 mL). The organic layer was separated, dried over Na2SO4, concentrated, and chromatographed with silica gel (50% EtOAc/hex, then 5-20% MeOH/CH2Cl2) to afford 2-(6-(difluoromethoxy)pyridin-2-yl)propan-2-amine (8.8 g, 92%) as a yellow oil.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.[CH3:29][C:30]([CH3:41])([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])[CH3:31]>ClCCl>[CH3:31][C:30]([CH3:41])([O:32][C:33]([N:35]1[CH2:36][CH2:37][N:38]([C:5]([N:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]2)=[O:11])[CH2:39][CH2:40]1)=[O:34])[CH3:29]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1.1 g of triphosgene (3.7 mMol) in 20 ml of dichloromethane, a mixture of 1.2 g (10 mMol) of 1-methyl-piperazine, 0.38 ml (22 mMol) of DIEA and 35 ml of dichloromethane was added dropwise at room temperature within 30 minutes, and then the solution of 1.9 g (10 mMol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 0.38 ml of DIEA in 20 ml dichloromethane were added. After stirring for an hour at room temperature, insoluble matter was filtered off and the filtrate evaporated down in vacuo. After purification of the raw product on silica gel (Amicon, 35-70 μm), using dichloromethane/methanol/conc. ammonia(80/20/1 v/v/v) for elution, 700 mg (22% of theory) of colourless crystals were obtained of Mp. 130° C.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13](=[O:38])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N:21]1[CH:26]=[CH:25][C:24](=[O:27])[C:23]([O:28]CC2C=CC=CC=2)=[C:22]1[CH2:36][CH3:37])=[O:17])=O)C1C=CC=CC=1.C(O)C.[ClH:42]>[Pd].O>[ClH:42].[Cl-:42].[NH2:11][CH2:12][C:13](=[O:38])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][N+:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[C:22]=1[CH2:36][CH3:37])=[O:17]
Reactant: CCc1c(OCc2ccccc2)c(=O)ccn1CCOC(=O)CCC(=O)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1c(O)c(O)cc[n+]1CCOC(=O)CCC(=O)CN
Product: [Cl-]
Reaction time: 2 h
Yield: 96 %

Procedure:
A stirred solution of 2-(3-(benzyloxy)-2-ethyl-4-oxopyridin-1(4H)-yl)ethyl 5-(benzyloxycarbonylamino)-4-oxopentanoate (7) (247 mg, 0.475 mmol) in 6:1 v/v ethanol:water (3.5 mL) was acidified to pH=1 by addition of hydrochloric acid (37% aq.). Palladium on activated charcoal (11 mg, 10% w/w) was added, the reaction vessel was evacuated then filled with hydrogen and the reaction was stirred under hydrogen (at atmospheric pressure) for 2 h. The resulting suspension was filtered through Celite®, eluting with ethanol and the filtrate was then concentrated in vacuo to give the product as a mixture of mono- and di-salts. Three cycles of dissolution in water, addition of hydrochloric acid (37% aq.) then concentration in vacuo gave the title compound 8 (169 mg, 96%) as a brown oil, δH (300 MHz; D2O) 7.82 (1H, d, J 8.0 Hz, Ar 6-H), 6.92 (1H, d, J 8.0 Hz, Ar 5-H), 4.27 (2H, t, J 6.0 Hz, OCH2CH2), 3.91 (2H, s, H3N+CH2), 3.74 (2H, t, J 6.0 Hz, OCH2CH2), 2.80 (2H, q, J 7.0 Hz, CH3CH2), 2.66 (2H, t, J 6.0 Hz, C(O)CH2), 2.45 (2 H, t, J 6.0 Hz, C(O)CH2) and 0.98 ppm (3H, t, J 7.0 Hz, CH3); δC (75 MHz; D2O) 204.3, 176.9, 158.6, 147.7, 142.5, 139.5, 111.0, 60.6, 57.8, 47.3, 34.6, 27.6, 20.1 and 11.3 ppm; m/z (ES+) 297.1445 (100%, [M-H-2Cl]+), C14H21N2O5 requires M, 297.1445.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].C(=O)(O)[O-].[Na+].[NH:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:15]([CH2:19][CH2:20][OH:21])[CH2:16][CH2:17][OH:18])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: OCCNCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: OCCN(CCO)c1nc(Cl)nc(Cl)n1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
25 Grams cyanuric chloride was dissolved in 145 ml. acetone and the solution poured over 100 grams of ice. Sodium bicarbonate (12.4 grams) was added. While maintaining the temperature at 10°C., diethanolamine (15.5 grams) was added dropwise over a period of about 30 minutes. The temperature was raised to 20°-25°C. and the mixture stirred for about 1 hour. The reaction mixture was filtered, washed witth water and dried to give 31.4 grams of product.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][NH:10][CH:11]=1)=[O:5].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:26]([O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[CH:11]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])[CH:8]=[N:9]1)[CH2:27][CH2:28][CH3:29]
Reactant: O=C(Nc1cn[nH]c1)c1c(F)cccc1F
Reactant: CCCCOc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccccc1Cn1cc(NC(=O)c2c(F)cccc2F)cn1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
2,6-Difluoro-N-1H-pyrazol-4-ylbenzamide (for a preparation see intermediate 2, 45 mg, 0.20 mmol), 1-(bromomethyl)-2-(butyloxy)benzene (for a preparation see intermediate 4, 56 mg, 0.23 mmol) and potassium carbonate (42 mg, 0.30 mmol) were weighed into a vial with a stirrer. DMF (0.5 ml) was added, the vial was capped and the mixture was stirred at ambient temperature for 26 h. The reaction mixture was filtered, washing with MeOH to give a total volume of 1 ml. This solution was purified by MDAP Sunfire C18 column (Method B) using acetonitrile-water with a formic acid modifier. The solvent was removed to give the title compound (25 mg) as a colourless gum; LCMS (System 4): MH+=386, tRET=3.02 min.