Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=O)[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>O1CCOCC1>[C:1](=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=[S:39])[CH2:24][O:23][CH2:22]2)[CH:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=O)N1
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=S)N1
Temperature: 80 °C

Procedure:
A solution of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-one (1.53 g, 3.94 mmol) in dioxane (30 ml) was treated with Lawesson's reagent (1.3 g, 3.15 mmol). The orange coloured suspension was heated in a sealed tube at 80° C. for 18 hours. For the workup, the meanwhile green coloured reaction mixture was evaporated at reduced pressure and the residue directly purified by flash chromatography on a silica-amine phase using a gradient of heptane/ethyl acetate=100:0 to 40:60 as the eluent. The (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-thione was obtained as a yellow solid (0.803 g, 50%); (calculated) C24H21FN2OS [404.51]; (found) [M+H]+=405.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
While 30 mL solution of 2.72 g 4-hydroxyacetophenone and 5.2 mL diisopropyl ethylamine in dichloromethane was stirred under ice-cooling in a stream of nitrogen, 4.2 mL 2-(trimethylsilyl)ethoxymethyl chloride was added thereto. Then, the reaction solution was stirred at room temperature for 4 hours. The reaction solution was evaporated, then ethyl acetate and water were added to the residue, the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 5.22 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]([N:6](C)C)=[CH2:5])[CH2:3][CH2:2]1.[F:9][C:10]([F:23])([F:22])[C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([N:15]=[C:16]=[O:17])=O.C([O-])(=O)C.[NH4+].C(O)(=O)C>O1CCCC1.O>[CH:1]1([C:4]2[N:6]=[C:13]([C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[C:10]([F:23])([F:22])[F:9])[NH:15][C:16](=[O:17])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C=NC(=O)c1ccccc1C(F)(F)F
Reactant: C=C(C1CC1)N(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1cc(C2CC2)nc(-c2ccccc2C(F)(F)F)[nH]1
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of (1-cyclopropyl-vinyl)-dimethylamine in tetrahydrofuran (400 mL) at 0° C. under nitrogen was added a solution of 2-trifluoromethylbenzoyl isocyanate in tetrahydrofuran (50 mL), in a dropwise fashion. The reaction was stirred for 0.5 hour, then ammonium acetate (78 g, 1000 mmol) and acetic acid (400 mL) was added. The reaction mixture was heated at reflux for 3 hours with continuous removal of tetrahydrofuran, then cooled and poured into water (1.2 L). The resulting precipitate was collected by filtration, washing with water and ether to provide 6-cyclopropyl-2-(2-trifluoromethyl-phenyl)-3H-pyrimidin-4-one (28.79 g, 56% yield) as a white solid which is a mixture of the title compound and (2-trifluoromethyl-benzoyl)-urea (91:9 by HPLC). 1H-NMR (500 MHz, DMSO-d6) δ 12.7 (br s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.79 (m, 2H), 7.73 (d, J=7.5 Hz, 1H), 6.32 (s, 1H), 1.93 (m, 1H), 0.90 (m, 4H), [urea: 10.8 (br s, 1H), 7.45 (br s, 1H)] ppm; LC-MS 280.96 (M+H); Rt (Method A) 2.961 minutes (title compound), 2.313 minutes (urea impurity).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH2:11][CH3:12])=[CH:8][C:7]([O:13][CH2:14][CH3:15])=[CH:6][C:5]=1[O:16][CH2:17][CH3:18])([O-])=O.[Cl-:19].[NH4+]>C(O)(C)C.[Fe]>[ClH:19].[CH2:17]([O:16][C:5]1[CH:6]=[C:7]([O:13][CH2:14][CH3:15])[CH:8]=[C:9]([O:10][CH2:11][CH3:12])[C:4]=1[NH2:1])[CH3:18]
Reactant: [Cl-]
Reactant: CCOc1cc(OCC)c([N+](=O)[O-])c(OCC)c1
Agent: [Fe]
Agent: [NH4+]
Solvent: CC(C)O
Product: CCOc1cc(OCC)c(N)c(OCC)c1
Product: Cl
Yield: 35.8 %

Procedure:
2-Nitro-1,3,5-triethoxybenzene (12.8 g) in isopropyl alcohol (80 ml) was reacted at 90° C. for 2 hours with an iron powder (28 g) and aqueous ammonium chloride solution (2.85 g/water 8.4 ml). This mixture was extracted with ethyl acetate and the solvent of the extract was distilled off. To the resulting solution was further added conc. hydrochloric acid (6 ml), and the mixture was washed with a small amount of aceton to obtain 2,4,6-triethoxyaniline hydrochloride (4.7 g). 2,4,6-Triethoxyaniline hydrochloride (2.6 g) was dissolved in methanol (50 ml) , and the solution was acidified with conc. hydrochloric acid (3.5 ml). Then, aqueous sodium nitrite solution (1.4 g/water 10 ml) was added slowly to this solution while cooling with ice. Two hours later, 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid (6.2 g) was added to the solution. One hour later, this mixture was extracted with methylene chloride, and the extract was washed with water. Then, the solvent of the resulting solution was distilled off to obtain 2,4,6-triethoxybenzenediazonium 2-hydroxy-4-methoxybenzophenone-5-sulfonate (4.5 g) as a pale yellow powder.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CCOCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CCOCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.6 h
Yield: 42.1 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 2.2 g.), conc hydrochloric acid (2 ml.) and methanol (30 ml.) was stirred at room temperature for 1.6 hours. After concentrating the resultant solution in vacuo, water was added to the residue, adjusted to pH 6.5 with sodium bicarbonate and washed with ethyl acetate. The aqueous solution was treated with activated charcoal and adjusted to pH 3.0 with conc. hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-aminothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.87 g.).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH:12](OC)(OC)OC.S(=O)(=O)(O)O>CO>[CH3:12][O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=1)[OH:11]
Reactant: O=C(O)c1cc(I)ccc1O
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)ccc1O

Procedure:
5-Iodosalicylic acid (Aldrich Chemical Company, Milwaukee, Wis.) is converted to the methyl ester by reaction with methanol, trimethyl orthoformate and sulfuric acid. The 5-iodosalicylic acid methyl ester thus obtained is reacted with (trimethylsilyl)acetylene (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium. The trimethylsilyl group is removed and two equivalents of the resultant 5-acetylenylsalicylic acid methyl ester is reacted with 4,4′-dibromobiphenyl (Aldrich Chemical Company, Milwaukee, Wis.) in the presence of palladium as above. The resultant alkynyl analogue of Chrysamine G, 4,4′-bis(3-methoxycarbonyl-4-hydroxyphenylacetylenyl)-biphenyl is prepared by hydrolysis of the ester as described above. This alkynyl analogue is reduced by conventional methods to form the vinyl analogue of Chrysamine G.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:22](=[O:24])[CH3:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:22](=[O:24])[CH:23]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:31][CH:32]=1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccc(Cl)cc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccc(Cl)cc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
p-Chlorobenzaldehyde (2.81 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(p-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (3.0 g., .009 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.), and extracted with ether to remove the excess p-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the yellowish solid which precipitates is collected and air-dried to yield 3.1 g., m.p. 65°-145°C. Several recrystallizations from n-butyl chloride yields a material with m.p. 176°-178.5°C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([NH:22][CH3:23])[CH2:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>O.C(#N)C>[CH3:33][N:34]([CH3:39])[S:35]([N:22]([CH3:23])[CH:21]1[C:12]2=[N:11][C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=3)=[O:9])=[C:15]([OH:16])[C:14](=[O:17])[N:13]2[CH2:18][CH2:19][CH2:20]1)(=[O:37])=[O:36]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CNC1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)N(C)C1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of crude compound obtained in Step 3 in a 2:1 mixture of tetrahydrofuran and 2 M aq. sodium hydroxide was added N,N-dimethylsulfamoyl chloride (4.6 eq.). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the product was isolated by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TEA) as eluents (column: C18). The pooled product fractions were lyophilized to afford the title compound as a fluffy, slightly pink material.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:17])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)=[N:4][N:3]=1.[CH2:22]([O:24][C:25]([N:27]=[C:28]=[S:29])=[O:26])[CH3:23]>O1CCCC1>[CH2:22]([O:24][C:25](=[O:26])[NH:27][C:28]([NH:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]([OH:17])=[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:12]=2)=[N:4][N:3]=1)=[S:29])[CH3:23]
Reactant: CC(C)(C)c1cc(-c2nnc(N)s2)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)Nc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-(5-amino-1,3,4-thiadiazole-2-yl)-2,6-bis(1,1-dimethylethyl)phenol (1.5 g, 0.005 mole) in tetrahydrofuran (10 ml) is added ethoxycarbonylisothiocyanate (0.64 g, 0.005 mole) dropwise. The resulting mixture is stirred 18 hours at room temperature, before concentrating in vacuo. The residue is recrystallized from ethanol/water to provide 1.7 g (2.2 g theor., 78%) of the title compound after drying in vacuo at 50° C., mp >25° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[Br:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([F:9])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: Oc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To a solution of 5.0 g (24.0 mmol) of 2,6 difluoro-4-bromophenol in 20 ml of DMF at rt was added 5 g (36.0 mmol) of K2CO3 followed by 4.5 g (26.3 mmol) of benzyl bromide. The mixture was stirred for 12 h, diluted with H2O, the organic phase washed with sat'd NaCl, and the aqueous phase was then extracted 3× with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography with a gradient of 0-15% ethyl acetate/hexanes (v/v) afforded 6.3 g (88%) of the title compound: 1H NMR (500 MHz) δ 5.17 (s, 21), 7.06-7.11 (2H). 7.34-7.45 (5H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:23]I>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ester from step (a) above (4.3 g, 15.5 mol) in DMF (30 mL) was added NaH (60% in mineral oil, 0.93 g, 23.2 mmol) and the mixture was stirred at 0° C. for 1 h. MeI (1.16 mL, 18.6 mmol, Aldrich) was added drop-wise with stirring at 0° C., and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with EtOAc (50 mL), washed with saturated solution of NH4Cl (25 mL) and brine (25 mL), dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue purified by silica gel chromatography, eluting with 10% EtOAc/hexane, to give the title compound as a light-yellow oil, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 292 (M+1).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[N:24]([CH3:25])[NH:23][C:22](=[O:26])[CH:21]=1>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:21]3[C:22](=[O:26])[NH:23][N:24]([CH3:25])[C:20]=3[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: O=C1COCC(=O)C1
Solvent: CCO
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(Br)c1
Yield: 46.5 %

Procedure:
2H-Pyran-3,5(4H,6H)-dione (0.34 g, 3 mmol), 3-bromo-4-fluoro-benzaldehyde (0.61 g, 3 mmol), and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.34 g, 3 mmol) in ethyl alcohol (6 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was cooled and the resulting precipitate was filtered off to provide 0.55 g (46%) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 3.5 (s, 3H), 4.1 (s, 2H), 4.53 (q, 2H), 4.98 (s, 1H), 7.18 (m, 1H), 7.21 (t, 1H), 7.4 (dd, 1H), 9.65 (bs, 1H), 10.52 (s, 1H); MS (ESI−) m/z 394,392 (M−H)−; Anal. calcd for C16H13N3BrFO3: C, 49.11; H, 4.35; N, 9.54. Found: C, 49.08; H, 3.83; N, 9.35.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:20]/[N:21]=[C:22]1\[NH:23][CH:24]=[CH:25][C:26]([I:28])=[CH:27]\1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(/C=N/N=c3/cc(I)cc[nH]3)nc12
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(I)ccn34)nc12
Reaction time: 0.08 h

Procedure:
8-(tert-butyldimethylsilyloxy)-2-((E)-((Z)-(4-iodopyridin-2(1H)-ylidene)hydrazono)methyl)quinoline was weighed into a 1 neck flask and dissolved in THF. Iodobenzene diacetate (IBD) (4.199 g) was added portionwise, and the reaction was stirred for 5 minutes. The reaction was quenched with saturated Na2S2O3 (20 mL). The phases were separated, followed by extraction of the aqueous phase with DCM. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (eluting with a 2:1 mixture of Hexanes/ethyl acetate), affording the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]=[C:11]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:13]=[CH:12]2)[CH:9]=1)[C:5]#[N:6].Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(C(C)C)C(C)C>CC(CC)CO>[Cl:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11](=[N:10][C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([NH:1][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:9]=3)[C:5]#[N:6])[CH:12]=[CH:13][N:14]2[CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1
Reactant: ClCCN1CCCCC1
Reactant: N#Cc1cc(N)cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)c1
Agent: Cl
Solvent: CCC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)cc(NCCN2CCCCC2)c1
Yield: 16.9 %

Procedure:
3-amino-5-({7-chloro-1-[2-(piperidin-1-yl)ethyl]-1,4-dihydroquinolin-4-ylidene}amino)benzonitrile prepared from example 21 (132 mg, 0.32 mmol), 1-(2-chloroethyl)piperidine hydrochloride (182 mg, 3 eq) and DIEA (0.51 mL, 9.3 eq) were refluxed in 15 mL of 2-methylbutan-1-ol for 10 h. The reaction mixture was then evaporated and the residue and was purified by preparative thin-layer chromatography (DCM/MeOH/NH4OH//95/5/1) to yield expected compound as a yellow oil (28 mg, 17% yield). m/z (ESI) 517.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N)(C)C>C1COCC1.CCOC(C)=O.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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)N
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(Cl)cc3)c2c1O
Temperature: 25 °C
Yield: 37.7 %

Procedure:
To a solution of 7-Bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (152.5 mg, 0.369 mmol) in THF (5.2 mL) were added Trimethylsilylacetylene (0.105 mL, 0.738 mmol), PdCl2(PPh3)2 (51.8 mg, 0.0738 mmol), CuI (28.1 mg, 0.147 mmol) and isopropylamine (0.32 mL, 2.28 mmol). The reaction mixture was refluxed for 16 h. After cooling to rt, the mixture was diluted with EtOAc (20 mL), and filtered. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2, gave the desired product (60 mg) as white solid: MS (m/z) 431.1 (M+1).
Reaction SMILES: O[CH:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[NH:5][C:4]([CH3:17])=[C:3]1[CH2:18][C:19]([O:21][CH3:22])=[O:20].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CC1=C(C)Nc2c(-c3ccccc3)cnn2C1O
Product: COC(=O)Cc1c(C)nc2c(-c3ccccc3)cnn2c1Cl
Temperature: 0 °C
Yield: 90 %

Procedure:
To methyl 2-(7-hydroxy-5-methyl-3-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.5 g, 1.68 mmol) was added POCl3 (1 mL). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid were filtered and washed with water, then dissolved in ethyl acetate. The organic solution was washed with saturated NaHCO3 and dried over sodium sulfate. The solvent was evaporated to give the title compound (0.48 g, 90%). 1H-NMR (500 MHz, MeOD) δ ppm 2.66 (3H, s), 3.77 (3H, s), 4.04 (2H, s), 7.26 (1H, s), 7.42 (2H, s), 8.09 (2H, s), 8.57 (1H, s).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Cl:29])[CH:16]=1)[C:10]([O:12]C)=[O:11].C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].[OH-].[Li+]>FC(F)(F)C(O)=O>[CH2:41]([O:40][C:38]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]2)=[C:17]([Cl:29])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:39])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)c(Cl)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)O)cc2Cl)S(=O)(=O)N1
Temperature: 130 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Methyl (2S)-2-amino-3-[3-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-propanoate trifluoroacetate (50.0 mg, 0.108 mmol) was dissolved in trifluoroacetic acid (3 mL) and heated in the microwave at 130° C. for 180 s. The reaction was concentrated in vacuo and then dissolved in methanol (1.0 mL). The solution was treated with triethylamine (75.6 μL, 0.542 mmol) and benzyl chloroformate (21.7 μL, 0.152 mmol). The reaction stirred at rt for 2 h. The reaction was then treated with aqueous lithium hydroxide solution (4.0 M, 0.14 mL) and allowed to stir for 2 h. The reaction was quenched with aqueous hydrochloric acid solution (1.0 N, 1.0 mL) and purified by reverse phase HPLC to afford the product as a white solid (26 mg, 51%). LCMS found for C20H20ClN2O7S (M+H)+: m/z=467.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](=O)[C:9](=[CH:12]N3CCOCC3)[CH2:8][CH2:7][C:5]=2[N:6]=1.Cl.[NH2:20][C:21]([NH2:23])=[NH:22].[OH-].[Na+]>CCO>[CH3:1][C:2]1[S:3][C:4]2[C:10]3[N:20]=[C:21]([NH2:23])[N:22]=[CH:12][C:9]=3[CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2c(s1)C(=O)C(=CN1CCOCC1)CC2
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2c(s1)-c1nc(N)ncc1CC2
Yield: 0.1 %

Procedure:
A mixture of 2-methyl-6-morpholin-4-ylmethylene-5,6-dihydro-4H-benzothiazol-7-one (2.24 g, 8.47 mol), guanidine hydrochloride salt (0.89 g, 9.32 mol) and NaOH (0.37 g, 9.32 mol) in EtOH (150 mL) was heated under reflux for 4 h. The reaction mixture was concentrated under vacuum. Flash column chromatography (50% EtOAc:hexane) afforded the title product as a yellow solid (1.66 g, 90%): mp 241-243° C. Anal. RP-HPLC: tR 8.7 min (0-60% MeCN, purity 100%). 1H-NMR (CDCl3): δ 8.06 (s, 1H, Py-H), 5.01 (brs, 2H, NH2), 2.99 (m, 4H, CH2—CH2), 2.76 (s, 3H, CH3). MS (ESI+): m/z 219.02 (M+H)+.