Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[I:14](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.O>CO.C(Cl)Cl>[C:1]([C:5]1[CH:12]=[C:11]([I:14])[CH:10]=[C:7]([CH:8]=[O:9])[C:6]=1[OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(C=O)c1O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(I)cc(C=O)c1O
Reaction time: 2 h

Procedure:
3-tert-butyl salicylaldehyde (1) (8.4 mmol) was dissolved in 100 ml of a mixture of methanol and methylene chloride (3:7). Benzyltrimethylammonium dichloroiodate (3.23 g; 9.2 mmol) and water free calcium carbonate (1.1 g; 11 mmol) were added. After two hours, the excess of calcium carbonate was filtered off. After removal of about 80% of the solvent, 20 ml of a sodium hydrogensulfite solution (5%) was added decolourizing the mixture. Extraction with diethyl ether, drying over sodium sulphate and removal of the solvent yielded the aldehyde as raw product. Purification by recrystallization from n-pentane produced 3-tert-butyl-5-iodosalicylaldehyde in a 48% yield as yellow crystals which are slightly light sensitive and should be stored in the dark.
Reaction SMILES: Br[C:2]1[C:3]([Cl:32])=[CH:4][C:5]([O:30][CH3:31])=[C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:7]=1.[Zn](CC)[CH2:34][CH3:35]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:32][C:3]1[C:2]([CH2:34][CH3:35])=[CH:7][C:6]([NH:8][C@@H:9]([CH3:29])[C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:21]3)[CH2:16][CH2:17]2)=[O:11])=[C:5]([O:30][CH3:31])[CH:4]=1
Reactant: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(N[C@@H](C)C(=O)N2CCN(C3CN(C(=O)OC(C)(C)C)C3)CC2)c(OC)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(4-(2-((5-bromo-4-chloro-2-methoxyphenyl)amino)propanoyl)piperazin-1-yl)azetidine-1-carboxylate (400 mg, 0.75 mmol), PdCl2(dppf) (95 mg, 0.13 mmol) in THF (20 mL) at RT, Et2Zn (2.86 mL, 2.86 mmol, 1.0 M in hexane) was added. The resulting mixture was stirred under argon at 80° C. for 4 h and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (methanol/dichloroethane=1:80) to afford the desired product (250 mg, 69% yield). ESI-MS m/z: 481.2[M+H]+.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:21][O:22]C1C=CC(B(O)O)=CC=1>>[CH3:21][O:22][C:8]1[CH:7]=[CH:6][C:5]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH2:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc2c(-c3cccc(C(F)(F)F)c3)cccn2n1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccn3nc(N)nc23)cc1

Procedure:
Made by following the procedure described for the preparation of 8-(3-(trifluoromethyl)phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-amine with 4-methoxyphenyl boronic acid and making non-critical variations.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=O.C1(C(=[N:31][C@@:32]2([C:38](OCC)=[O:39])[CH2:34][C@H:33]2[CH2:35][O:36][CH3:37])C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[K+].C(O)(=O)C>C1COCC1.C(O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[C:6]3[C:5]([CH3:16])=[C:4]([CH3:17])[S:3][C:2]=3[NH:1][C:38](=[O:39])[C@@:32]3([CH2:34][C@H:33]3[CH2:35][O:36][CH3:37])[N:31]=2)=[CH:10][CH:11]=1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: CCOC(=O)[C@]1(N=C(c2ccccc2)c2ccccc2)C[C@H]1COC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC[C@@H]1C[C@]12N=C(c1ccc(Cl)cc1)c1c(sc(C)c1C)NC2=O
Temperature: 25 °C

Procedure:
To a solution of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (7.09 g, 26.7 mmol) and (1S,2R)-ethyl 1-((diphenylmethylene)amino)-2-(methoxymethyl)cyclopropanecarboxylate (6 g, 17.78 mmol) in anhydrous THF (100 mL) was slowly (over 5 min) added a solution of potassium tert-butoxide (1 M in THF) at rt. The reaction was heated to 60° C. for approximately 20 h before acetic acid (10.68 g, 178 mmol) and absolute ethanol (20 mL) were added at 60° C. THF was distilled off, and the reaction was heated to reflux for 3 h. The reaction was cooled to rt before silica gel was added, and the solvent was removed under vacuum. The dry silica gel was packed and the product was purified by flash chromatography (EtOAc/hexane 1:19 to 6:14) to give (1S,2R)-5′-(4-chlorophenyl)-2-(methoxymethyl)-6′,7′-dimethylspiro[cyclopropane-1,3′-thieno[2,3-e][1,4]diazepin]-2′(1′H)-one a solid (3.7 g). LRMS (M+H)+: 375 m/z.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)=[CH:7][C:6]=1[CH2:20][N:21](CC1C=CC(OC)=CC=1OC)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C.CCC([O-])(C)C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:26]([O:25][C:23]([C:22]1[N:21]=[CH:20][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)[CH:7]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2ccc(Cl)c(F)c2)ccc1C(=O)OCC
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To an ice-water bath cooled solution of 4-(4-chloro-3-fluoro-phenoxy)-2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (2.529 g) in THF (20 mL) was added a solution of potassium tert-pentoxide (4.5 mL, 1.7 M in toluene); the mixture was stirred at rt for 60 min after addition; then the mixture was quenched with 2 M HCl, diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (30 mL) and treated with thionyl chloride (0.63 mL) overnight. Then concentrated, the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (580 mg). LC MS ESI: 362 (M+1)+.
Reaction SMILES: Br[C@:2]12[C@@H:19]([OH:20])[CH2:18][C@@:16]3([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]3=[O:21])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:23])[CH2:4][CH2:5][C:6](=[O:22])[CH:7]=1.C(O)(=O)CS.O>CN(C=O)C>[OH:20][C@H:19]1[CH2:18][C@@:16]2([CH3:17])[C@@H:12]([CH2:13][CH2:14][C:15]2=[O:21])[C@H:11]2[C@H:2]1[C@:3]1([CH3:23])[C:8]([CH2:9][CH2:10]2)=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3CCC(=O)[C@@]3(C)C[C@H](O)[C@@]12Br
Agent: O=C(O)CS
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Yield: 85.3 %

Procedure:
A solution of 9α-bromo-11β-hydroxyandrost-4-ene-3,17-dione (III, 3.00 g) thioglycolic acid (3.0 ml) in DMF (17 ml) is stirred under nitrogen in a 45°-50° water bath. A chromous sulfate solution (1.4 M, 7.0 ml) is added dropwise over about 5 minutes. The mixture is allowed to cool, and the resulting slurry is diluted by slow addition of water (50 ml). The mixture is cooled to about 5° and filtered. The filter cake is washed with water and air dried to give the title compound (2.03 g, 85.3% chemical yield) which is identical with an authentic sample. The filtrate is extracted to give additional material (0.34 g, 14.3%).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23](B(O)O)=[CH:24][CH:25]=[CH:26][CH:27]=1.[CH2:37]([SH:40])[CH:38]=[CH2:39]>>[CH2:37]([S:40][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:38]=[CH2:39]
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: C=CCS
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3-c3ccccc3)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 2-biphenylboronic acid. Bromination and coupling reaction with allyl mercaptan gave 13 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:14]3[N:15]=[C:16]([S:27][CH3:28])[C:17]([N:18]([CH2:23][CH:24]4[CH2:26][CH2:25]4)[CH2:19][CH:20]4[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.C([Sn]([C:44]1[S:45][CH:46]=[CH:47][N:48]=1)(CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:20]1([CH2:19][N:18]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[C:17]2[C:16]([S:27][CH3:28])=[N:15][N:14]3[C:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([C:44]5[S:45][CH:46]=[CH:47][N:48]=5)=[CH:3][C:4]=4[O:29][CH3:30])=[CH:10][CH:11]=[CH:12][C:13]=23)[CH2:22][CH2:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1cc(Br)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nccs2)cc(C)c1-c1cccc2c(N(CC3CC3)CC3CC3)c(SC)nn12
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
After dissolving N-[7-(4-bromo-2-methoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine (45 mg) in toluene (0.60 mL), tributylstannylthiazole (52 mg) and tetrakis (triphenylphosphine)palladium (0) complex (9 mg) were added, the mixture was heated and stirred at 120° C. for 2 hours and then cooled to room temperature, and ethyl acetate was added. After filtering out the precipitated insoluble portion, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to obtain the title compound (30 mg) as white crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][N:21]=[N+]=[N-])([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O>[C:1]([N:8]1[CH2:9][CH2:10][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)([CH2:20][NH2:21])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN=[N+]=[N-])(C2CCCCC2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 26.5 %

Procedure:
A 25-mL, round-bottomed flask was charged with Intermediate 1c (0.259 g, 0.803 mmol), 8 mL of THF, and triphenylphosphine (0.32 g, 0.884 mmol). The mixture was stirred at room temperature for 3.5 h and then 0.10 mL of water was added. The resulting reaction mixture was stirred at room temperature for 66 h, and then diluted with ethyl acetate and water. The layers were separated, and the organic phase was washed with water and saturated sodium chloride solution, dried over potassium carbonate, filtered and concentrated. The crude product was purified by column chromatography (gradient elution: 1:4 ethyl acetate-hexane, 9:1 ethyl acetate-methanol, and then 100% methanol) to give the free amine (0.063 g) as a clear oil.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7](=[O:19])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:11]=2)=[N:4][N:3]=[N:2]1.[S:20](Cl)([OH:23])(=O)=[O:21].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH:4]1[C:5]([NH:6][C:7](=[O:19])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH:18][S:20]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)(=[O:23])=[O:21])[CH:11]=2)=[N:1][N:2]=[N:3]1
Reactant: O=S(=O)(O)Cl
Reactant: Clc1ccccc1
Reactant: NCCc1cccc(OCC(=O)Nc2nnn[nH]2)c1
Product: O=C(COc1cccc(CCNS(=O)(=O)c2ccc(Cl)cc2)c1)Nc1nnn[nH]1

Procedure:
In a manner analogous to that described in Example 1, by the reaction of the appropriate 3-(2-aminoethyl)-phenoxyacetic acid (1H-tetrazol-5-yl)-amide with 4-chlorobenzene sulphochloride, there is obtained the title compound; m.p. 190°-196° C. (decomp.), after crystallisation from glacial acetic acid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].[S:14](=[O:18])(=O)(O)[OH:15]>O>[CH2:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([Cl:3])(=[O:18])=[O:15])=[CH:10][CH:9]=1)[CH3:7]
Reactant: CCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: CCc1ccc(S(=O)(=O)Cl)cc1
Temperature: 69 °C
Reaction time: 2 h

Procedure:
With stirring, 929.0 g phosphorus oxychloride was added to 836.0 g ethylbenzene. The resulting mixture was heated to approximately 69° C. and 599.0 g of 100 percent sulfuric acid was added over approximately sixteen minutes with the temperature rising to approximately 78° C. and it continued to slowly rise over approximately thirty-seven minutes to approximately 84° C. The mixture was held at approximately 80° C. for about two hours and then maintained at approximately 90° C. for an additional three hours. After cooling to approximately 82° C. the reaction mixture was poured slowly onto a mixture of 1500.0 ml water and 1500.0 g ice keeping the temperature under 5° C. with the addition of 440.0 g ice. After approximately ten minutes of stirring, the agitation was stopped and the mixture separated into two layers. The lower layer containing the product was separated and immediately poured onto 500.0 g of ice and 3500.0 ml of ice water was added. After approximately twenty minutes of stirring, the layers were separated to obtain 1400.0 ml of 4-ethylbenzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)[S:4][N:3]=1.[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1B1OC(C)(C)C(C)(C)O1)[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([C:23]1[C:28](/[CH:29]=[CH:30]/[O:31][CH3:32])=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)[S:4][N:3]=1)[CH3:22]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Temperature: 120 °C
Yield: 97.5 %

Procedure:
To a solution of 3-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (D45) (487 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (573 mg) and tripotassium phosphate (845 mg) in N,N-dimethylformamide (DMF) (4 mL) and water (0.800 mL) stirred under nitrogen at room temp was added Pd(Ph3P)4 (153 mg). The reaction mixture was sealed and heated under microwave at 120° C. for 10 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazole (D49) (580 mg) as a colorless oil. MS (ES): C23H23F3N2O2S requires 448. found 449.1 (M+H+).
Reaction SMILES: [C:1](/[CH:3]=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:2].[S:10]1C=CC=C1CC(O)=O.CCN(C(C)C)C(C)C.C1C[O:31][CH2:30][CH2:29]1>>[C:30]([S:10][CH:3]([C:1]#[N:2])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:31])[CH3:29]
Reactant: CCOC(=O)/C=C\C#N
Reactant: O=C(O)Cc1cccs1
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C#N)SC(C)=O
Reaction time: 4 h
Yield: 65 %

Procedure:
(Z)-ethyl 3-cyanoacrylate (5.01 g, 40.00 mmol) in 80 ml of THF at −20° C. was added the solution of thiol acetic acid (5.0 ml, 70.15 mmol) and DIPEA (16.0 ml, 92.03 mmol) in 20 ml of THF in 30 min. The reaction was kept at −20° C. for 4 hr then room temperature overnight. The mixture was concentrated, diluted with CH2Cl2, washed with saturated NaHCO3, dried over MgSO4, filtered, evaporated and purified by SiO2 chromatography (1:4 EtAC/Hexane) to afford 5.22 g (65%) of the title compound. Rf=0.25 (1:4 EtAC/Hexane); 1H NMR (CDCl3), 4.44 (m, 1H), 4.11 (dd, 2H, J=7.1, 14.3 Hz), 3.38 (m, 1H), 3.15 (m, 1H), 2.17 (s, 3H), 1.19 (t, 3H, J=7.2 Hz); 13C NMR 194.12, 173.21, 119.82, 61.35, 33.52, 30.08, 14.62; MS m/z+ 225.9 (MW+Na), m/z− 201.7 (MW−H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[C:5]([C:6]#[N:7])=[C:4]([F:18])[CH:3]=1.C(Cl)Cl.B(Br)(Br)Br>O>[Br:1][C:2]1[CH:9]=[C:8]([OH:10])[C:5]([C:6]#[N:7])=[C:4]([F:18])[CH:3]=1
Reactant: N#Cc1c(F)cc(Br)cc1OCc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(O)cc(Br)cc1F
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a 500-mL RBF was added 4-bromo-2-fluoro-6-[(phenylmethyl)oxy]benzonitrile (5 g, 16.33 mmol) and CH2Cl2 (100 mL). The flask was cooled in an ice-water bath and BBr3 (49.0 mL, 49.0 mmol) (solution in CH2Cl2) was added dropwise via syringe. The red solution was allowed to warm to room temperature over 1 hour. The solution was poured into water (200 mL) and extracted with EtOAc (3×200 mL). The combined organics were concentrated to a yellow residue. The residue was treated with CH2Cl2, and a precipitate formed which was collected to afford the title compound (2.830 g) as a fine yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.03 (t, J=1.4 Hz, 1H), 7.29 (dd, J=9.0, 1.6 Hz, 1H), 12.23 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.Cl.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>C(O)C>[ClH:1].[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Agent: Cl
Solvent: CCO
Product: Clc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1

Procedure:
A mixture of 0.972 g (3.8 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine, 0.656 g (4 mmol) 4-chloroaniline hydrochloride (Research Organics, Inc., Cleveland, Ohio, USA) and 20 ml ethanol is heated for 2 h under reflux. The reaction mixture is cooled in an ice bath, filtered, and the crystallizate washed with a little ethanol and ether. After drying under HV for 8 h at 110° C. and for 10 h at 150° C., the title compound is obtained as a result of thermal removal of HCl; m.p. >270° C.; 1H NMR (DMSO-d6) 9.80-11.40 (br), 8.89-8.94 (m, 1H), 8.67 (d, 2H), 8.25-8.30 (m, 1H), 8.06-8.17 (m, 2H), 7.87 (d, 2H), 7.69 (d, 2H), 7.49 (d, 2H), 4.81 (s, 2H); ESI-MS: (M+H)+=347.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[NH:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](CO)[CH:28]=1>C(Cl)Cl>[N:13]1([C:5]([O:6][CH2:7][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:11])[C:22]2[C:17](=[CH:18][C:19]([C:23]([O:25][CH3:26])=[O:24])=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: OCc1cccnc1
Reactant: COC(=O)c1ccc2c(c1)CCCN2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)CCCN2C(=O)OCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.7 %

Procedure:
A solution of triphosgene (0.489 g, 1.61 mmol) in DCM (5 mL) was treated with compound 212 (0.286 g, 1.50 mmol) and the solution was stirred under N2 atmosphere at room temperature for 18 h. The DCM was removed under reduced pressure, the residue was dissolved in pyridin-3-yl methanol (1.0 mL, 10.3 mmol) and the solution was stirred at room temperature for 8 h then diluted with DCM, washed with saturated NaHCO3, H2O, dried over MgSO4, filtered and concentrated to give title compound 213 (0.527 g, 100% yield).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH2:32])([O-:24])=[O:23].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:32]1)([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Reactant: C=Cc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4[N+](=O)[O-])C3)cs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.80 g) and 1-nitro-2-vinylbenzene (1.60 g) in ethyl acetate (50 ml) were added, at room temperature, potassium hydrogencarbonate (4.50 g) and N-chlorosuccinimide (1.44 g) and then one drop of water. After stirring at 60° C. overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.10 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28]O)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Diethyl azodicarboxylate (630 μL, 4.00 mmol) was added to a mixture of 2-hydroxypyridine (0.380 g, 4.0 mmol), tert-butyl(2-hydroxyethyl)carbamate (0.322 g, 2.0 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in THF (6.0 mL). The mixture was stirred overnight at RT, and concentrated. The residue was chromatographed on silica gel with EtOAc in hexanes to give the product (0.353 g, 74.1%). LCMS: (M+H)=239.2.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CNCCc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCc1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
A solution of chloroacetylchloride (10.0 g, 88.7 mmol) in tetrahydrofuran (50 mL) was added to a solution of N-methylphenethylamine (10.0 g, 73.9 mmol) and triethylamine (11.2 g, 110.8 mmol) in tetrahydrofuran (200 mL) cooled by a water/ice bath. The reaction mixture was allowed to warm to ambient temperature. After stirring for 6 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give SiO2, 1:1 ethyl acetate/hexane) to give 13.5 g (86.6%) of brown oil.