Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:29])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[NH:25][C:24]([CH2:26][CH3:27])=[N:23][C:22]=3[Cl:28])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:30]([B-](F)(F)F)=[CH2:31].[K+].C(N(CC)CC)C.O>C(O)CC.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].C(Cl)Cl>[Cl:28][C:22]1[N:23]=[C:24]([CH2:26][CH3:27])[NH:25][C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([CH:30]=[CH2:31])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:29])=[O:20]
Reactant: C=C[B-](F)(F)F
Reactant: CCc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(Br)c3)c2F)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CC)nc3Cl)c2F)c1
Temperature: 100 °C
Yield: 82.1 %

Procedure:
A solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-2-ethyl-1H-imidazole-5-carboxamide (240 mg, 0.46 mmol), potassium vinyltrifluoroborate (122 mg, 0.92 mmol), PdCl2(dppf)-DCM (15 mg, 0.0184 mmol) and triethylamine (0.13 mL, 0.92 mmol) in n-PrOH (5 mL). The reaction was heated at 100° C. for 6 h, cooled to rt and water was added (20 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the organic extracts were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography (5% to 100% EtOAc/hexanes gradient) to afford the title compound (177 mg, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.14 (br s, 1H), 7.47 (d, 1H), 7.35-7.30 (m, 2H), 7.01 (s, 1H), 6.81 (d, 1H), 6.72-6.64 (m, 2H), 5.92 (d, 1H), 5.35 (d, 1H), 4.51 (d, 2H), 2.58 (q, 2H), 1.16 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(O)[CH:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:18][CH:19]=1
Reactant: CC(n1cncn1)C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)n1cncn1

Procedure:
1,1-bis(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)propan-1-ol (2.0 g) from Example 3xi was dissolved in dry toluene (40 ml), and a catalytic amount of p-toluene sulphonic acid added. The mixture was refluxed in a round bottom flask fitted with a soxhlet extractor filled with molecular sieves (4A) and condenser. Reflux was continued until there was no starting material remaining on tlc. The mixture was poured into water and extracted, washed with water (3X) then dried over anhydrous magnesium sulphate and evaporated on a rotary evaporator. The product was purified by chromatography on silica gel eluted with CH2Cl2 /ethylacetate (3:2). 1,1-bis(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)prop-1-ene was obtained as a white solid (1.0 g) by recrystallisation from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:28])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:23]1[S:24][CH:25]=[CH:26][N:27]=1)[CH3:28]
Reactant: CC(C)(N)c1nccs1
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=398.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41]([O:43]C)=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41]([OH:43])=[O:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C[C@H]1CN(C(=O)c2c(Cc3cccc(F)c3C)c(-c3ccccc3)c3ccccn23)CCN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1
Temperature: 50 °C
Yield: 100.4 %

Procedure:
To a solution of the compound of step 4 (1.40 g, 2.33 mmol) in 15.5 ml of dioxane was added 3.5 ml of a 1 M aqueous solution of lithium hydroxide and the mixture was heated at 50° C. for 1 h. The solvents were evaporated under reduced pressure and the residue was dissolved in 45 ml of water. The solution was cooled to 0° C. and acidified to pH 2 with 5 N hydrochloric acid. The obtained suspension was extracted with EA and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. 1.37 g of the title compound were obtained as a green solid melting at 103-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.O1CCOCC1>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Reactant: C1CNCCN1
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCNCC2)c(Cl)c1

Procedure:
3,4-Dichloronitrobenzene (10 g), piperazine (30 g) and dioxan (10 ml) were stirred for 4 hours under gentle reflux (internal temp. 120°-130°). The mixture was then cooled and water (50 ml) was added; the desired product crystallized out and was filtered off, washed with water and dried: yield of the compound 11.32 g. A small portion (0.6 g) was recrystallized from petroleum b.p. 60°-80°/ethyl acetate, yielding the product, (0.36 g), m.p. 100°-102°.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:15]=[C:16]([NH:17][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 54.9 %

Procedure:
Using 5-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=1[C:41]([F:44])([F:43])[F:42].CCN(CC)CC>C(Cl)Cl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:23][C@@:15]([C:4]2[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:37])=[CH:34][C:33]=1[C:41]([F:42])([F:43])[F:44]
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (30 mg, 0.079 mmol) in CH2Cl2 (0.2 mL) was added 4-fluoro-3-(trifluoromethyl)benzoyl chloride (0.048 mL, 0.158 mmol), followed by Et3N (0.04 mL, 0.158 mmol). The resulting mixture was stirred at room temperature for 5 h. The crude product was purified on a preparative HPLC column type using 30 to 100% CH3CN in H2O with 0.1% TFA for 10 minutes as mobile phase. The solvent was removed under reduced pressure to afford (R)-4-fluoro-N-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (35 mg, 80% yield) as white powder. LC-MS (ESI) 568.30 (M+H), retention time=4.27 min (0-100% MeOH in H2O with 0.1% TFA in a 4-min run); Analytical HPLC: 3.95 min (0-100% CH3CN in H2O with 0.1% TFA in a 4-min run, purity 100%); 1H NMR (400 MHz, CD3OD) δ ppm 3.88-4.01 (m, 1H), 4.10 (d, J=13.18 Hz, 1H), 6.69 (d, J=7.47 Hz, 2H), 6.97-7.51 (m, 11H), 7.99 (d, J=5.71 Hz, 2H), 8.90 (s, 1H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([OH:52])[CH2:46]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(N(C(C)C)CC)(C)C.[N+:65]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][C:69]=1[S:74](Cl)(=[O:76])=[O:75])([O-:67])=[O:66]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:53])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][S:74]([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][C:68]=3[N+:65]([O-:67])=[O:66])(=[O:75])=[O:76])[CH2:46]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OS(=O)(=O)c4ccccc4[N+](=O)[O-])C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg) in dry methylene chloride (20 ml) is added diisopropylethylamine (150 μl) followed by 2-nitrobenzenesulonyl chloride (60 mg), then 4-dimethylaminopyridine (27 mg). The solution is stirred at room temperature under nitrogen atmosphere for 4 h, then quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is washed (water, sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4) and the solvent is removed in vacuo. Chromatography on silica gel gives the title compounds.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[C:14]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:28]([C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:27][CH:26]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(NCC(C)C)c(C)c1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Solvent: c1ccncc1
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2,4-dimethylphenyl)(2-methylpropyl)amine (1.00 g, 5.64 mmol) in pyridine (20 mL) was added 4-[(phenylmethyl)oxy]benzenesulfonyl chloride (1.754 g, 6.20 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo then redissolved in ethyl acetate and washed with a 10% solution of citric acid. At this stage a white precipitate formed and was isolated by filtration, LCMS analysis confirmed the precipitate was the desired product. The organic phase was then washed with 2 M NaOH and further precipitate was collected, again confirmed as the desired product by LCMS analysis. The organic phase was dried with magnesium sulfate, concentrated in vacuo and treated with dichloromethane to give a cloudy suspension, which was filtered to provide more of the desired product. Finally the filtrate was concentrated in vacuo and treated with methanol, whereupon additional product crystallised from the solution. The collected batches of product were combined (974 mg, 2.300 mmol) and used without further purification in the next step. LCMS [LCMS1] Rt 1.54 min, m/z (ES+) 424 (M+H).
Reaction SMILES: CS([Cl:5])(=O)=O.[Cl:6][C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:16](=[O:28])[C:17]3[S:24][C:23]([CH2:25]O)=[C:22]([CH3:27])[C:18]=3[N:19]([CH3:21])[CH:20]=2)=[O:14])=[CH:9][CH:8]=1.N1C(C)=CC(C)=CC=1C>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:16](=[O:28])[C:17]3[S:24][C:23]([CH2:25][Cl:5])=[C:22]([CH3:27])[C:18]=3[N:19]([CH3:21])[CH:20]=2)=[O:14])=[CH:29][CH:30]=1
Reactant: Cc1c(CO)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: CN(C)C=O
Product: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
Methanesulfonyl chloride (0.23 mL, 3.0 mmol) was added to a mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (446 mg, 1.19 mmol), collidine (0.39 mL, 3.0 mmol) and DMAP (22 mg, 0.18 mmol) in DMF (21 mL). The reaction was stirred at room temperature for 1 hour 15 minutes, going to an orange/amber solution. The reaction was cooled in an ice bath before diluting with water to a total volume of 100 mL. The mixture was stirred vigorously for 5 minutes before the solid precipitate was collected by filtration, washed with water and dried in vacuo, leaving the title compound as a white solid (460 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:19][C@@H:20]([CH3:23])[CH2:21]O)=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([NH:19][C@@H:20]([CH3:23])[CH2:21][N:8]2[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Br)ccc2N[C@@H](C)CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3ccc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A 3-L, three-necked, round bottomed flask fitted with a nitrogen inlet, overhead stirrer, and thermocouple was charged with (S)-N-(5-bromo-2-(1-hydroxypropan-2-ylamino)phenyl)-4-methylbenzenesulfonamide (77.0 g, 193 mmol), THF (1925 mL), and triphenylphosphine (60.7 g, 231 mmol). The solution was cooled to 0° C., and diisopropyl azodicarboxylate (DIAD) (41.2 mL, 212 mmol) was slowly added while maintaining the internal temperature below 7° C. The reaction mixture stirred at 0° C. for 1.5 h and was then warmed to room temperature. The mixture was concentrated and the residue was purified by column chromatography on silica gel (eluting with dichloromethane). The product-containing fraction were combined and concentrated under reduced pressure. The material was treated with a mixture of 4:1 hexanes-dichloromethane, and the slurry was stirred for 3 h and then filtered. The solids were rinsed with cold (ca. 0° C.) solution of 4:1 hexanes-dichloromethane (50 mL) and dried to afford (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydroquinoxaline (61.8 g, 84%) as a white solid. MS (ESI, pos. ion) m/z 381 [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].[CH3:21]O>O.Cl>[CH3:21][O:19][C:18](=[O:20])[C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:5])[OH:6])[NH2:1]
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Agent: Cl
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The α-L-aspartyl-L-phenylalanine (20 g, 0.071 mole) is dissolved in the mixture of water (12.2 ml) and methanol (9.5 ml) and concentrated hydrogen chloride (26 ml) is added while stirring for 48 hours at room temperature to obtain as a precipitate the hydrogen chloride salt of α-L-aspartyl-L-phenylalanine methyl ester (20.3 g, 0.055 mole). After filtration, the cake of precipitate is dissolved in 355 ml of water. Then, the mixture is adjusted to a pH of 4.8 with 50% caustic solution (3.8 ml) and kept overnight at 5° C. to obtain a precipitate and separated by filtration. The filtered precipitate is washed with water (13 ml) at 5° C. and dried to obtain α-L-aspartyl-L-phenylalanine methyl ester (12.4 g, 0.042 mole).
Reaction SMILES: [CH:1]1[N:9]=[C:8](Br)[C:7]2[C:3](=[N:4][S:5][N:6]=2)[C:2]=1Br.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>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.C1(C)C=CC=CC=1>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:8]1[C:7]2=[N:6][S:5][N:4]=[C:3]2[C:2]([C:19]2[S:18][CH:17]=[CH:21][CH:20]=2)=[CH:1][N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1cnc(Br)c2nsnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1csc(-c2cnc(-c3cccs3)c3nsnc23)c1
Temperature: 140 °C
Reaction time: 0.6 h

Procedure:
A 5 mL microwave tube was charged with 4,7-dibromo-pyridal[2,1,3]thiadiazole (PTBr2, 0.556 g, 1.885 mmol), 2-(tributylstannyl)thiophene (Bu3Sn—Th, 1.477 g, 3.957 mmol), Pd(PPh3)4 (0.020 g, 0.018 mmol), toluene (3 mL), and sealed with a teflon cap. The reaction mixture was heated to 120° C. for 3 minutes, 140° C. for 3 minutes, and 170° C. for 36 minutes, using a Biotage microwave reactor. Upon cooling, the residue was passed through a short silica plug eluting with methylene chloride (200 mL). All volatiles were removed in vacuo to give the crude product as a red solid. The solid was slurried in MeOH (100 mL), sonicated for 10 minutes, and filtered. The solid was washed with copious amounts of MeOH and then dried under vacuum for 24 hours. The product was collected as a bright red solid. Recovered yield: 535 mg (94%). 1H NMR (CD2Cl2): δ 8.81 (s, 1H, PT-CH), 8.68 (d, 3JH-H=4 Hz, 1H, Th′—CH), 8.11 (d, 3JH-H=4 Hz, 1H, Th—CH), 7.61 (d, 3JH-H=5 Hz, 1H, Th′—CH), 7.51 (d, 3JH-H=5 Hz, 1H, Th—CH), 7.27 (dd, 3JH-H=4 Hz, 3JH-H=4 Hz 1H, Th′—CH), 7.23 (dd, 3JH-H=4 Hz, 3HH-H=4 Hz 1H, Th—CH), 13C{1H} NMR (CD2Cl2): 155.50, 148.62, 146.91, 142.53 (s, quaternary), 141.28 (s, PT-CH), 137.18 (s, quaternary), 131.97 (s, Th′—CH), 131.00 (s, Th′—CH), 129.40 (s, Th—CH), 128.61 (s, Th—CH), 128.38 (s, Th′—CH), 127.88 (s, Th—CH), 121.00 (s, quaternary). Anal. Calcd. for C13H7N3S3: C, 51.80; H, 2.34; N, 13.94. Found: C, 51.8; H, 2.40; N, 13.7%. UV-vis: (o-DCB) λmax=302, 470 nm, λonset=550 nm, ε=22150 cm−1M−1. PL: (o-DCB) λmax=607 nm. HRMS (EI) m/z, calcd for C13H7N3S3 (M+): 300.98; found: 301.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([C:21]3[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=3)[OH:20])[CH:8]=2)[N:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:19]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)[OH:20])[CH:8]=3)[N:3]3[N:34]=[N:35][N:36]=[C:2]3[N:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Temperature: 90 °C
Reaction time: 2 h
Yield: 57.6 %

Procedure:
A mixture of intermediate 7 (0.0125 mol) and sodium azide (0.038 mol) in DMF (60 ml) was stirred at 90° C. for 2 hours, then brought to room temperature, poured out into ice water and stirred. The precipitate was filtered, washed with water, taken up in DCM, filtered, washed with diethyl ether and dried under a vacuo, yielding 3.5 g (58%) of intermediate 8. The filtrate was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-40 μm) (eluent: DCM/MeOH/NH4OH 95/5/0.1). The pure fractions were collected and the solvent was evaporated. The residue (0.9 g, 15%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.7 g (12%) of 5-(3-chlorophenyl)-α-(4-fluorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-methanol (intermediate 8), mp. 200° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[CH3:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:11][C:10]=1[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:11][C:10]=1[C:21]1[CH:22]=[N:23][N:24]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])[CH:25]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1sc(Nc2ccccn2)nc1-c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cn1cc(-c2nc(Nc3ccccn3)sc2C)cn1
Temperature: 70 °C
Yield: 32.2 %

Procedure:
According to Scheme 18 Step 1: Ethyl-2-bromoacetate (0.27 mmol, 45.4 mg) was added to a suspension of N-(5-methyl-4-(1H-pyrazol-4-yl)thiazol-2-yl)pyridin-2-amine (0.27 mmol, 70 mg) and K2CO3 (0.54 mmol, 82 mg) in DMSO (4 mL) and then the reaction mixture was heated at 70° C. for 3 hours. Water was added and the aqueous phase was extracted with AcOEt. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using cyclohexane/AcOEt (90:10 to 30:70) as eluent to afford ethyl 2-(4-(5-methyl-2-(pyridin-2-ylamino)thiazol-4-yl)-1H-pyrazol-1-yl)acetate (87 μmol, 30 mg, 32%) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([OH:16])=[O:15])([O-:3])=[O:2].[CH3:17][Si](C=[N+]=[N-])(C)C>>[CH3:17][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
2,4-diaminophenylacetic acid methyl ester is obtained by reacting 2,4-dinitrophenylacetic acid with trimethylsilyldiazomethane to obtain 2,4-dinitrophenylacetic acid methyl ester, followed by reducing 2,4-dinitrophenylacetic acid methyl ester using a strong reducing agent.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:5]([CH2:12][CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:4]>C(O)(=O)C>[CH2:12]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([Br:1])=[CH:8][CH:7]=1)[CH2:3][CH3:4])[CH3:13]
Reactant: BrBr
Reactant: CCN(CC)c1ccccc1
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 95.1 %

Procedure:
93 g of bromine were added dropwise to a solution of 86 g of N,N-diethylaniline in 400 ml of acetic acid and the mixture was poured into an ice-water mixture. The mixture was extracted with methylene chloride and the organic phase was washed with aqueous sodium bicarbonate solution, dried and evaporated to dryness to obtain 125 g of 4-(N,N-diethylamino)-bromobenzene boiling at 97° C. at 0.6 mm Hg.