Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:16]1([CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=1)[OH:17].[OH-].[Na+]>CS(C)=O>[Cl:8][C:7]1[C:2]([O:17][C:16]2[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][CH:18]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Oc1ccc(O)cc1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
In procedures similar to those in Example 1 above, except that a 2,3,5-trichloropyridine was used in place of the bis reactant, it was found that reaction of equimolar amounts of the pyridine reactant, hydroquinone and 50% NaOH in dimethylsulfoxide (DMSO) at 100°-116° C. for about 11/2 hours gave product yields of 33% 1,4-((bis(3,5-dichloro-2-pyridinyl)oxy))benzene and about 49% of the desired mono compound, i.e., 4-(3,5-dichloro-2-pyridinyloxy)phenol. Reaction of 0.1 mole of the pyridine reactant with 0.2 mole of the hydroquinone and 0.15 mole of the 50% NaOH (added portionwise to the reaction mixture over a period of about 20 minutes) in 80 ml of DMSO at 90°-100° C. for about 5.5 hours resulted in a product yield of about 16.6% of the bis compound named above and about 75.9% of the desired mono compound. Further operations using equimolar amounts of pyridine reactant to hydroquinone reactant (0.4 mole each) and a mole ratio of base to hydroquinone of 2:1 (0.8 mole 50% caustic, 0.4 mole hydroquinone) in 250 ml of DMSO at temperatures of 100°-113° C. for about 2.5 hours resulted in a product yield of only 4% of the bis compound and 84.4% of the desired mono compound.
Reaction SMILES: C[C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18]C2C=CC=CC=2)=[O:15])=[N:10][CH:9]=1)(C)[C:3]([OH:5])=[O:4].ClCC[C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:36].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:16]([CH2:17][CH2:18][C:35](=[O:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:2][C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: O=C(CCCl)c1ccccc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCC(=O)c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 3-chloro-1-phenyl-propan-1-one and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [K].O[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([O:7]CC)=O.Cl.Cl.[NH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[NH2:19]>C(O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:18]1[C:5](=[O:7])[C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:3][NH:19]1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(=CO)c1ccccc1
Agent: Cl
Agent: [K]
Solvent: CCO
Product: O=c1c(-c2ccccc2)c[nH]n1-c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
22.7 g (0.1 mol) of the potassium salt of ethyl α-hydroxymethylene-phenylacetate and 18.2 g (0.1 mol) of 2-hydrazino-pyridine dihydrochloride in 200 ml of ethanol are stirred for 30 minutes at room temperature and then boiled under reflux for 5 hours. After the mixture has been cooled to room temperature, 19.1 g (1.7 mol) of potassium tert.-butylate are introduced in portions while nitrogen is simultaneously passed over the mixture. The mixture is stirred for 4 hours at room temperature and left to stand overnight. The precipitate formed is filtered off under suction and suspended in 100 ml of water, and the suspension is slightly acidified with acetic acid. The crystals are filtered off under suction, washed with water and dried in the air. 17.2 g (72.5% of theory) of 1 -pyrid-2-yl-4-phenyl-pyrazoline-5-one of melting point 132° to 133° C. (ethanol) are obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([Sn](C)(C)C)=[CH:6]1)(=[O:4])=[O:3].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C)C=O.C(Cl)Cl.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>[CH3:1][S:2]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)n1cc([Sn](C)(C)C)c2ccccc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(-c3cn(S(C)(=O)=O)c4ccccc34)c2cc1OC
Temperature: 90 °C

Procedure:
A solution of 1.33 g (4.01 mmol) of N-methylsulfonyl-3-trimethylstannylindole, 750 mg (3.34 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 0.19 g (5 mol % 0.16 mmol) of Pd (PPh3)4 in 10 ml of dry dimethylformamide is flushed thoroughly with nitrogen and heated to 90° C. for 12 hours. The reaction mixture is diluted with methylene chloride washed with 10% ammonium hydroxide and stirred vigorously and then washed with water and the combined organics are washed with brine (75 mL), dried (MgSO4) and evaporated to dryness. Recrystallized from ethyl acetate yields 4-(1-methylsulphonylindol-3-yl)-6,7-dimethoxyquinazoline (m.p. >220° C.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Nc1cc(N)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cc(NS(C)(=O)=O)ccc1F
Temperature: 25 °C
Yield: 94 %

Procedure:
61.1 g (533 mmol) of methanesulfonyl chloride was added dropwise to a mixture of 96.0 g (485 mmol) of ethyl 5-amino-2-fluorocarbanilate, 46.0 g (582 mmol) of pyridine and 700 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the solvent was distilled off, the resultant product was dissolved in ethyl acetate and washed with diluted hydrochloric acid twice, then with water, and with saturated saline solution. The resultant solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude procut (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 126 g of the objective product (yield: 94%) in the form of light brown crystals.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].CC1C2C(=CC3C(C=2)=CC=CC=3)C=CC=1.C(OCCCO)(=O)C(C)=C.C(OCC)(=O)C(C)=C.C([O:43][CH:44]([CH3:48])[CH2:45]OC)(=O)C>>[CH3:45][CH:44]([OH:43])[CH2:48][O:5][C:1]([C:2]([CH3:4])=[CH2:3])=[O:6]
Reactant: COCC(C)OC(C)=O
Reactant: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OCC
Agent: C=C(C)C(=O)OCCCO
Agent: Cc1cccc2cc3ccccc3cc12
Product: C=C(C)C(=O)OCC(C)O
Temperature: 40 °C

Procedure:
A polymer feed solution was prepared by combining 30.76 g methylanthracene methacrylate monomer, 16.6 g 3-hydroxypropyl methacrylate monomer, 16.0 g ethyl methacrylate, and 50 g propylene glycol monomethyl ether acetate (PGMEA) in a 250 ml three neck, round-bottom flask fitted with a mechanical stirrer, thermal controller, thermal probe, heating mantle and nitrogen purge inlet (sweep). The reaction mixture was heated until the temperature of the reaction mixture reached 80° C. 16.15 g PGMEA solution containing 10 wt % Vazo 67 azo initiator (white powder, Dupont) was next added to the flask. The flask was heated until the temperature of the reaction mixture reached 90° C. and maintained for 8 hours with stirring. Heating was stopped and the reactor was allowed to cool down to 40° C. The resulting polymer solution was precipitated with methyl alcohol (10× excess of reaction mixture), filtered and vacuum dried, to provide Poly(ANTMA-co-HPMA-co-EMA) polymer [Mw=8K; PDI=2.5; ANTMA:HPMA; EMA=30:30:40 mol %, by 13C-NMR].
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17](O)[NH:16][C:15]1=[O:22]>N1C=CC=CC=1>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:7]=1[N:14]1[C:19](=[O:20])[CH:18]=[C:17]([Br:2])[NH:16][C:15]1=[O:22]
Reactant: O=c1cc(O)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Product: O=c1cc(Br)[nH]c(=O)n1-c1c(Cl)cc(Cl)cc1Cl
Temperature: 0 °C

Procedure:
10 ml of phosphorus tribromide was added dropwise to 0.60 g of pyridine with stirring at 0° C. and, after stirring this solution at 0° C. for 15 minutes, 1.6 g of the obtained 3-(2,4,6-trichlorophenyl)-6-hydroxy-2,4(1H,3H)-pyrimidinedione was added thereto. The mixed solution was stirred at 80° C. for 3 hours, then added into ice water and extracted with 100 ml of ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and then the solvent was distilled away under reduced pressure to form a crude product. This crude product was recrystallized from a mixed solvent of hexane and isopropyl ether to obtain 0.62 g of the objective compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(COc1ccc2ccc(=O)oc2c1)c1ccccc1
Temperature: 0 °C
Yield: 54.6 %

Procedure:
To a solution of 7-hydroxycoumarin (1.62 g, 10 mmol) in acetone (60 ml) were added 2-bromoacetophenone (1.99 g, 10 mmol) and potassium carbonate (5.53 g, 40 mmol). The mixture was refluxed for 3 h. (monitored by TLC). Evaporation of the solvent gave a residue which was poured into ice water (50 ml). The resulting solid was collected and crystallized from ethyl acetate to afford 7-(2-oxo-2-phenylethoxy)-2H-1-benzopyran-2-one (4a) (1.53 g, 73.1%) as a needle crystal. mp: 163°-165° C.; IR(KBr) νmax : 1728, 1702, 1627; UV(CHCl3) λmax (log ε): 320 (4.16), 249 (4.13); 1H-NMR (CDCl3): δ5.39 (s, 2H, OCH2), 6.27 (d, 1H, 3-H), 6.80 (d, 1H, 8-H), 6.93 (dd, 1H, 6-H), 7.40 (d, 1H, 5-H), 7.49-7.68 (m, 4H, 4-H and aromatic H). Anal Calcd for C17H12O4 : C, 72.85; H, 4.32. Found: C, 72.98; H, 4.35.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][NH:16][CH3:17])[C:5]([Cl:18])=[CH:4][N:3]=1.C(O[C:23](=[O:25])[CH3:24])(=O)C.N1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]([CH3:17])[C:23](=[O:25])[CH3:24])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: CNCc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)N(C)Cc1ccccc1Nc1nc(Cl)ncc1Cl
Yield: 24 %

Procedure:
A solution of (2,5-dichloro-pyrimidin-4-yl)-(2-methylaminomethyl-phenyl)-amine in THF (25 mL) was treated with acetic anhydride (60 mg, 0.59 mmol, 1.2 eq) and pyridine (50 mg, 0.63 mmol, 1.3 eq.) at 25° C. for 2 h. The solvent was evaporated and the residue was purified by semi-preparative HPLC to give N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-N-methyl-acetamide (40 mg, 0.12 mmol, 24%). 1H NMR (300 MHz, CDCl3): δ 8.22 (s, 1H), 7.73 (d, 1H), 7.3 (m, 3H), 4.48 (s, 2H), 3.24 (s, 3H), 2.12 (s, 3H); MS (m/e) 325 (M+1).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([C:7]1[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=1[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6])[CH3:3].[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=O)=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]>C(#N)C.N12CCCN=C1CCCCC2>[C:33]([C:37]1[N:38]=[C:39]([C:42]2[O:43][C:44]3[CH:50]=[CH:49][C:48]([CH:51]=[CH:9][C:8]4[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=4[C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:47][C:45]=3[CH:46]=2)[S:40][CH:41]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Reactant: CCOC(=O)c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1ccccc1C=Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Yield: 65 %

Procedure:
To a solution of 2-ethoxycarbonylbenzyltriphenylphosphonium bromide (605 mg) and 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (285 mg) in acetonitrile (5.00 ml), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.317 ml) was added. The resulting solution was heated under reflux for 10 hours. After concentration under reduced pressure, diisopropyl ether was added to the residue. The resulting insoluble material was removed by filtration. After concentration of filtrate under reduced pressure, n-heptane was added to the residue. The resulting insoluble material removed again by filtration. After concentration of filtrate, the residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-[5-{2-(2-ethoxycarbonylphenyl)ethenyl}benzofuran-2-yl]thiazole (280 mg) as a mixture of E and Z isomer as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:3][O:4][CH2:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:17]([O:16][CH2:15][C@H:2]1[NH:1][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[CH2:5][O:4][CH2:3]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC[C@@H](N)COCc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC[C@@H]1COCc2ccccc2C(=O)N1
Reaction time: 16 h
Yield: 46.4 %

Procedure:
To a solution of compound 14d (394 mg, 1.4 mmol) and HATU (639 mg, 1.68 mmol) in DMF (20 mL) at rt was added DIPEA (1 mL). The reaction mixture is stirred for 16 h, quenched with H2O and extracted with EA (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by CC on silica gel, eluting with PE/EA=4:1 to give compound 14e (171 mg, 46% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[CH3:21])=[CH:3][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(N)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)cc2)c1

Procedure:
N-(3-amino-4-chlorophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.182 mmol) was used in general procedure 1 with 4-chlorobenzoyl chloride (0.228 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-chlorobenzoamido)phenyl)-2-methyl-6-(trifluoromethyl)-nicotinamide. MS (Q1) 469 (M)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](#[N:17])[CH2:15]C>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:14]([CH3:15])=[N:17][N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=1)=[O:13]
Reactant: CCC#N
Reactant: COC(=O)C=CNc1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1cn(-c2ccccc2)nc1C
Yield: 16 %

Procedure:
According to AVV A, 3-phenylamino acrylic acid methylester (177.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 19 hours at 120° C. The orange-brown oily raw product (191.2 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→0:100), whereby the pure product was obtained in the form of a white solid (37.2 mg, 0.16 mmol, 16%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:37][C:38]([Cl:43])([Cl:42])[C:39](O)=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:37][C:38]([Cl:43])([Cl:42])[C:39]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])=[O:40]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(OC(=O)C(Cl)(Cl)Cl)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 163 mg (1 mmole) of trichloroacetic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 398 mg (Yield: 92%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([NH2:17])=[O:16])=[C:13]([NH:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])=[O:20])[S:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-:28].[Na+]>>[NH2:17][C:15]([C:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:11][S:12][C:13]=1[NH:18][C:19]([NH:21][CH2:25][CH2:24][CH2:23][C:22]([OH:28])=[O:26])=[O:20])=[O:16]
Reactant: [OH-]
Reactant: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)N1CCCC1=O
Agent: Cl
Agent: [Na+]
Product: NC(=O)c1c(-c2ccc([N+](=O)[O-])cc2)nsc1NC(=O)NCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-Nitro-phenyl)-5-[(2-oxo-pyrrolidine-1-carbonyl)-amino]-isothiazole-4-carboxylic acid amide (12.5 g) added to 1 N sodium hydroxide (250 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for overnight (reaction mixture clear solution). Reaction mixture acidified with 2 N HCl. The solid which formed was collected by filtration and washed with water then dried in vacuo to give the title compound as off white solid (11.5 g, 88%).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].CON(C)[C:11]([CH:13]1[CH2:17][S:16][C:15](=[O:18])[N:14]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:14]2[C@H:13]([C:11](=[O:12])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:17][S:16][C:15]2=[O:18])=[CH:25][CH:24]=1
Reactant: COP(C)(=O)OC
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)SC[C@H]2C(=O)CP(=O)(OC)OC)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with dimethyl methylphosphonate (36.7 mL, 0.338 mol) and 0.5 L of THF. The solution was purged with nitrogen and cooled to −70° C. 126 mL of a 2.55 M solution of n-butyllithium was added dropwise maintaining an internal reaction temperature less than −60° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (50.0 g, 0.161 mol) was dissolved in 300 mL of dry THF. The resulting solution was added to the solution of dimethyl methylphosphonate anion at a rate maintaining an internal reaction temperature less than −60° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 50 mL of a 10% citric acid solution at a rate that maintained a temperature of less than 5° C. The mixture was diluted with 0.35 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 300 mL of ethyl acetate. The organic phase was separated and a suspension was formed by the addition of 250 mL of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 57 g of (R)-dimethyl 2-(3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-2-oxoethylphosphonate was obtained (94% yield). 1H NMR (300 MHz, DMSO) δ 7.16 (d, 8.5 Hz, 2H), 6.89 (d, 8.5 Hz, 2H), 4.78 (d, J=15.2 Hz, 1H), 4.69-4.61 (m, 1H), 3.79-3.55 (m, 11H), 3.51-3.27 (m, 3H). 13C NMR (75 MHz, DMSO) δ 36.3, 38.0, 46.9, 53.5, 55.08, 66.1, 114.7, 129.0, 129.9, 159.4, 171.9, 199.0; [α]25.0D-29.60 (c=1.00, EtOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.C([Sn](CCCC)=O)CCC.C[Si]([N:28]=[N+:29]=[N-:30])(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[NH:30][N:29]=[N:28][N:13]=2)[CH:3]=1
Reactant: Cn1ncc2c(C#N)cc(Br)cc21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1ncc2c(-c3nnn[nH]3)cc(Br)cc21
Temperature: 110 °C
Reaction time: 28 h
Yield: 99.4 %

Procedure:
6-Bromo-1-methyl-1H-indazole-4-carbonitrile (514 mg, 2.177 mmol) was dissolved in toluene (20 mL) and dibutyl(oxo)stannane (108 mg, 0.435 mmol) and trimethylsilyl azide (0.573 mL, 4.35 mmol) were added over 2 mins. The mixture was then stirred at 110° C. under nitrogen for 28 h. Further trimethylsilyl azide (0.03 mL, 0.228 mmol) was added and the mixture continued stirring at 110° C. under nitrogen for 44 h. The solvent was removed in vacuo to give a white solid. 2M sodium hydroxide in methanol was added and the mixture heated to 50° C. and then filtered whilst hot to remove insoluble impurities. The filtrate was cooled and then acidified via dropwise addition of 2M hydrochloric acid. The resultant precipitate was filtered and dried in a vacuum oven to give the title compound as a white solid (604 mg).
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[CH:4]=1)=O.[NH:32]1[CH2:39][CH2:38][CH2:37][C@@H:33]1[C:34]([NH2:36])=[O:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[NH2:36][C:34]([C@H:33]1[CH2:37][CH2:38][CH2:39][N:32]1[CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:21][CH2:22][N:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH2:24][CH2:25]2)[CH:4]=1)=[O:35]
Reactant: NC(=O)[C@H]1CCCN1
Reactant: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC(C)S(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5C(N)=O)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of 5-(5-formyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added D-prolinamide (114 mg, 1 mmol) and 2 drops of acetic acid. The resulting mixture was stirred at room temperature for 4 h followed by an addition of sodium triacetoxyborohydride (212 mg, 1.0 mmol). The mixture was reacted overnight. It was then purified by Gilson Preparatory HPLC to give 20.4 mg of the title compound.