Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.C([O:34][C:35](=[O:37])[CH3:36])(=O)C.C1C=CC=CC=1.CCCCCC>N1C=CC=CC=1>[OH:1][C@@H:2]1[C@@:27]2([CH3:28])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:29])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:22])[CH2:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH2:5][C@@H:4]([OH:30])[CH2:3]1.[CH3:27][C:2]([CH2:3][C:4]([CH2:36][C:35]([OH:34])=[O:37])=[O:30])=[O:1]
Reactant: CC(=O)OC(C)=O
Agent: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 0 °C

Procedure:
The triol from (b) above (0.5 g) in pyridine (0.5 ml) and acetic anhydride (8 ml) was heated at reflux for 1.5 hours. The solution was cooled, poured into ice-water and stirred to decompose the anhydride. Work up by extraction with ethyl acetate as usual gave a brown oil which was chromatographed on alumina (act. III, 25 g). Elution with hexane-benzene (7:3) gave a trace of non polar material. Benzene-hexane (1:1) yielded the title compound (0.58 g) as a very soluble colourless oil which resisted all attempts at crystallization. This material was homogeneous on t.l.c. on silica gel, alumina and silica gel-silver nitrate. νmax. (film) 1730 cm-1 (CDCl3) 5.50 (1 proton, narrow multiplet, H6), δ5.2-4.6 (2 protons, one broad and one narrow multiplet, H1 and H3 with H1 as a narrow multiplet at δ5.03), 2.00, 1.98, 1.91 (singlets, acetates), 1.40, 1.05, 0.67 (singlets, C26-27, C19, C18 methyls respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=O)[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.[NH2:24][NH2:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]([C:19]3[CH:18]=[CH:17][C:16]([OH:22])=[CH:15][C:14]=3[OH:13])=[N:24][NH:25][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2coc3cc(O)ccc3c2=O)cc1OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2c[nH]nc2-c2ccc(O)cc2O)cc1OC
Yield: 55.3 %

Procedure:
This compounds was synthesised in the same manner as described above. 3-(3,4-Dimethoxy-phenyl)-7-hydroxy-chromen-4-one (0.5 g, 1.68 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). The crude product was columned to give 4-[4-(3,4-Dimethoxy-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a pale yellow solid (0.29 g, 55.3%); Rf 0.2 Cf SM 0.7 ethyl acetate/hexane (75/25).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].[OH:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:32]2[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][OH:26])[CH2:30][CH2:31]2)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: OCCN1CCNCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCN(CCO)CC2)n(C)c(=O)c1OCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
To a solution of 5-Benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.10 g, 0.27 mmol) dissolved in THF (1 mL) was added 1-(2-hydroxyethyl)piperazine (0.05 mL, 0.41 mmol). The resulting mixture was stirred at 70° C. for 3 hours. The mixture was concentrated and the resulting residue was purified by flash chromatography, eluting with 2% MeOH/CH2Cl2 to yield the title compound as a pale yellow oil (0.0423 g, 38% yield). 1H NMR (500 MHz, CDCl3) δ: 7.45 (2H, d, J=7.0 Hz), 7.35–7.27 (3H, m), 5.14 (2H, s), 4.30 (2H, q, J=7.1 Hz), 3.63 (2H, t, J=5.3 Hz), 3.49 (3H, s), 3.21 (4H, t, J=4.7 Hz), 2.63 (4H, bs), 2.59 (2H, t, J=5.3 Hz), 1.27 (3H, t, J=7.2 Hz). HRMS (M+H) calcd for C21H29N4O5: 417.21381. found: 417.2147.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[NH:11][CH2:12][CH2:13][OH:14].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:11][CH2:12][CH2:13][OH:14]
Reactant: O=[N+]([O-])c1cccc(Cl)c1NCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc(Cl)c1NCCO
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
To a solution of 2-[(2-chloro-6-nitrophenyl)amino]ethanol (120 g, 0.554 mol) in methanol (1.5 l) at 60° C. is added a solution of Na2S2O4 (85%, 318 g, 1.55 mol) in water (1.12 l) over 20 min. The obtained suspension is stirred at 60° C. for additional 20 min. The decolourized mixture is allowed to cool and concentrated under vacuum. In an ice bath, 800 ml of 1.5 M NaOH solution is added and the mixture is extracted three times with 500 ml of AcOEt. The organic phase is washed with brine and dried over magnesium sulphate. The solvents are evaporated to give the desired product (72.4 g, 70%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:10]1[CH:14]=[C:13]([CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[S:24][C:20]=3[C:19](=[O:31])[N:18]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:17]2=[O:38])[N:12]=[N:11]1)[CH3:9].[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:62]=[CH:61][C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.S([O-])(O)(=O)=O.[K+]>C(Cl)Cl>[CH2:39]([O:41][C:42]1[C:51]([O:52][CH3:53])=[CH:50][C:49]2[C:48]([C:54]3[CH:55]=[CH:56][C:57]([C:58]([N:35]4[CH2:36][CH2:37][CH:32]([N:18]5[C:19](=[O:31])[C:20]6[S:24][C:23]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)=[CH:22][C:21]=6[N:16]([CH2:15][C:13]6[N:12]=[N:11][N:10]([CH2:8][CH3:9])[CH:14]=6)[C:17]5=[O:38])[CH2:33][CH2:34]4)=[O:59])=[CH:61][CH:62]=3)=[N:47][C@@H:46]3[CH2:63][CH2:64][S:65][CH2:66][C@@H:45]3[C:44]=2[CH:43]=1)[CH3:40]
Reactant: CCn1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)nn1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: O=S(=O)([O-])O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cn(CC)nn5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 1-[(1-ethyl-1H-1,2,3-triazol-4-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione trifluoroacetate (250 mg; compound B47), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (180 mg; compound C10), EDCI (174 mg) and HOBT hydrate (123 mg) in DCM (12 ml) DIPEA (0.24 ml) is added. After 1.5 h at RT additional 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (100 mg; compound C10) is added and the reaction mixture is stirred for additional 5 d at RT. Aqueous potassium hydrogen sulfate solution (10% w/w) is added and the mixture is filtered using a phase separator. The organic layer is concentrated under reduced pressure and the residue is purified by flash column chromatography [silica gel, eluent: DCM/MeOH, 95/5 (v/v)] to afford the title compound as a solid.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.[O:20]=[C:21]1[NH:25][CH2:24][CH2:23][N:22]1[CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1CCCC1=O>[C:12]1([C:4]2[C:5]([C:7]3[S:8][CH:9]=[CH:10][CH:11]=3)=[N:30][C:29]([NH:28][CH2:27][CH2:26][N:22]3[CH2:23][CH2:24][NH:25][C:21]3=[O:20])=[N:31][CH:3]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=C(C(=O)c1cccs1)c1ccccc1
Reactant: N=C(N)NCCN1CCNC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1NCCN1CCNc1ncc(-c2ccccc2)c(-c2cccs2)n1
Temperature: 100 °C

Procedure:
3-(Dimethylamino)-2-phenyl-1-(thiophen-2-yl)prop-2-en-1-one (1 g, 3.88 mmol) in N-methyl pyrrolidone (10 mL) was treated with 1-(2-(2-oxoimidazolidin-1-yl)ethyl)guanidine hydrochloride (1 M solution in N-methyl pyrrolidone 5.82 mL, 5.82 mmol) and cesium carbonate (1.26 g, 3.88 mmol). The mixture was heated at 100° C. overnight. The reaction was then allowed to cool to room temperature and poured into cold water. The aqueous layer was extracted three times with dichloromethane. All the organic layers were combined and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, reduced in vacuo and purified by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=1.2 g. MS (M+H)+ 366.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)C.[Fe]>[CH2:1]([NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH3:28])=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COc1ccc(C(=O)NCc2ccccc2)c2c1oc1ccc(N)cc12
Yield: 78.7 %

Procedure:
N1-benzyl-4-methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (125 mg, 0.33 mmol) (from step 1) and iron powder (56 mg, 1.0 mmol) was suspended in 50% aqueous ethanol (10 ml) and reflux for 10 min. To this was added a solution of concentrated HCl (7 ul in 5 ml 50% aqueous ethanol) and refluxed for 4 h. The reaction mixture was filtered hot through celite and the filterate was basified with 15% ethanolic KOH, filtered and the filterate was concentrated in vaccuo. The residue was triturated with water, to obtain a solid which was filtered dried to give the product as white solid (90 mg) mp: 228° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[C:9]([F:12])([F:11])[F:10].C([O-])(=O)C.[Na+].Cl.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][NH2:29].ClCCl>C(O)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]([C:9]([F:12])([F:11])[F:10])=[N:29]1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1ccccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(2-furyl)-4,4,4-trifluorobutane-1,3-dione (105 g, 0.51 mole) in glacial acetic acid (220 mL) was added sodium acetate (42 g 0.51 mole). The temperature rose to about 34° C. 2-Chlorophenylhydrazine hydrochloride (90 g, 0.5 mole) was added portionwise over a period of 10 minutes to give a creamy suspension. The mixture was warmed to about 60° C. for about 45 minutes. The bulk of the acetic acid was removed by stripping on a rotary evaporator at a bath temperature of 65° C. The remaining oily residue was added to about 800 ml of water with vigorous stirring and a heterogeneous mixture resulted. After about 15 minutes, dichloromethane (500 mL) was added and the mixture was partitioned. The aqueous phase was extracted with 300 ml of dichloromethane. The combined organic phases were washed with water and saturated sodium bicarbonate solution and then dried with MgSO4 and filtered. Volatiles were removed on a rotary evaporator. The crude product consisted of 151 g of a dark red oil, which contained approximately 89% of the desired product and 11% of the regioisomeric pyrazole (determined by NMR analysis).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH3:28])=[N:23]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:28][C:22]1[CH:21]=[CH:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[O:17][CH2:16][CH2:15][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(OCCN3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Temperature: 70 °C

Procedure:
tert-Butyl piperazine-1-carboxylate (1.4 g, 7.52 mmol) was added to a mixture of 5-(2-bromoethoxy)-2-methylquinoline (2 g, 7.52 mmol) and potassium carbonate (4.16 g, 30.1 mmol) in N,N-dimethylformamide (20 mL). The reactants were heated at 70° C. for 16 h under an atmosphere of argon. The reaction mixture was poured into water (200 mL) and extracted into ethyl acetate (3×200 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography, eluting with 30% ethyl acetate in hexane affording the title compound as a tan solid (1.04 g, 37%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:22]#[N:23]>O>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[CH:21]([C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:22]([NH2:23])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#CC(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Solvent: O
Product: NC(=O)C(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To 30 parts of a sulfuric acid solution in water (90:10 by volume) were added portionwise during a period of 5 minutes 2 parts of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile at room temperature. Upon completion, stirring was continued for 2 hours at 80° C. The reaction mixture was poured into ice water. The product was filtered off, washed with water and purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was stirred in 2,2'-oxybispropane. The product was filtered off and dried, yielding 1.1 parts (54%) of 2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-benzeneacetamide; mp. 160.7° C. (intermediate 26).
Reaction SMILES: [CH3:1][C:2]1([CH2:14][CH:15]=[O:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1.C[Si](C)(C)[C:19]([F:22])([F:21])[F:20].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:20][C:19]([F:22])([F:21])[CH:15]([OH:16])[CH2:14][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CSc1ccc2c(c1)C(C)(CC=O)CCO2
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(C)(CC(O)C(F)(F)F)CCO2
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To 383 mg (1.6 mmol) of (4-methyl-6-methylsulfanylchroman-4-yl)acetaldehyde and 0.335 mL (1.4 mmol) of trimethyl(trifluoromethyl)silane in 5 mL of tetrahydrofuran was added 3 drops of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture stirred for 1 hour and then an additional 1.8 mL (1.8 mmol) of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran was added. After 18 hours, the mixture was concentrated in vacuo and diluted with 1N aqueous HCl and extracted with three 50 mL portions of diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.45 g of 1,1,1-trifluoro-3-(4-methyl-6-methylsulfanylchroman-4-yl)propan-2-ol as a mixture of diastereomers. The crude oil was used without further purification.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1([CH2:11][C:12](OC)=[O:13])[CH2:6][C:7](OC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][C:2]1([CH2:6][CH2:7][OH:8])[CH2:11][CH2:12][OH:13]
Reactant: COC(=O)CC1(CC(=O)OC)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1(CCO)OCCO1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a solution of 2.6 g (12 mmol) of dimethyl 2,2′-(1,3-dioxolane-2,2-diyl)diacetate in 100 mL of dry THF was added 1.4 g (36 mmol) of LAH at 0° C. The reaction mixture was then refluxed for 1 h, was quenched with 15% NaOH aqueous solution (3 mL) and water (3 mL). The mixture was stirred overnight, filtered through celite. The residue was washed twice with THF (100 mL×2). The combined organic phase was evaporated. Chromatography on silica gel afforded 1.3 g (8.0 mmol, yield: 66%) of 2,2′-(1,3-dioxolane-2,2-diyl)diethanol: MS (m/e): 163 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1C=O.[CH:13]([O:18][CH3:19])([O:16][CH3:17])OC>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:13]([O:16][CH3:17])[O:18][CH3:19]
Reactant: COC(OC)OC
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Solvent: CO
Product: COC(OC)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxy-5-nitrobenzaldehyde (3.34 g) was dissolved in methanol (30 ml). Trimethyl orthoformate (20 ml) and then Dowex 50W×8 (H+ form)(generally 2 ml) were added to this solution. The mixture was stirred for 30 min. at room temperature. The resin was removed from the reaction mixture by passing the mixture through an alumina. The filtrate was evaporated to give the title compound (4.0 g) having the following physical data.
Reaction SMILES: [Cl:1][CH:2]([C:8](=O)[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:17]>CO>[NH2:17][C:8]([CH2:9][CH2:10][CH3:11])=[C:2]([Cl:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCC(=O)C(Cl)C(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCCC(N)=C(Cl)C(=O)OCC
Yield: 95.5 %

Procedure:
61.5 g (0.32 mol) of ethyl 2-chloro-3-oxohexanoate are reacted with 61.5 g (0.80 mol) of ammonium acetate in 120 ml of methanol and worked up in analogy to Example 2. Yield: 95.5% [GC]
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc(C(F)(F)F)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
3-Trifluoromethylaniline (0.483 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.235 g, 0.454 mmol, 45%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1>O1CCOCC1>[Br:16][C:14]1[N:15]=[C:11]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)[S:12][CH:13]=1
Reactant: CC(C)N1CCNCC1
Reactant: Brc1csc(Br)n1
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2nc(Br)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 mL round bottom flask, 1-isopropylpiperazine (306 mg, 2.38 mmol) was dissolved in 4 mL dioxane. 2,4-Dibromothiazole (870 mg, 1.5 eq.) was added and the reaction was stirred at room temperature overnight. TLC and LC-MS showed desired product. DIEA (0.83 mL, 2 eq.) was added. The reaction was stirred at room temperature for 4 hours, then heated to 50° C. for 5 hours. Reaction was cooled and extracted using ethyl acetate/brine. The organic layer was concentrated and purified via combiflash to give desired compound. LCMS-ESI+: calc'd for C10H17BrN3S: 290.0 (M+H+); Found: 290.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16]2.[OH-].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([F:12])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(c1cc(Cl)nc(Cl)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g (9.5 mmol) 2,6-dichloro-pyridine-4-carboxylic acid chloride in 50 mL DCM were cooled in the ice/EtOH bath and combined with 1.3 g (9.6 mmol) 5-fluoro-2,3-dihydro-1H-indole. In addition 9.6 mL (9.6 mmol) of a 1N aqueous sodium hydroxide solution were added dropwise and the mixture was stirred for 2 h while being cooled and for 1 h at RT. Then 50 mL of a saturated sodium hydrogen carbonate solution were added and the mixture was stirred for a further 10 min. The organic phase was separated off, extracted with 1N aqueous hydrochloric acid solution and with water, dried on sodium sulphate and evaporated down.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:7][C:6]2[CH:21]=[CH:22][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCCBr
Reactant: Clc1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCN1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To a solution of the product from step 2 (1.50 g, 4.43 mmol) in DMF (20 mL) was added potassium carbonate (1.23 g, 8.90 mmol) and methyl 4-bromobutyrate (0.64 mL, 5.56 mmol). The resulting suspension was stirred at ambient temperature overnight. The reaction mixture diluted with water and ethyl acetate. The crude residue was extracted into ethyl acetate. The organic portion was washed with water, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography using hexane/EtOAc (gradient system) to give the title compound (1.22 g, 69%) as a yellow oil.