Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:8]1.[OH-].[Na+].O.Cl.O1CCOCC1>ClCCl.CO>[ClH:26].[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C@@H:9]3[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])[CH2:8]3)=[CH:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)CCCN1CC[C@@H](Oc2ccc(Oc3ccc(Cl)cc3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCN1CC[C@@H](Oc2ccc(Oc3ccc(Cl)cc3)cc2)C1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
4-{(R)-3-[4-(4-Chloro-phenoxy)-phenoxy]-pyrrolidin-1-yl}-butyric acid methyl ester (86.8 mg, 0.222 mmol) was taken into 1.029N NaOH solution in water (0.433 mL, 0.445 mmol), and methanol (2 mL). The reaction was sealed and heated to 60° C. and left to react for 24 h. The reaction was concentrated to dryness and taken into 4N HCl in dioxane (0.111 ml, 0.445 mmol) and dichloromethane (1 mL). The reaction was stirred for 15 minutes, and then concentrated to dryness. The residue was taken into dichloromethane and filtered through a syringe filter. The filtrate was then treated with excess 4N HCl in dioxane, stirred for 15 minutes and then concentrated to dryness. The crude product was purified by reverse phase semi-prep HPLC to obtain the title product (43 mg, 47%); LCMS; m/z 376 (M, free amine); 1H NMR (400 MHz, DMSO); δ 1.63-1.70 (m, 2H), 1.74-1.82 (m, 1H), 2.21-2.29 (m, 3H), 2.42-2.45 (m, 3H), 2.62-2.73 (m, 2H), 2.85-2.89 (m, 1H), 4.85 (s, 1H), 6.91-6.96 (m, 4H), 6.98-7.01 (m, 2H), 7.36-7.40 (m, 2H), 8.21 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[OH:20].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CBr
Reactant: CCOCn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCn1nccc1C(=O)c1ccc(OCC(=O)OCC)c(Cl)c1Cl
Yield: 88.9 %

Procedure:
1.67 g of 2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenol, 1.15 g of ethyl bromoacetate and 1.68 g of potassium carbonate are added to 60 ml of acetone, and the mixture is refluxed for 1 hour. The reaction mixture is filtered and the filtrate is evaporated to remove solvent. The residue is dissolved in benzene, and the solution is treated with activated charcoal and evaporated to give an oil, which is then crystallized from isopropyl ether to give 1.89 g of ethyl [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetate.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11]CC)=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(O)C.[OH-].[K+].Cl>O.C(OCC)C>[C:4]([CH:3]([CH2:1][CH3:2])[C:9]([OH:11])=[O:10])([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(CC)C(=O)O

Procedure:
Diethyl ethylmalonate was stirred overnight with 95% ethanol in the presence of 1M KOH. The white precipitate that forms was filtered out of solution, and the filtrate was concentrated under reduced pressure (e.g., on a rotary evaporator). The yellowish oil obtained upon concentration of the filtrate was added to the precipitate and the mixture was dissolved in a minimum amount of water. After acidification with dilute aqueous HCl to a pH of 2, an oil separates from the solution. The oil was taken up into diethyl ether and the aqueous layer was extracted three times with further with diethyl ether. The ether extracts were combined, dried over magnesium sulfate and filtered. A quantitative yield of 2-carboethoxybutyric acid was obtained as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].[N:12]1([CH2:18][CH2:19]O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[C:9]([O:10][CH2:19][CH2:18][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(O)c1F
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1c(I)ccc(OCCN2CCOCC2)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Example 68A (250 mg, 0.95 mmol), 2-(4-morpholinyl)ethanol (0.19 mL) and triphenylphosphine on resin (630 mg, 3 mmol/g, 1.9 mmol) in THF (5 mL) was treated with DEAD (0.179 mL) and stirred at room temperature for about 18 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified twice by flash column chromatography on silica gel, first eluting with 5% methanol/dichloromethane then with 50% ethyl acetate/hexanes to provide 180 mg of the desired product. MS (ESI(+)) m/e 377 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:33][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: NCc1ccc(F)cc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccc(F)cc1
Yield: 51 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and 4-fluorobenzylamine to give Compound 29 (0.13 g, 51%) as a white solid.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:14]2[CH2:13][CH2:12][S:11][C:10]=2[C:9]([O:15]C)=[CH:8][CH:7]=1.OC1C2N=CSC=2C=CC=1>>[F:5][C:6]1[C:14]2[CH2:13][CH2:12][S:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1
Reactant: COc1ccc(F)c2c1SCC2
Agent: BrB(Br)Br
Agent: Oc1cccc2scnc12
Product: Oc1ccc(F)c2c1SCC2

Procedure:
A BBr3 demethylation of 4-fluoro-7-methoxy-2,3-dihydrobenzo[b]thiophene similar to that described for 4-hydroxy benzothiazole affords the title compound as a brown solid 251 Mg: δH (300 MHz, CDCl3) 6.57-6.48 (2H, m, ArH), 4.67 (1H, br. s, OH) and 3.43-3.23 (4H, m, SCH2CH2).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]([NH2:11])=[O:10])=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:12]NC(NC(N)=O)=O>>[CH2:1]([N:5]1[CH:12]=[N:11][C:9](=[O:10])[NH:8][C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)NC(N)=O
Reactant: CNC(=O)NC(N)=O
Product: CCCCn1cnc(=O)[nH]c1=O
Yield: 92 %

Procedure:
Following the procedure described in Preparation 2, Part B, above, but substituting the n-butylbiuret prepared in Part A, above, for the methylbiuret, there is prepared 60 gm. (92% yield) of 1-n-butyl-5-azauracil.
Reaction SMILES: C1([NH:7][NH2:8])C=CC=CC=1.[C:9]1([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([CH:15]=[CH:16][C:17](=[N:7][NH2:8])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NNc1ccccc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: CCO
Product: NN=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 125.2 %

Procedure:
Another colorant stabilizer of the present invention is a basic fuschin hydrazone, prepared as follows. To a 500 ml round bottom flask, fitted with a magnetic stirrer and a heating mantle, was placed 50 g (0.46 mole) phenyl hydrazine (Aldrich), 96.3 g (0.46 mole) chalcone (Aldrich), and 300 ml. of anhydrous ethanol. The reaction mixture refluxed overnight and then cooled to room temperature. A white precipitate formed and was filtered to yield a white solid which was washed with cold ether. 128 g (93%) chalcone hydrazone was obtained. This reaction is shown below.
Reaction SMILES: CCO.[ClH:4].[NH:5]1[CH2:12][CH2:11][CH2:10][C@@H:6]1[C:7]([NH2:9])=[O:8].C([O-])([O-])=O.[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CS(C)=O>[ClH:4].[NH:5]1[CH2:12][CH2:11][CH2:10][C@@H:6]1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:5]2[CH2:12][CH2:11][CH2:10][C@@H:6]2[C:7]([NH2:9])=[O:8])=[CH:22][CH:21]=1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: NC(=O)[C@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)[C@H]1CCCN1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 117.4 %

Procedure:
(R)-Prolinamide hydrochloride was prepared according to G. Flouret et al. J. Med. Chem. 16 (1973) 1137 in a yield of 64% (lit. 53%); mp 180°-181° C. (lit. 178°-180° C.); [α]D22 =+67° (c=0.80, EtOH) (lit. [α]D23 =+69.5° (c=2, EtOH). To a mixture of (R)-prolinamide hydrochloride (4.3 g, 23 mmol) and K2CO3 (8.3 g, 60 mmol) in 20 ml dry DMSO was added a solution of p-fluorobenzylbromide (4.5 g, 23.5 mmol) in 3 ml DMSO at room temperature. The reaction mixture was stirred overnight, poured into 200 ml of ice-water and extracted twice with Et2O. The organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was recrystallized from iPr2O to give 3.0 g (59%) pure title compound, mp 82°-83° C.; [α]D22 =+77° (c=0.8, CHCl3). From the mother liquor was obtained another 1.0 g (20%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH2:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[N:35]=[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[O:49][CH3:50])[N:33]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]1[CH:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH:23][C:36]2[N:35]=[C:34]([NH:39][C@@H:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH3:50])[N:33]=[C:32]([Cl:31])[N:37]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N)C[C@H]1COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(N[C@H]2CC(O[Si](C)(C)C(C)(C)C)[C@H](COCc3ccccc3)C2)n1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a solution of (1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanamine (486.5 mg, 0.001450 mol) and triethylamine (0.55 mL, 0.0040 mol) in THF (2.1 mL) was added 4,6-dichloro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (410 mg, 0.0013 mol) and the mixture was stirred for 2 hours. The reaction was concentrated and the residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to obtain 250 mg (31%) of the title compound. LC/MS: Rt=2.96 min, ES+ 610 (FA standard).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:4]2[C:3]=1[I:12].[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:17]([NH:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:4]2[C:3]=1[I:12])[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Cc1cn2ccc(N)c(I)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: C=CCNc1ccn2cc(C)nc2c1I
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.2 %

Procedure:
To a solution of 23 (250 mg, 0.92 mmol) in anhydrous THF (20 mL), NaH (60% in mineral oil, 44 mg, 1.098 mmol), allyl bromide (133 mg, 1.10 mmol) and tetrabutylammonium bromide (354 mg, 1.10 mmol) were added under argon atmosphere. The mixture was stirred for 15 h at room temperature. After removal of the solvent, the residue was diluted with H2O (20 mL) and extracted with CH2Cl2 (3×20 mL). The CH2Cl2 extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography using CH2Cl2/EtOAc (4/1, v/v) as eluent to afford compound 30 (156 mg, yield: 54%); as an oil; 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 3H), 3.92 (m, 2H), 4.70 (m, 1H), 5.22 (m, 2H), 5.93 (m, 1H), 6.25 (d, 1H, J=7.3 Hz), 7.21 (s, 1H), 7.75 (d, 1H, J=7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 14.5, 46.6, 64.3, 100.7, 109.1, 116.8, 125.7, 134.5, 142.7, 145.8, 146.3. Anal. Calcd for C11H12IN3: C, 42.19; H, 3.86; N, 13.42. Found: C, 42.39; H, 3.95; N: 1328.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:29][NH:30]C.CC(O)=O.[BH3-]C#N.[Na+]>CS(C)=O.CO>[O:28]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:25]([NH2:27])=[O:26])[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:30][CH3:29])[CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)c1
Reaction time: 1 h
Yield: 15 %

Procedure:
To 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(3-formylphenyl)-1H-indole-7-carboxamide (0.160 g, 0.404 mmol) in DMSO (1.8 ml) and MeOH (1.8 ml) was added 2M dimethyl amine in methanol (1.0 ml, 2.0 mmol) and HOAc (0.46 ml, 8.1 mmol). The mixture was allowed to stir for 1 hour, and then NaCNBH3 (0.051 g, 0.808 mmol) was added. After 1 hour, the reaction mixture was concentrated and purified via RP-HPLC (0.1% NH4OH in water/acetonitrile). The fractions containing product were combined and concentrated, giving 0.027 g (15%) of the title compound.
Reaction SMILES: Cl.C([O:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)[CH:14]=1)C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([N:22]2[CH2:21][CH2:20][N:19]([C:15]3[CH:14]=[C:13]([O:12][CH2:11][CH2:10][OH:9])[CH:18]=[CH:17][N:16]=3)[CH2:24][CH2:23]2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ccc(N2CCN(c3cc(OCCOCc4ccccc4)ccn3)CC2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(N2CCN(c3cc(OCCO)ccn3)CC2)cc1
Temperature: 72.5 °C
Yield: 78.9 %

Procedure:
Conc. HCl (6 mL, 65.7 mmol) was added to a solution of 1-[4-(2-benzyloxy-ethoxy)-pyridin-2-yl]-4-(4-nitrophenyl)-piperazine-(0.8 g, 1.84 mmol) in TFA (10 mL) at r.t. followed by heating to 70-75° C. for 7 h. The excess TFA and HCl were evaporated, the residue diluted with water and basified with saturated aq. sodium bicarbonate solution to pH 8-9 and extracted with dichloromethane. The organic layer was washed with water followed by brine solution and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was triturated with petroleum ether to afford 2-{2-[4-(4-nitrophenyl)-piperazin-1-yl]-pyridin-4-yloxy}-ethanol (0.5 g, 84%) as a solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)[C:41]1[CH:46]=[CH:45]C=[CH:43][CH:42]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[C:1]([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=[O:3])[C:2]1[CH:45]=[CH:46][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl)c1ccccc1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirred solution of Example 13 Part A compound (197 mg, 0.4 mmol) under argon at 0-5° C. in THF (1.5 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and benzoyl chloride (70 μL, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and after 15 h, it was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 161 mg (71% yield). LC/MS gave the correct molecular ion [(M+H)+=564] for the desired compound.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]1[S:8][C:9]([C:13]2[N:14]=[C:15]([C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]4[O:25]C(C)(C)[O:27][C:28](=[O:29])[C:23]=4[CH:22]=3)=[O:19])[S:16][CH:17]=2)=[C:10]([CH3:12])[N:11]=1)(=[O:5])[CH3:4].Cl.O>C1COCC1>[C:3]([NH:6][C:7]1[S:8][C:9]([C:13]2[N:14]=[C:15]([C:18]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([OH:25])=[C:23]([CH:22]=3)[C:28]([OH:29])=[O:27])=[O:19])[S:16][CH:17]=2)=[C:10]([CH3:12])[N:11]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc4c(c3)C(=O)OC(C)(C)O4)n2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc(O)c(C(=O)O)c3)n2)s1
Reaction time: 0.83 h

Procedure:
Sodium hydroxide 5N solution (109 μl; 5 M; 0.55 mmol; 12.50 eq.) is added to a solution of 2′-(acetylamino)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-4′-methyl-4,5′-bi-1,3-thiazole-2-carboxamide, obtained in Step I as described above (20 mg; 0.04 mmol; 1 eq.) in THF (1 ml) at rt. After 50 min, the deprotection is complete. Hydrogen chloride (109 μl; 5 M; 0.55 mmol; 12.50 eq.) is added, followed by water (2 ml). The resulting precipitate is isolated by filtration, washed with water and dried under vacuo. Compound (22) is isolated as yellow solid (14 mg; 77%).
Reaction SMILES: [C:1](=O)([S:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][C@H:13]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14]([N:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH3:17])=[O:15])[CH:7]=1)[CH3:2].[OH-].[K+].C([N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=C1CBr)(=O)C.Cl>C(O)C>[C:30]([O:29][C:27]([NH:26][C@H:13]([C:14]([N:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH3:17])=[O:15])[CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][CH2:4][S:3][CH2:1][C:2]1[NH:40][C:48]2[C:43]([C:42]=1[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CCSC(C)=O)c2)NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)Cc1c(CBr)n(C(C)=O)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)Cc1c(CSCCc2cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c3ccc(OC)cc3)c2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of (S)—S-3-(2-(tert-butoxycarbonylamino)-3-((4-methoxyphenyl)(methyl)amino)-3-oxopropyl)phenethyl ethanethioate (2.8 g, 5.74 mmol) in ethanol (20 ml) was added potassium hydroxide (0.64 g, 11.4 mmol). After 10 minutes, ethyl 2-(1-acetyl-2-(bromomethyl)-1H-indol-3-yl)acetate (2.2 g, 6.47 mmol) was added to the solution. The reaction was stirred for 2 hours at room temperature. The reaction was neutralized with 1N (aq) HCl and then extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (3-6% MeOH/DCM) to provide the desired product (2.0 g, 3.0 mmol), 52.3%. MS (m/z) 660 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([NH:26][C:27](=[O:43])[CH:28]=[CH:29][CH2:30][N:31]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH2:32][CH2:33][OH:34])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:44][CH3:45])=[C:23]([NH:26][C:27](=[O:43])[CH:28]=[CH:29][CH2:30][N:31]([CH2:35][C:36]([OH:38])=[O:37])[CH2:32][CH2:33][OH:34])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCO)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Br)c3)c2cc1NC(=O)C=CCN(CCO)CC(=O)O
Reaction time: 24 h

Procedure:
1 ml of trifluoroacetic acid is added dropwise within two minutes to a solution of 330 mg of 4-[(3-bromophenyl)amino]-6-[(4-{N-[(tert-butyloxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-methoxy-quinazoline in 4 ml of methylene chloride while cooling with an ice bath. The reaction mixture is stirred for half an hour while cooling with an ice bath and then for a further 24 hours at ambient temperature. For working up, the mixture is evaporated to dryness in the rotary evaporator. The crude product is stirred with ethyl acetate, the solid precipitate is filtered off, washed with ethyl acetate and dried in vacuo at 50° C. Yield: 169 mg (57% of theory), Rf value: 0.50 (Reversed phase ready-made TLC plate (E. Merck), acetonitrile/water/trifluoroactic acid=50:50:1) Mass spectrum (ESI−): m/z=528, 530 [M−H]−
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=O)[C:6]2=[CH:12][CH:13]=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[N:20]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:7](=[O:9])[C:6]2=[CH:12][CH:13]=1
Reactant: CC(C)CN
Reactant: O=C1OC(=O)c2cc(C(F)(F)F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)CN1C(=O)c2ccc(C(F)(F)F)cc2C1=O
Temperature: 140 °C

Procedure:
4-Trifluoromethyl-N-isobutylphthalimide is prepared as described in Example 2, starting with 14.8 g of 4-trifluoromethylphthalic anhydride, 7.2 cm3 of isobutylamine and a catalytic amount of para-toluenesulfonic acid in 160 cm3 of toluene. The reaction mixture is heated at a temperature in the region of 140° C. for 5 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and the residue is taken up in 250 cm3 of ethyl acetate and 200 cm3 of saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is separated out after settling has taken place and then extracted twice with 250 cm3 of ethyl acetate. The organic extracts are combined, washed with saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 14.9 g of 4-trifluoromethyl-N-isobutylphthalimide are thus obtained in the form of a yellow powder (Rf=0.59, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [C:1]([CH:5]([CH:7](C(OC)=O)O)[OH:6])([O:3][CH3:4])=[O:2].C(OC)(=O)C=O.S([CH2:29][N+:30]#[C-])(C1C=CC(C)=CC=1)(=O)=O>>[O:6]1[C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:7][N:30]=[CH:29]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)C(O)C(O)C(=O)OC
Agent: COC(=O)C=O
Product: COC(=O)c1cnco1

Procedure:
For B.4274, dimethyl tartrate was oxidised11 to methyl glyoxylate which reacted 12 with tosylmethyl isocyanide to give methyl oxazole-5-carboxylate.13This was reduced by lithium aluminium hydride by the method of Fallab14 to the alcohol.15