Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S)C=CC=CC=1.BrC1C=C(F)C=C([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](OC)=[C:20](OC)[CH:19]=2)C=1.[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][C:34](=O)[CH3:35].CCC(=[O:42])CC>>[OH:42][C:33]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][OH:16])([C:29]1[S:28][CH:32]=[CH:31][N:30]=1)[CH2:34][CH3:35]
Reactant: COc1ccc(COc2cc(F)cc(Br)c2)cc1OC
Reactant: CCC(=O)CC
Reactant: CC(=O)Cc1nccs1
Agent: Sc1ccccc1
Product: CCC(O)(c1cccc(CO)c1)c1nccs1

Procedure:
Following the procedure described for Phenol 2, Step 2 and for Phenol 7, Step 3 but substituting the compound from Step 1 for 1-bromo-3-(3,4-dimethoxybenzyloxy)-5-fluorobenzene and 1-(thiazol-2-yl)propanone (from Phenol 1, Step 2) for 3-pentanone the title compound was obtained.
Reaction SMILES: C1(P([N:15]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[Cl:18][C:19]1[C:28](C(O)=O)=[CH:27][C:26]2[C:21](=[CH:22][C:23]([C:32]([F:35])([F:34])[F:33])=[CH:24][CH:25]=2)[N:20]=1.CCCCCC.CC(=O)OCC>C1C=CC=CC=1>[Cl:18][C:19]1[C:28]([NH2:15])=[CH:27][C:26]2[C:21](=[CH:22][C:23]([C:32]([F:35])([F:34])[F:33])=[CH:24][CH:25]=2)[N:20]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)cc2nc1Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Nc1cc2ccc(C(F)(F)F)cc2nc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
20.6 g (75 mmol) of diphenyiphosphoryl azide were added at RT to a solution of 1.4 g (5 mmol) of 2-chloro-7-(trifluoromethyl)quinoline-3-carboxylic acid in benzene (500 ml), and the mixture was then heated for 5 h at 90° C. Concentration in vacuo was then carried out and the residue was taken up in THF (80 ml). 4N aq. LiOH soln. (30 ml) was added to this solution, and stirring was carried out for 1 h at RT. Dilution with water and extraction with EA were then carried out. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 9:1) of the residue yielded 310 mg (1.3 mmol, 26%) of 2-chloro-7-(trifluoromethyl)quinolin-3-amine.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.Br[C:40]1[C:41]2[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=2[S:43][C:44]=1[CH3:45]>>[CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:40]4[C:41]5[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=5[S:43][C:44]=4[CH3:45])=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Reactant: Cc1sc2ccccc2c1Br
Product: Cc1sc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1

Procedure:
Following General Procedure G for Stille coupling, N,N-dimethyl-1-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine and 3-bromo-2-methylbenzo[b]thiophene were reacted to give 229. LCMS m/z: 508.7 (MH+)
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH:12]([O:14][CH2:15][C:16]3([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH3:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2>FC(F)(F)C(O)=O>[F:35][C:32]1[CH:33]=[CH:34][C:29]([C:16]2([CH2:15][O:14][CH:12]([C:10]3[CH:11]=[C:3]([N:2]([CH3:1])[CH3:36])[CH:4]=[C:5]4[C:9]=3[NH:8][N:7]=[CH:6]4)[CH3:13])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:30][CH:31]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(N(C)C)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(N(C)C)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-tert-Butyl 4-((1-(5-(dimethylamino)-1H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (138 mg, 0.278 mmol) was dissolved in trifluoroacetic acid (20% in dichloromethane, 7.5 mL) and stirred at room temperature for 30 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 101 mg (92%). LC/MS (HPLC method 3): tR=1.133 min, 397.42(MH)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[F:1][C:2]([F:13])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:7][C:8]=1[N+:15]([O-:17])=[O:16]
Reactant: FC(F)(F)c1ccc(C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(F)(F)F
Yield: 35 %

Procedure:
A process of nitrating 1,4-bis(trifluoromethyl)benzene by means of 100 mass % nitric acid at from 90 to 105° C. by using 24% fuming sulfuric acid as a solvent to obtain 2,5-bis(trifluoromethyl)nitrobenzene in a yield of 35% (J. Amer. Chem. Soc., 75, 4967 (1953)).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([Cl:25])[C:3]=1[O:4][CH2:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.Cl.[CH2:27]([O:30][NH2:31])[CH2:28][CH3:29].Cl>N1C=CC=CC=1>[CH2:27]([O:30][N:31]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:18][C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])=[CH:16][C:15]=2[Cl:25])=[CH:8][CH:9]=1)[CH2:28][CH3:29]
Reactant: CCCON
Reactant: O=Cc1ccc(CCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCON=Cc1ccc(CCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To a mixture of 0.55 g of 4-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethyl)benzaldehyde (which had been produced in Intermediate Production Example 3 as described below) and 5 ml of pyridine was added 0.18 g of O-propylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.45 g (yield, 72%) of 4-(2-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)ethyl)benzaldehyde O-propyloxime, m.p., nD24.5 1.5773.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[Cl:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[CH:30]=1>>[ClH:24].[CH3:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][CH2:27][CH2:26][CH2:25][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23]
Reactant: Cc1cccc(OCCCCl)c1
Reactant: COc1cc2c(cc1OC)C(=O)N(CCC1CCCCN1)CC2
Product: COc1cc2c(cc1OC)C(=O)N(CCC1CCCCN1CCCOc1cccc(C)c1)CC2
Product: Cl

Procedure:
Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(3-methyl-phenoxy)-propane analogously to Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:39]3[CH:38]=[CH:37][C:36]([CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)=[CH:41][CH:40]=3)[CH:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1ccc(CN2CCOCC2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, a 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford the desired compound (0.02 g, 16%). LCMS: 543.22 (M+1)+; HPLC: 99.53% (@254 nm) (Rt; 4.181; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.17 (t, 1H, J=4.4 Hz), 7.98 (s, 1H), 7.73 (d, 1H, J=7.6 Hz), 7.57 (d, 2H, J=7.6 Hz), 7.37 (s, 2H), 7.17 (s, 1H), 5.85 (s, 1H), 4.27 (d, 2H, J=4.8 Hz), 3.44-3.57 (m, 7H), 2.54 (s, 3H), 2.32-2.36 (m, 4H), 2.23 (s, 3H), 2.19 (s, 3H), 2.09 (s, 3H), 1.69-1.72 (m, 2H), 1.61 (m, 2H), 1.43-1.50 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1)=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2cncc(Br)c2)cc1

Procedure:
The intended compound was produced according to the method of Example 92 but using 5-bromonicotinic acid and 4-isopropylaniline as the starting materials.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:14])=O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C)cc(C(=O)O)c1
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
3,5-Dimethylbenzoic acid (25 g, 0.17 mol) and dimethylformamide (0.1 mL) were added to thionyl chloride (50 mL) at 0° C. The mixture was refluxed under beating for 2 h. The excess thionyl chloride was evaporated under reduced pressure and to the residue was added toluene (50 mL). Toluene was evaporated under reduced pressure to give oily 3,5-dimethylbenzoyl chloride. A solution of propyleneimine (14 mL, 0.18 mol) in tetrahydrofuran (160 mL) was added to 1N aqueous sodium hydroxide solution (180 mL). 3,5-Dimethylbenzoyl chloride was added dropwise to this mixture at 0° C. After completion of dropwise addition, the mixture was stirred further for 30 min. The reaction mixture was extracted with ethyl acetate. The extract was dried, and the solvent was evaporated to give the title compound (31 g, 0.16 mol, yield 99%). oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10](Br)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2].C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:31](=[O:33])[CH3:32])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C(C)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-bromo-1H-benzimidazole (200 mg, 0.5 mmol), tributyl(1-ethoxyvinyl)tin (0.34 ml, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (29 mg) in toluene (10 mL) is heated at reflux for 1 h under argon. The solvent is removed in vacuo, the residue is then dissolved in 10% HCl (5 mL) and THF (5 mL). The mixture is stirred at room temperature for 0.5 h, then extracted with ethyl acetate. The aqueous layer is adjusted to pH 9, extracted with dichloromethane, and the organic layer dried (Na2SO4), concentrated, and the residue purified by preparative silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole. 1H NMR (CDCl3): δ 8.36 (d, 1H); 7.99 (dd, 1H); 7.645 (d, 1H); 7.25-7.49 (m, 4H); 7.14 (m, 1H); 6.21 (d, 1 h); 4.36 (s, 2H); 4.02 (g, 2H); 2.68 (s, 3H); 1.24 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:18]([CH3:19])=[CH:17][S:16][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:7]=1.[N:20]1([C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([N:23]2[CH2:22][CH2:21][N:20]([C:26]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])[CH2:25][CH2:24]2)[C:3]2[C:18]([CH3:19])=[CH:17][S:16][C:4]=2[N:5]=1
Reactant: CC(C)COC(=O)N1CCNCC1
Reactant: COc1ccccc1-c1nc(Cl)c2c(C)csc2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1-c1nc(N2CCN(C(=O)OCC(C)C)CC2)c2c(C)csc2n1
Yield: 93.5 %

Procedure:
A solution of 4-chloro-2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidine (0.1 g, 0.34 mmol), isobutyl piperazine-1-carboxylate (0.06 g, 0.34 mmol), and Et3N (0.096 mL, 0.68 mmol) in DMF (1.2 mL) was heated in a microwave oven at 180° C. for 5 min. The reaction was cooled and diluted with CH2Cl2. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum to give isobutyl 4-(2-(2-methoxyphenyl)-5-methylthieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate (0.14 g, 47% yield). LC/MS: m/z 441.3 (M+H)+ at 2.91 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12].[N+:17](NC1C=CC=CC=1)([O-])=[O:18].Cl>C(O)C.O>[CH2:11]([N:13]([N:17]=[O:18])[C:14]([NH:16][C@@H:9]1[O:10][CH2:2][C@@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:15])[CH3:12]
Reactant: O=[N+]([O-])Nc1ccccc1
Reactant: CCNC(N)=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCN(N=O)C(=O)N[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 3 g of D-xylose, 1.9 g of ethylurea, 0.3 g of nitroaniline and 0.2 ml of a concentrated hydrochloric acid is refluxed in 15 ml of ethanol for 10 minutes. The precipitate in the amount of 2.8 g is separated, then added with 15 ml of glacial acetic acid, 2.5 ml of distilled water and 1.74 g of sodium nitrite and stirred for 2 hours at 0° C. The solution is evaporated and recrystallized from an alcohol to give 2.54 g (80% of the theoretical) of the product. M.p. 104° C. (decomposition), [α]D -13.6° (water), Rf =0.76. Found, %: N 16,42. Calculated, %: N 16.86.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([NH2:16])=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.O>N1C=CC=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]#[N:16])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: -30 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 (11.44 g, 35.2 mmol) in pyridine (115 mL) at −30° C. was added phosphorus oxychloride (8.4 mL, 91 mmol) dropwise over 10 minutes. The mixture was stirred at −30° C. for 1 hour then allowed to warm to RT and stirred for 2 hours. The mixture was poured into water, stirred for 10 minutes and the solid was collected by filtration. The solid was dissolved in EtOAc and washed with copper sulfate solution. The organic layer was passed through a silica pad eluting with EtOAc and the solvent was removed in vacuo to afford 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonitrile (7.78 g, 72%). 1H NMR δ (ppm) (DMSO-d6): 8.25 (1H, d, J=8.61 Hz), 7.38 (1H, dd, J=8.68, 2.23 Hz), 7.32-7.30 (1H, m), 4.39 (2H, t, J=5.01 Hz), 3.50-3.44 (2H, m)
Reaction SMILES: C([O:3][C:4](=[O:30])[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[N:6]([C:8](=[O:17])[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[CH:10]=1)[CH3:7])C.O.[OH-].[Li+].O>CO.O1CCCC1>[CH3:15][C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([CH3:16])[CH:12]=1)[C:8]([N:6]([CH3:7])[C@H:5]([C:4]([OH:30])=[O:3])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][N:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:17]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccno2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C)cc(C(=O)N(C)[C@@H](Cc2ccc(-c3ccno3)cc2)C(=O)O)c1

Procedure:
N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine ethyl ester is treated with lithium hydroxide monohydrate (5 mg) in methanol (0.5 ml), tetrahydrofuran (0.25 ml), and water (0.25 ml) for 3 hours at room temperature. The mixture is then partitioned between water and ether, the water phase acidified with 1N hydrochloric acid, and subsequently extracted with ethyl acetate. The ethyl acetate phase is washed with brine, dried, and evaporated to give N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-isoxazolyl)-phenyl]-alanine. NMR (CDCl3, 400 MHz) δ [ppm] 8.48 (s), 8.30 (s), 7.80 (m), 7.43 (m), 7.13 (m), 7.03 (s), 6.94 (s), 6.75 (s), 6.69 (s), 6,54 (s), 6.36 (s), 5.16 (m), 4.65 (m), 3.55 (m), 3.40 (m), 3.25 (m), 3.10 (m), 2.80 (s), 2.26 (s), 2.14 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1>CC(C)=O.[OH-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: NCc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Cl)cc1C(=O)NCc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 5.0 g 5-chloro-2-methoxybenzoyl chloride in 10 ml acetone is added, with ice cooling, to a solution of 5.0 g 4-aminomethyl-phenylacetic acid hydrochloride in 25 ml 2 N aqueous sodium hydroxide solution and 25 ml acetone. The reaction mixture is then stirred for 3 hours at ambient temperature, diluted with water, filtered with charcoal and the filtrate acidified with 2 N hydrochloric acid. The precipitate obtained is filtered off with suction and dried and then recrystallized from ethyl acetate/petroleum ether. There is obtained 1.8 g (21% of theory) 4-(5-chloro-2-methoxybenzamidomethyl)-phenylacetic acid; m.p. 140°-141° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[N:18]3)=[CH:8][CH:7]=1>O.O1CCCC1.CO>[N:18]1[C:19]2[C:14](=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:23])=[O:4])=[CH:7][CH:8]=3)[CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Nc2cccc3ncccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Nc2cccc3ncccc23)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of sodium hydroxide (7 g, 0.18 mol) in water (100 ml) was added to a solution of the product from stage (a) in a mixture of tetrahydrofuran (100 ml) and methanol (350 ml). The reaction mixture was stirred at 50° C. for 3 h before the solvent was removed under reduced pressure. The resultant residue was purified by dissolving in water (1000 ml) adjusted to pH10 with 2M NaOH and precipitating the crude product by acidification to pH3 with 2N HCl. The precipitate so formed was collected by filtration and washed with water (250 ml). This purification procedure was repeated a further two times before the product was dried to give 12.3 g of an orange powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6](=[O:17])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)[Cl:9]>>[C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:17].[ClH:9].[NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: c1c[nH]cn1
Product: Cl
Product: O=C(c1ncc[nH]1)c1ncc[nH]1

Procedure:
Reaction of imidazole with bis (trichloromethyl) carbonate produces carbonyl diimidazole and crystalline imidazole hydrochloride. Insoluble imidazole hydrochloride is removed from the reaction mixture quantitatively by filtration and the carbonyl diimidazole is recovered by removing the solvent or crystallization under cooling or a combination thereof.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[N:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([OH:33])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:35]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]I)(=[O:38])[CH:36]=[CH2:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH3:34])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[N:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([O:33][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][C:35](=[O:38])[CH:36]=[CH2:37])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(N=Nc2ccc(N=Nc3ccc(O)c4ccccc34)cc2)c2ccccc12
Reactant: C=CC(=O)OCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCCCOc1ccc(N=Nc2ccc(N=Nc3ccc(N(C)C)c4ccccc34)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A mixture consisting of 0.44 g of 1-[4-(4-(dimethylamino)naphthylazo)phenylazo]-4-hydroxy-naphtalene, 0.56 g of 6-iodohexyl acrylate, and 0.28 g of potassium carbonate in 10 ml of DMF was stirred under nitrogen atmosphere for 3 h at 60° C. After cooling to room temperature the reaction mixture was quenched with 100 ml 3N HCl and the resulting precipitate was filtered off, washed with water (100 ml) and ethanol (50 ml) to give 0.5 g of pure 1-[4-(4-(dimethylamino)naphthylazo)-phenylazo]-4-(6-acryloyloxyhexyloxy)naphtalene as a brownish powder; λmax. (CB 483): 504 nm.