Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].Cl>C(O)C.[OH-].[Na+]>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][CH2:15][CH2:16][C:17]2[CH:28]=[CH:27][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[NH:3])[NH2:4]
Reactant: COC(=O)COc1ccc(CCNS(=O)(=O)c2ccc(C(=N)N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)c1ccc(S(=O)(=O)NCCc2ccc(OCC(=O)O)cc2)cc1
Yield: 96.4 %

Procedure:
A solution of 2.0 g of methyl p-[2-(p-amidinobenzenesulphonamido)ethyl]phenoxyacetate hydrochloride in 100 ml of ethanol and 50 ml of 1N sodium hydroxide solution was stirred under argon for 90 minutes. For the working up, dilute hydrochloric acid was used to neutralize to pH 6-7, and the mixture was concentrated in vacuo up to 50° C. The crystals which separated out were filtered off with suction and dried over KOH in vacuo at 50° C. 1.70 g of pure p-[2-(p-amidinobenzenesulphonamido)ethyl]phenoxyacetic acid, melting point 292°-293° C., were thus isolated.
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1.CCN(S(F)(F)[F:38])CC>C(Cl)Cl>[F:38][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[O:19])[CH2:3]1
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@H](F)CN1Cc1cccc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
A solution of (2R,4R)-3-(trifluoromethyl)benzyl 4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D8) (200 mg, 0.45 mmol) in DCM (20 ml) cooled at −20° C. was treated with DAST (0.148 ml, 1.11 mmol) and the mixture was first stirred 1 h at −20° C. then 18 hrs at RT. The reaction was quenched with NaHCO3 sat. sol. and the aqueous phase extracted with DCM (3×5 ml), dried over MgSO4 and evaporated. The residue was purified by Biotage SNAP-Si column (25 g) eluting with petroleum ether/EtOAc from 90/10 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D9) (110 mg)
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([NH:31][OH:32])=N>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:32][N:31]=[C:29]([C:28]([CH3:34])([CH3:33])[CH2:27][OH:26])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(CO)C(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CC(C)(CO)c1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 3,N-dihydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.08 min; Mass spectrum (ESI+): m/z=452 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:41])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[N:23]=[C:22]([NH:24][C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30](C(OC(C)(C)C)=O)[N:29]=[CH:28]4)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH:11]=[CH:12][CH:13]=1)([CH3:3])[CH3:2].[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=[C:14]([C:10]4[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=4)[O:7][CH2:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[O:41])[N:23]=3)=[CH:33][CH:32]=2)[CH:28]=[N:29]1
Reactant: CC(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 5-(2-(3-(2-(isopropylamino)-2-oxoethoxy)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (4.30 g, 7.79 mmole) in TFA (20 mL) and CH2Cl2 (20 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and to the crude residue was added ca. 50 mL Et2O. The resulting bright yellow suspension was stirred for 15 minutes and filtered and dried giving 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide trifluoroacetate salt. (4.1 g, mmol, %).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[C:7]2=[CH:8][C:9]3[N-:13][C:12]4[C:14]([C@@H:57]([C:60]([O:62][CH3:63])=[O:61])[C:58](=[O:59])[C:11]=4[C:10]=3[CH3:64])=[C:15]3[N:19]=[C:18]([CH:20]=[C:21]4[N-:26][C:24](=[CH:25][C:5](=[N:6]2)[C@@H:4]1[CH3:65])[C:23]([C:27]([CH3:29])=[O:28])=[C:22]4[CH3:30])[C@@H:17]([CH3:31])[C@@H:16]3[CH2:32][CH2:33][C:34]([O:36]C/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C)=[O:35].[Mg+2]>FC(F)(F)C(O)=O.O>[CH3:1][CH2:2][C@H:3]1[C:7]2=[CH:8][C:9]3[NH:13][C:12]4[C:14]([C@@H:57]([C:60]([O:62][CH3:63])=[O:61])[C:58](=[O:59])[C:11]=4[C:10]=3[CH3:64])=[C:15]3[N:19]=[C:18]([CH:20]=[C:21]4[NH:26][C:24](=[CH:25][C:5](=[N:6]2)[C@@H:4]1[CH3:65])[C:23]([C:27]([CH3:29])=[O:28])=[C:22]4[CH3:30])[C@@H:17]([CH3:31])[C@@H:16]3[CH2:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: CC[C@H]1c2cc3[n-]c4c(c3C)C(=O)[C@H](C(=O)OC)c4c3nc(cc4[n-]c(cc(n2)[C@@H]1C)c(C(C)=O)c4C)[C@@H](C)[C@@H]3CCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Mg+2]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1c2cc3[nH]c4c(c3C)C(=O)[C@H](C(=O)OC)c4c3nc(cc4[nH]c(cc(n2)[C@@H]1C)c(C(C)=O)c4C)[C@@H](C)[C@@H]3CCC(=O)O
Reaction time: 3 h
Yield: 98 %

Procedure:
A solution of bacteriochlorophyll a (15) (45 mg, 0.05 mmol, a product of Sigma-Aldrich Corp.) in a mixture of trifluoroacetic acid (1.2 mL) and water (0.3 mL) was kept at room temperature for 3 hours, concentrated in vacuum (˜20 mmHg) at room temperature, diluted with water and extracted with dichloromethane. The extracts were washed with water, dried, concentrated, and purified on Silica gel with a mixture of 5% MeOH—CHCl3 to give 31 mg (98%) of bacteriopheophorbide a (14).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[O:33])[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1)[CH3:13]>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][C:32]([NH2:34])=[O:33])[C:18]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N+:21]([O-:9])=[CH:20][C:19]=2[N:28]=1)[CH3:13]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCC(N)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3cccnc3c2n1CCCC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 136.6 %

Procedure:
mCPBA (1.80 g, 7.28 mmol) was added to a solution of 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]butanamide (1.63 g, 5.20 mmol) in chloroform (50 mL); the reaction was stirred for three hours at ambient temperature. An analysis by LC/MS indicated the reaction was incomplete; therefore, additional mCPBA (1.2 equivalents) was added. The reaction was stirred for two hours and then diluted with saturated aqueous sodium bicarbonate (75 mL) and chloroform (75 mL). The aqueous layer was extracted with dichloromethane (2×30 mL) and chloroform (12×20 mL), and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.34 g of 4-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c][ 1,5]naphthyridin-1-yl]butanamide as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=2[O:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(=O)=O.C(OCC)C>[Br:22][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15](=[O:17])[CH3:16])[CH:11]=[CH:10][C:9]=2[O:18][C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(C)cc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C=O
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(CBr)cc2)c1

Procedure:
A mixture of 28.4 g. (0.1 mole) of 4'-methyl-2,5-diacetoxy-1,1'-biphenyl prepared in section (a) of this Example, 18.7 g. (0.105 mole) of N-bromosuccinimide, and 0.25 g. (0.001 mole) of dibenzoyl peroxide in 250 ml. of carbon tetrachloride was heated at reflux for about 6 hours. The mixture was cooled and the precipitated succinimide was removed by filtration. The filtrate solvent was removed on a rotary evaporator yielding about 42 g. of a syrupy residue. The residue was mixed with 80 ml. of low boiling petroleum ether, the mixture heated to reflux with stirring, and the petroleum ether decanted. This extraction process was repeated twice more yielding 35.5 g. of a syrupy residue. This residue was then dissolved in 180 ml. of diethylether and the solution diluted with 120 ml. of n-hexanes. Cooling of the solution in dry-ice and scratching the sides of the container induced crystallization of the product. A first crop of 17.2 g. of 4'-bromomethyl-2,5-diacetoxy-1,1'-biphenyl was obtained. The mother liquor was concentrated and crystallization induced as above to yield an additional 6.5 g. of product. The procedure was repeated once again to yield a third crop of 8.3 g. Total yield was thus 32.0 g. Nuclear magnetic resonance analysis of the combined product in deuterochloroform was consistent with the structure of 4'-bromomethyl-2,5-diacetoxy-1,1'-biphenyl. The melting range of the product was 51°-53° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=[CH:17][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:33](O)[CH2:34][OH:35]>>[OH:35][CH2:34][CH2:33][O:20][C:19](=[O:21])[CH2:18][C:15]1[CH:16]=[CH:17][C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=1
Reactant: CN1Cc2ccccc2C(=O)c2cc(CC(=O)O)ccc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)OCCO)ccc21

Procedure:
5,6-Dihydro-5-methyl-11oxodibenz[b,e]azepine-2-acetic acid (2g), ethylene glycol (150 ml), and p-toluene-sulfonic acid (0.05 g) were put into an esterification apparatus, and refluxed for 3 hours. After the reaction, excess ethylene glycol was distilled off under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with a 5% aqueous solution of potassium carbonate, washed in water, and dried over MgSO4. Then, the solvent was distilled off to give 2.1 g of an oily material. The oily material was purified by column chromatography over 50 l g of Wakogel C-200 l and elution of the column with chloroform gave 1.3 g of an oily matter.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OC)=O)[CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:3]([C:22]#[N:23])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[CH3:21])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](C)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1[nH]c(C(=O)N[C@@H]2CCNC[C@@H]2C)c(C#N)c1Cl
Yield: 63.7 %

Procedure:
A solution of methyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate (Intermediate 42, 3.3 g, 8.39 mmol), potassium hydroxide (3.3 g, 58.77 mmol), and hydrazine hydrate (2.97 mL, 58.77 mmol) in ethylene glycol (200 mL) was stirred for 48 h at 120° C. The reaction mixture was poured in to water (200 mL), then extracted with ethyl acetate (2×250 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to yield the crude product, which was triturated with water (100 mL) to afford 4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide 1.5 g (63%) as solid.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:1]([N:14]1[CH2:17][CH:16]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 8 h

Procedure:
To a solution of 1-benzhydrylazetidin-3-ol (20 g, 0.835 mol) in pyridine (167 mL) was added DMAP (12.24 g, 0.1 mM) and p-toluene sulphonylchloride at −40° C. The reaction mixture was stirred overnight. The reaction mixture was partitioned between dichloromethane (200 mL) and water. Solvent was evaporated off, purified by column chromatography using silica gel, 100-200 mesh) and 10% ethyl acetate hexane as eluent to obtain 1-benzhydryl-3-(toluene-4-sulfonyl)-azetidine. 1H-NMR (400 MHz, CDCl3,), δ ppm 7.76-7.74 (m, 2H), 7.34-7.15 (m, 12H), 4.89-4.85 (m, 1H), 4.32 (s, 1H), 3.47-3.43 (m, 2H), 3.06-3.03 (m, 2H), 2.43 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1B(O)O.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccccc3F)ccc2c1
Temperature: 85 °C
Yield: 62.8 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.9 mmol), 2-fluorophenyl boronic acid (532 mg, 3.8 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (266 mg, 0.38 mmol) and cesium fluoride (2.6 g, 17.1 mmol) in 150 mL degassed acetonitrile and heat at 85° C. for 2 hours. Cool the reaction, filter and purify on an SCX column, eluting with 2N ammonia/methanol. Concentrate and purify on a silica column eluting with 1 0-10% gradient of methanol/methylene chloride to give 560 mg (63%) of the title compound: mass spectrum (ion spray) m/z=470 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]2)[CH:21]=[C:20]([CH:34]2[CH2:37][CH2:36][CH2:35]2)[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([C:18]1[N:19]=[C:20]([CH:34]2[CH2:35][CH2:36][CH2:37]2)[CH:21]=[C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][N:3]=3)[CH2:26][CH2:25]2)[N:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCl)CC2)n1
Reactant: Oc1ccncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCOc3ccncn3)CC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
0.2 g of 4-hydroxy-pyrimidine (2.08 mmol) were dissolved in 15 ml of dimethylformamide. After addition of 0.58 g of potassium carbonate (4.16 mmol) and 0.73 g of 2-tert-butyl-4-[4-(3-chloro-propyl)-piperazin-1-yl]-6-cyclobutyl-pyrimidine (2.08 mmol), the mixture was stirred at 90° C. for 3 h. The dimethylformamide was removed under reduced pressure and the resulting residue was partitioned between 40 ml of ethyl acetate and 20 ml of water. The aqueous phase was re-extracted with ethyl acetate, the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel with ethyl acetate-methanol (2-10%). Fractions containing the product were combined. The solvent was evaporated. The product crystallized upon standing (yield: 0.2 g).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:22]1[CH2:32][C:30](=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1.O>C1COCC1>[CH2:2]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:32]1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCCc2ccccc21
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: C=C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
N-Butyl lithium (Aldrich) (47 cm3, 74.8 mmol, 1.6 M solution in hexane) was added dropwise to a solution of methyl triphenylphosphonium iodide (Aldrich) (27.65 g, 68 mmol) in dry THF (150 cm3), under nitrogen at 0° C. α-Tetralone (Aldrich) (10 g, 68 mmol) in dry THF (100 cm3 was then added dropwise and the mixture stirred for 17 hours at room temperature. The reaction mixture was then added to water and extracted with ethyl acetate. The combined extracts were then dried (Na2SO4), filtered and concentrated in vacuo. Purification was by column chromatography on a neutralised silica column (Et3N) (Eluant: Pet. Ether 40-60° C.) produced a colourless mobile oil.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:21][CH2:22]1)=[O:35]
Reactant: Cc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.6 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 153 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)-piperidin-4-yl]-2-(2-methylphenyl)ethanone, the mixture was stirred for 5 hours at room temperature. Aqueous 1N sodium hydroxide was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added and the insoluble portion was filtered out to obtain the title compound (66 mg, 51% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:37])=[C:4]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:5]=1)[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3c[nH]c4ccccc34)C(N)=O)ccc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3c[nH]c4ccccc34)C(N)=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(1H-indol-3-yl)propanamide (100 mg, 0.240 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 1 h. HOAc (1 mL) was added. The mixture was purified by HPLC to give the titled compound (51 mg). MS 435.2 (M+H); UV 221.7, 292.8 nm.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24](C)[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40]>CCOCC>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@H:13]3[N:24]([C:39]([O:41][CH2:42][C:43]([Cl:46])([Cl:45])[Cl:44])=[O:40])[CH2:23][CH2:22][C@@:19]4([C:20]=2[CH:21]=1)[C@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18]4)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(Oc2ccccc2)cc13
Yield: 98.2 %

Procedure:
To a mixture of 2.3 g (0.007 mol) of (--)-3-phenoxy-N-methylmorphinan, 150 ml of benzene and 0.35 g of potassium carbonate was added dropwise, 3.3 g of 2,2,2-trichloroethyl chloroformate. The reaction mixture was stirred at reflux for 6 days. The mixture was diluted with ether and extracted with 4 N hydrochloride acid. The organic phase was washed with dilute ammonium hydroxide, water, and dried. Removal of solvent gave 3.4 g (99%) of the product (--)-3-phenoxy-N-trichlorocarbethoxymorphinan. For analysis, a sample of this compound was distilled, bp 230°-240°/0.05 mmHg, [α]25D-119.65° (c 0.95, MeOH).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[CH3:9][OH:10]>>[CH3:9][O:10][CH:6]1[CH2:5][CH2:4][CH2:3][C:2](=[O:7])[CH2:1]1
Reactant: O=C1CCCCC1=O
Reactant: CO
Product: COC1CCCC(=O)C1

Procedure:
If methanol is used as solvent (example 5), which esterifies with cyclohexane-dione to yield 3-methoxy-cyclo-hexanone, resorcinol-monomethyl ether is formed as by-product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1Cl)=[O:5])[CH3:2].C(O)C.[CH2:21]([NH2:23])[CH3:22]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:17])=[N:8][C:9]([Cl:16])=[C:10]([N+:13]([O-:15])=[O:14])[C:11]=1[NH:23][CH2:21][CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CCN
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNc1c(C(=O)OCC)c(C)nc(Cl)c1[N+](=O)[O-]
Yield: 69 %

Procedure:
27.9 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester (0.1 mol.) are dissolved in 100 ml. of ethyl alcohol and 12 g. of triethylamine. At reflux temperature a solution of 4.5 g. of ethylamine in 50 ml. of alcohol is slowly added dropwise with continual stirring. After the addition is completed, the reaction mixture is refluxed for an additional 30 minutes. The solvent is then removed in vacuo and the residue is dissolved in 300 ml. of petroleum ether. The triethylamine hydrochloride is filtered off and the filtrate cooled to 0°; 6-chloro-4-ethylamino-2-methyl-5-nitropyridine-3-carboxylic acid ethyl ester crystallizes, yield: 69%, m.p. 36°-37° (methanol).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11]OS(C(F)(F)F)(=O)=O)[CH2:7][C:6]=2[CH:5]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:7][C:6]=2[CH:5]=[C:4]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: CCOC(=O)c1cc(Cl)c2c(c1)CC(COS(=O)(=O)C(F)(F)F)O2
Product: CCOC(=O)c1cc(Cl)c2c(c1)CC(CCCc1ccccc1)O2
Yield: 58 %

Procedure:
Following the process described in example 3 (point B), starting from ethyl 7-chloro-2-trifluoromethanesulfonyloxymethyl-2,3-dihydrobenzofuran-5-carboxylate and 2-bromoethylbenzene, the title compound was prepared, which was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl acetate, 95:5 (58% yield).