Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C[Li].[CH2:9]([Sn:13](Cl)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12]>CCOCC>[CH3:1][C:2]1[N:3]=[C:4]([Sn:13]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:9][CH2:10][CH2:11][CH3:12])[S:5][CH:6]=1
Reactant: Cc1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
4-Methylthiazole (0.5 ml, 5.50 mmol) was dissolved in Et2O (10 ml) and cooled to −78° C. Methyllithium (1.6 M in hexanes, 5.15 ml, 8.24 mmol) was added slowly and the mixture stirred at −78° C. for 1 hour. Tri-n-butyltin chloride (1.640 ml, 6.05 mmol) was then added slowly, the mixture stirred briefly at −78° C. then allowed to warm to RT and stirred overnight. The reaction mixture was quenched with water and extracted with Et2O. The organic phase was washed with brine, dried over sodium sulphate and evaporated under vacuum to afford the title product as a crude pale yellow oil. The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[CH:28]=[N:27][N:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:32]4[CH:33]=[CH:34][C:29]([N:24]5[CH:28]=[N:27][N:26]=[N:25]5)=[CH:30][CH:31]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(-n2cnnn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-n5cnnn5)cc4)ncnc32)CC1
Yield: 7.2 %

Procedure:
4-[4-(4-Tetrazol-1-yl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 7%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tertbutyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-tetrazol-1-yl-phenol (Enamine Ltd., Kiev, Ukraine; 29 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][CH2:5][CH2:6]O.P(Cl)(Cl)(Cl)(Cl)[Cl:24].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][CH2:5][CH2:6][Cl:24]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1NCCO
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1NCCCl
Yield: 75.9 %

Procedure:
An amount of 4.5 gm of 2-chloro-3-(4-chlorophenoxy)-6-nitro-N-2-hydroxyethylaniline was dissolved in 40 ml of toluene and mixed with 2.9 gm of PCl5, spontaneous heating and gas generation taking place. After 30 minutes the mixture was shaken with water and sodium bicarbonate solution and is evaporated. 3.6 gm of a yellowy brown oil were obtained (76% of theory).
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH:11]1[C:16]([C:17]([CH2:19][CH2:20][CH2:21][Cl:22])=[O:18])=[CH:15][CH:14]=[C:13]([F:23])[CH:12]=1.[NH4+].[Cl-]>CCOCC>[F:23][C:13]1[CH:12]=[CH:11][C:16]([C:17]([OH:18])([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([F:2])=[CH:4][CH:5]=2)[CH2:19][CH2:20][CH2:21][Cl:22])=[CH:15][CH:14]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: OC(CCCCl)(Cc1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
A Grignard solution was prepared from 13.8 g (0.575 mol) of magnesium filings and 83.1 g (0.575 mol) of 4-fluorobenzyl chloride in 560 ml of absolute ether. This solution was added dropwise to a solution of 92 g (0.46 mol) of ω-chloro-4-fluorobutyrophenone in 300 ml of absolute ether and the mixture was heated under reflux for 2 hours. It was then poured onto 500 ml of ice, 1 liter of NH4Cl solution was added, the mixture was extracted several times with ether and the organic phases were dried and concentrated.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)[O:16][B:15](B2OC(C)(C)C(C)(C)O2)[O:14]1.ClCCl.C([O-])(=O)C.[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:11][C:8]([C:5]1[N:6]=[CH:7][C:2]([B:15]([OH:16])[OH:14])=[CH:3][CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccc(Br)cn1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(B(O)O)cn1
Temperature: 120 °C

Procedure:
A mixture of 2-(5-bromopyridin-2-yl)propan-2-ol (70 mg, 0.3 mmol), 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (90.0 mg, 0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (10 mg, 0.01 mmol), and potassium acetate (100 mg, 1 mmol) in 1,4-dioxane (5 mL) was heated at 120° C. overnight. The reaction was complete by LC/MS, was concentrated in vacuo to give crude [6-(1-hydroxy-1-methylethyl)pyridin-3-yl]boronic acid. LCMS calculated for C8H13BNO3 (M+H)+: m/z=182.1; found: 182.1.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([C:16]([CH:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[C:10]1([C:16]2[S:8][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][C:18]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Solvent: CC(C)O
Product: c1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)s2)cc1

Procedure:
Thiobenzamide (13.7 g, 0.10 mole) and desyl chloride (23.1 g, 0.10 mole) are heated under reflux in isopropyl alcohol (100 ml) for three hours. When the reaction mixture is cooled, the white solid precipitate formed is filtered off, washed twice with isopropyl alcohol, and dried. The yield of triphenylthiazole, m.p. 84°-85.5° C., is 21.5 g or 69%.
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19]O)[N:16]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=4[F:41])[N:29]=[CH:28][C:27]=3[C:26]([CH3:43])([CH3:42])[CH2:25]2)=[O:23])[CH2:15][C@H:14]1[CH3:44])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19][Cl:5])[N:16]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=4[F:41])[N:29]=[CH:28][C:27]=3[C:26]([CH3:43])([CH3:42])[CH2:25]2)=[O:23])[CH2:15][C@H:14]1[CH3:44])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Chloroacetyl chloride (0.995 mL, 12.0 mmol) was added dropwise to a stirred solution of 6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (3.10 g, 10.0 mmol) and triethylamine (4.6 mL, 33.0 mmol) in anhydrous DCM (50 mL) and the mixture was stirred at room temperature for 16 hours. (2R,5R)-5-Hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.76 g, 12.0 mmol) was added and the mixture was stirred at room temperature for a further 16 hours. Further triethylamine (1 mL) and (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (700 mg) were added and the mixture stirred for a further 16 hours. The mixture was diluted with DCM, washed with water, the organic layer separated and the solvent removed in vacuo. Chromatography (silica, elution with 30-100% ethyl acetate in petroleum ether) afforded (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 80%) as a pale tan foam. MS: [M+H]+ 545. Methanesulfonyl chloride (0.78 mL, 10.0 mmol) was added dropwise to a stirred solution of (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 8.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in anhydrous DCM (40 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed successively with saturated aqueous sodium hydrogen carbonate and then water. The organic layer was separated and the solvent removed in vacuo to afford the title compound (4.0 g, 71%) as a pale yellow foam. MS: [M+H]+=563, 565.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=1>C1(C)C(C)=CC=CC=1>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=2)[CH2:3][CH2:2]1)=[O:8])[CH3:11]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)N1CCN(c2ccc(C(=O)O)cn2)CC1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of 10.1 g of ethyl 1-piperazine carboxylate, 5.0 g of 6-chloronicotinic acid and 15 ml of xylene was stirred at 140°-150° C. for 3 hours. After cooled crystals were filtered, to the crystals was added a solution of 2.6 g of sodium hydroxide in 30 ml of water followed by extraction with toluene. Concentrated hydrochloric acid was added to the aqueous layer, and crystals precipitated were filtered, washed with water and dried to afford 7.1 g of 6-(4-ethoxycarbonyl-1-piperazinyl)nicotinic acid (yield 80%).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12]>C(N(CC)CC)C.[Cu]I.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>[CH3:9][C:5]1[CH:6]=[C:7]([NH:8][C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH:2]=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c(N)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Cc1cncc(NC#C[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 35.7 %

Procedure:
2-Chloro-5-methyl-pyridin-3-ylamine (10 g, 70.13 mmol), trimethylsilylacetylene (13.8 g, 140.3 mmol), copper(I) iodide (534 mg, 2.81 mmol) and bis(triphenylphosphine)palladium(II) chloride (1.97 g, 2.81 mmol) were dissolved in triethylamine (140 ml) and stirred at 80° C. for 5 h. After cooling to room temperature, the reaction mixture was filtered over a plug of celite, and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel, EA/HEP) to give 5.12 g of the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)[CH:6]=1)(=O)C.Cl.[OH-].[Na+]>COCCO>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)[CH:6]=1
Reactant: CC(=O)Nc1ccc2cc(OCc3ccccn3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1ccc2cc(OCc3ccccn3)ccc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 2-acetylamino-6-(2-pyridylmethyloxy)-naphthalene (0.76 g,) in 2-methoxyethanol (15 ml) was added 1N-hydrochloric acid (15 ml) and the resulting mixture was stirred with heating under reflux for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, made basic with an aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title compound (0.65 g) as the crude product. The NMR spectrum is as follows.
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:17]2[NH:21][CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[C:7]1([CH:17]2[N:21]([C:24](=[O:25])[CH2:23][Cl:22])[CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc2c(C3NCCO3)cccc2c1
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCOC1c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nineteen and nine tenths (19.9) ml. of a benzene solution containing 5 g. of 2-α-naphthyl oxazolidine was combined with 50 ml. of benzene and 2.8 g. of chloroacetyl chloride. To this was added 2.6 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred at room temperature for 30 minutes after addition was complete, washed with water, separated and dried over magnesium sulfate. The solvent was stripped under vacuum. There was obtained a yield of 6.7 g. of an oil, the title compound, ND30 =1.6030.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[CH2:23]([O:22][P:21]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])([O:25][CH2:26][CH3:27])=[O:28])[CH3:24]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Temperature: 150 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
A mixture of 18.04 g of 1-bromo-6-(nonafluorobutyl)hexane and 19.6 g of triethyl phosphite was heated at 150° C. After 18 hr, an additional 10.0 g of triethyl phosphite was added, and heating was continued for 8 hr more. Diethyl ethylphosphonate and other volatiles were removed by distillation, b.p. 30-50° C. at 0.05 torr (7 Pa), and bulb-to-bulb distillation of the concentrate provided 18.88 g of 1-(diethylphosphono)-6-(nonafluorobutyl)hexane as a clear, colorless liquid, b.p. 120-130° C. at 0.05 torr (7 Pa).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10]C(=O)N)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCOC(C)=O.C(#[N:25])C.CC(OI(OC(C)=O)C1C=CC=CC=1)=O>O>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][NH2:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Temperature: 16 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A slurry of N-Boc-L-asparagine (5.00 g, 21.5 mmol), EtOAc (24 mL), acetonitrile (24 mL), water (12 mL), and PIDA (8.32 g, 25.8 mmol) was cooled and stirred at 16° C. for 30 min. The temperature was then allowed to reach 20° C., and the reaction was stirred until completion (ca. 4 h). The mixture was cooled to 0° C. and filtered. The filter cake was washed with EtOAc (10 mL) and dried in vacuo to give 1 (2.73 g, 62% yield). 1H NMR (CD3OD and a drop of TFA) δ4.05 (1H), 3.20-3.08 (2H), 1.45 (9H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]1([S:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[Cl:4][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[S:12][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc(Sc2c[nH]c3ccccc23)cc1
Solvent: ClCCl
Product: Clc1[nH]c2ccccc2c1Sc1ccccc1

Procedure:
Sulfuryl chloride (0.07 ml, 0.119 g, 0.88 mmol) was added dropwise at 0° to a stirred solution of 3-phenylthioindole (0.200 g, 0.88 mmol) in dry dichloromethane (20 ml). After 1 h the reaction mixture was washed with saturated sodium bicarbonate solution, the organic phase was dried and evaporated in vacuo. The residue was subjected to thin layer chromatography on silica gel eluting the product with hexane-ethyl acetate (7:3). There was obtained the desired product which had m.p. 98°-99° after crystallization from dichloromethane-pentane, and was identical to the material prepared in Example 13.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:8]([NH2:11])[CH:9]=[CH2:10]>O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:11][CH2:8][CH:9]=[CH2:10])[CH3:7]
Reactant: C=CCN
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Product: C=CCNCC(=O)OCC
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 46.9 %

Procedure:
A solution of ethyl bromoacetate 52 (3 g, 18.0 mmol) in dry tetrahydrofuran (20 cm3) was added dropwise to an ice-cold solution of allylamine 53 (2.05 g, 36 mmol) in dry tetrahydrofuran (20 cm3) over 3 min. The solution was stirred at 0° C. for 2.5 h (a white precipitate was observed after 2 h), concentrated in vacuo and suspended in diethyl ether. The white suspension was filtered through Celite™ and the solvent removed to yield the crude product which was purified by chromatography (silica gel, 1:1, hexane:ethyl acetate) to give alkene 54 (1.209 g, 47%) as a light yellow oil: δH (300 MHz; CDCl3; Me4Si) 1.17 (3H, t, J 7.1, OCH2CH3), 1.70 (1H, br s, N—H), 3.16 [2H, d, J 5.9, CH2(allyl)], 3.28 (2H, s, CH2Gly), 4.08 (2H, q, J 7.1, OCH2CH3), 4.98-5.12 (2H, m, ═CH2) and 5.70-5.85 (1H, m, C(H)═CH2); βC (75 MHz; CDCl3) 13.9 (CH3, OCH2CH3), 49.7 (CH2), 51.6 (CH2), 60.4 (CH2, OCH2CH3), 116.2 (CH2, ═CH2), 135.9 (CH, C(H)═CH2) and 172.2 (quat., CO).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.O.[OH-].[Na+].[CH3:17]I>C(O)C>[CH3:13][C:4]1[S:3][C:2]([S:1][CH3:17])=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: Cc1sc(S)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc(-c2ccccc2)c(C)s1
Reaction time: 2 h

Procedure:
To 14.9 g. of 2-mercapto-5-methyl-4-phenyl-thiazole is added 60 ml. of water and 19.5 ml. of a 15% aqueous solution of sodium hydroxide and the mixture is stirred until most of the material dissolves. The stirred mixture is then treated with methyl iodide (5 ml.) in ethanol (20 ml.). After two hours, the reaction is complete (tlc) and the reaction mixture is extracted with ether. The combined ether extracts are washed successively with a 10% solution of sodium carbonate and brine, dried and concentrated in vacuo to an oil, b.p. 138°-140° C. at 0.04 mm Hg.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:20])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Br.[CH3:54][O:55][C:56](=[O:70])[CH2:57][CH2:58][C:59]1[O:63][N:62]=[C:61]([CH:64]([NH2:69])[CH2:65][CH:66]([CH3:68])[CH3:67])[CH:60]=1>C(Cl)Cl.O>[CH3:54][O:55][C:56](=[O:70])[CH2:57][CH2:58][C:59]1[O:63][N:62]=[C:61]([CH:64]([NH:69][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])=[O:20])=[CH:15][CH:14]=2)[CH2:65][CH:66]([CH3:68])[CH3:67])[CH:60]=1
Reactant: COC(=O)CCc1cc(C(N)CC(C)C)no1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)CCc1cc(C(CC(C)C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a stirred solution of [4-(3-o-tolyl-ureido)-phenyl]-acetic acid (305 mg, 1.07 mmol), DIEA (1.3 ml), HOBT (120 mg, 0.89 mmol) and EDCl (170 mg, 0.89 mmol) in CH2Cl2 (8 ml) at room temperature was added a solution of 3-[3-(1-amino-3-methyl-butyl)-isoxazol-5-yl]-propionic acid methyl ester hydrobromide (272 mg, 0.85 mmol) in CH2Cl2 (12 ml). After stirring for 16 h at room temperature the mixture was diluted with CH2Cl2 (20 ml) and poured into water. The layers were separated and the aqueous layer was extracted with CH2Cl2 (20 ml×3). The combined organics were dried over MgSO4; filtered; and concentrated under reduced pressure. The residue was purified by Flash 40 chromatography using a silica gel column and eluting with 65% EtOAc/hexane to give 220 mg of the title compound as a white amorphous solid. MP 153-4° C.; MS [M+ 1]+507.2; 1H nmr (400 MHz, CDCl3) δ0.88 (d, J=6.4 Hz, 6H), 1.53-1.66 (m, 3H), 2.21 (s, 3H), 2.66 (t, J=7.6 Hz, 2H), 3.00 (t, J=7.6 Hz, 2H), 3.49 (s, 2H), 3.68 (s, 3H), 5.15 (dt, J=6.2 and 8.7 Hz, 1H), 5.85 (s, 1H), 6.11 (d, J=8.5 Hz, 1H), 6.65 (s, 1H), 7.00 (s, 1H), 7.05-7.24 (m, 7H), 7.53 (d, 1H); Anal. calcd. for C28H34N4O5: C (66.39), H (6.76), N (11.05). Found: C (66.29), H (7.11), N (11.11).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)O.[CH2:9]([NH2:12])[CH:10]=C.C=O>C1(C)C=CC=CC=1>[O:6]1[C:5]2[CH:4]=[CH:3][CH:1]=[CH:8][C:7]=2[CH:10]=[CH:9][NH:12]1
Reactant: Oc1ccc(O)cc1
Reactant: C=CCN
Agent: C=O
Solvent: Cc1ccccc1
Product: C1=Cc2ccccc2ON1

Procedure:
Hydroquinone (8.23 g, 75 mmol), allylamine (8.57 g, 150 mmol) and toluene (100 mL) were placed in a 250 mL flask. Paraformaldehyde (9.0 grams, equivalent to 300 mmole formaldehyde) was added along with a magnetic stir bar. The flask was equipped as described in Example 1 and brought to reflux. The full theoretical amount of water was collected within forty-five minutes of reflux. The toluene solution was washed with six 25 ml portions of 5% aqueous sodium hydroxide, and three 30 ml aliquots of water. The toluene solution was then dried over anhydrous magnesium sulfate and then passed over 26 grams of activated, neutral alumina. The toluene was removed to yield 11.0 grams (54% of theory) of a red, semi-solid material.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[O:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[CH3:21][C:19]1[CH:20]=[C:16]([CH2:15][NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:23])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])[O:17][C:18]=1[CH3:22]
Reactant: COC(=O)c1cccc(NCc2cc(C)c(C)o2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: Cc1cc(CNc2cccc(C(=O)O)c2C(=O)O)oc1C

Procedure:
3-[(4,5-Dimethyl-furan-2-ylmethyl)-amino]-phthalic acid dimethyl ester (0.95 g, 3 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]2=[N:5][C:4]2[CH:14]=[CH:15][S:16][C:3]1=2.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[NH:17]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([CH:8]=2)[C:2](=[O:1])[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[N:5]=3)=[N:13][N:19]=[N:18]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2nc3ccsc3c(=O)n2c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=c1c2sccc2nc2ccc(-c3nnn[nH]3)cn12
Temperature: 0 °C

Procedure:
A mixture of 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitrile (0.6 g., 0.0026 mol), sodium azide (0.56 g., 0.0086 mol) and ammonium chloride (0.46 g., 0.0036 mol) in dimethylformamide (75 ml) is heated at 100°-105° C. for 18 hours under nitrogen. The reaction mixture is cooled, poured into ice water (700 ml) and acidified with concentrated hydrochloric acid (1 ml). The precipitate is filtered off, washed with water, with acetone and dried. Recrystallization from dimethylformamide gives a crystalline product (0.39 g.) mp 300° C. (dec).