Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[N:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].C([Sn](Cl)(CCCC)CCCC)CCC.[N-:32]=[N+:33]=[N-:34].[Na+].Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[NH:34][N:33]=[N:32][N:17]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc(=O)c2cc(C#N)ccc2[nH]1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCc1nc(=O)c2cc(-c3nnn[nH]3)ccc2[nH]1
Temperature: 25 °C
Yield: 114.7 %

Procedure:
A mixture of 1.1 g of 2-Butyl-6-cyano-4(1H)-quinazolinone 3.2 g of tri-n-butyltin chloride and 640 mg of sodium azide in 30 ml of toluene is heated at reflux for 48 hours. The reaction mixture is cooled to room temperature and dry HCl gas passed through the reaction mixture for 10 minutes. The reaction mixture is diluted with hexane and filtered. The residue is dried, washed with water and dried to give 1.5 g of the desired product as a solid, m.p. 225° C.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:6](=[O:7])[CH2:5]1.C[OH:11]>>[O:7]1[CH2:2][CH2:3][CH:4]([C:9]([OH:8])=[O:11])[CH2:5][CH2:6]1
Reactant: CO
Reactant: O=C1CC(CCO)CO1
Product: O=C(O)C1CCOCC1

Procedure:
It is known that 3-(2-hydroxyethyl)butyrolactone can be reacted with methanol to give esters of tetrahydropyran-4-carboxylic acid (EP-A-284 969). This reaction results in a mixture containing esters of tetrahydropyran-4-carboxylic acid, 3-(2-hydroxyethyl)butyrolactone, 3-(2-methoxyethyl)butyrolactone, 3-spirocyclopropylbutyrolactone, methanol, possibly water, possibly acetic acid and possibly methyl acetate, which involves problems in working up.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=1.O>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[CH3:2])=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 150 °C
Yield: 71.2 %

Procedure:
A vigorously stirred solution of 13.25 g (66 mmol) of 2-bromoacetophenone and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannane in 190 mL of dimethylformamide under a nitrogen atmosphere was treated with 8.64 g (12 mmol) of bis(triphenylphosphine) palladium(II) chloride and the resulting mixture heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into water (1000 mL) and the resultant suspension extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1), to give 9.8 g (47 mmol, 71%) of the product as an oil. EI-MS: calculated for C15H14O 210: found 210 (M+). 1H NMR (200 MHz, CDCl3): 1.98 (s, 3H), 2.37 (s, 3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[O:14][C:9]3([CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7]=2[C:6]([C:16]2[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[NH:19][N:20]=2)=[CH:5][CH:4]=1.CC1C=CC(S(O[CH:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)(=O)=O)=CC=1>>[CH3:1][O:2][C:3]1[C:15]2[O:14][C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[CH2:8][C:7]=2[C:6]([C:16]2[C:17]([CH3:23])([CH3:22])[C:18](=[O:21])[N:19]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[N:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=NNC(=O)C2(C)C)c2c1OC1(CCCC1)C2
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC1(CCCC1)C2

Procedure:
Prepared analogously as described for the example B1 (Alternative 1) using 5-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one (compound C6) and tert-butyl 4-(Toluene-4-sulfonyloxy)-piperidine-1-carboxylate (compound E1) as starting compounds resulting in the hydrochloride salt of the title compound. (compound B6*HCl)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CCc3ccccc3)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=302.2 (M+H30), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and (2-bromoethyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:28][C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH2:35]Cl)[CH:34]=1.O>CN(C=O)C>[Br:28][C:29]1[CH:34]=[C:33]([CH2:35][N:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:12]2)[CH:32]=[N:31][CH:30]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Reactant: ClCc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(Cc2cncc(Br)c2)nc(-c2ccc(Cl)cc2)n1CC(O)C(F)(F)F
Temperature: 40 °C
Reaction time: 20 h

Procedure:
300 mg (0.98 mmol) of the compound from Example 4A and 953 mg (2.93 mmol) of cesium carbonate were dissolved in 4 ml of DMF, and 261 mg (1.10 mmol) of 3-bromo-5-(chloromethyl)-pyridine hydrochloride were added. The mixture was stirred initially at 40° C. for 20 h and then at 70° C. for 24 h. To bring the reaction to completion, a further 130 mg (0.55 mmol) of 3-bromo-5-(chloromethyl)pyridine hydrochloride and 450 mg (1.38 mmol) of cesium carbonate were then added, and the reaction was stirred at 70° C. for another 20 h. After cooling to RT, 10 ml of water were added and the mixture was extracted three times with in each case 10 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC [Method 19]. This gave 263 mg (56% of theory) of the target compound.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>O1CCCC1>[CH:10]1([NH:6][C:5]2[CH:7]=[CH:8][C:2]([I:1])=[CH:3][C:4]=2[CH3:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1cc(I)ccc1N
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(I)ccc1NC1CCCC1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A mixture of 2.5 g (10.7 mmol) of 4-iodo-2-methylaniline, 1.0 ml (11.8 mmol) of cyclo-pentanone, 0.9 ml (16.1 mmol) of glacial acetic acid and 0.1 g of p-toluenesulphonic acid are stirred in 50 ml tetrahydrofuran for 30 minutes. Then 3.1 g (13.9 mmol) of sodium-triacetoxyborohydride are added and the mixture is stirred for a further 26 hours at ambient temperature. The solvent is distilled off and the residue is chromatographed on silica gel, eluting with petroleum ether/ethyl acetate 0 to 10%.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=[C:29]([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCCC1C=NC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:39]3[CH:40]=[N:36][CH:29]=[CH:37][CH:38]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Br
Agent: BrCCc1cccnc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3cccnc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(2-bromoethyl)pyridine hydrobromide and isolated as white solid. MS (m/e): 388.3 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C-:23]#[N:24].[Na+]>CS(C)=O>[C:23]([CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:24]
Reactant: [C-]#N
Reactant: CCCN(CCC)C(=O)c1cc(CBr)cc(C(=O)OCC)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCN(CCC)C(=O)c1cc(CC#N)cc(C(=O)OCC)c1
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20-25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20-25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH2:13])=[O:6])#[N:2].C1C=CC2N(O)N=NC=2C=1.[Cl:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[C:30]([C:34](O)=[O:35])[NH:31]2)=[CH:27][CH:26]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[NH:13][C:34]([C:30]1[NH:31][C:32]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([Cl:24])[CH:33]=2)=[O:35])=[O:6])#[N:2]
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Reactant: N#CCNC(=O)C1CCCCC1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N#CCNC(=O)C1CCCCC1NC(=O)c1cc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of 2-amino-cyclohexanecarboxylic acid cyanomethyl-amide (6.4 g, 35.31 mmol) in DMF (70 ml), were added HOBT (5.25 g, 38.84 mmol), 6-chloro-2-indolecarboxylic acid (7.60 g, 38.84 mmol), N-methylmorpholine (19.4 ml, 176.45 mmol), and EDCI (7.45 g, 38.84 mmol) respectively at 0° C. The reaction was stirred at room temperature for 16 hours, then 1N HCl (500 ml) was added and the resulting cloudy solution was extracted with ethyl acetate (3×200 ml). The organic layer was filtered through a Celite pad, washed with 1N NaOH (200 ml), brine (200 ml), dried over magnesium sulfate and concentrated in vacuo yielding 6-chloro-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide, (6.25 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[N+:19]([O-:21])=[O:20])[C:3]=1[C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].CI.[C:30](OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[N:7]([CH3:30])[C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N(C)C(C)=C(C(=O)OC)C1c1ccccc1[N+](=O)[O-]

Procedure:
12 g nifedipine was introduced into a 100-mL three-neck flask and dissolved in 50 mL tetrahydrofuran under nitrogen. 1.66 g of a 60% dispersion of sodium hydride in oil was then added with stirring. After stirring for a short period of time, 10 mL methyl iodide was added and the reaction was stirred for 1 hour at 38° C. 200 mL ethyl acetate was then added, and the organic layer was thereafter washed several times with water and dried over sodium sulfate. The sodium sulfate was subsequently filtered off and the solvent was then pulled off from the filtrate on a rotary evaporator. The obtained solid was dissolved in 200 mL MIBK, and the addition of hexane to this solution then yielded 8.9 g N-methylnifedipine as yellow crystals. mp=184°-187° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[OH:16])[C:10]([OH:12])=[O:11]>C(O)(=O)C.CN(C)C=O>[Cl:4][C:14]1[CH:13]=[C:9]([CH:8]=[C:7]([F:6])[C:15]=1[OH:16])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(F)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (4.7 mL) is added to a solution of 3-fluoro-4-hydroxy-benzoic acid (2.97 g) in acetic acid (20 mL) stirred at 50° C. in N,N-dimethylformamide (3 mL) at room temperature. The resulting solution is stirred for 2 h, prior to the addition of another portion of sulfuryl chloride (1.0 mL). The solution is stirred at 60° C. for another 1.5 h and then cooled to ambient temperature. The solution is poured into ice-cold water and the precipitate formed is separated by filtration, washed with ice-cold water, and dried at 50° C. to afford the title compound as a beige solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(Cl)Cl>[C:18]([NH:9][CH:10]([CH2:16][SH:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)C(N)CS
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NC(CS)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.5 mL) was added to a suspension of ethyl 2-amino-3-mercaptopropanoate hydrochloride (5 g) in DCM (50 mL). The resulting mixture was cooled in an ice/salt bath and butyryl chloride (3.3 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a white solid. Yield 3 g.
Reaction SMILES: Br[C:2]1[N:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:16])[NH:5][C:4](=[O:17])[C:3]=1[CH2:18][CH3:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([SH:26])[CH:21]=1>>[CH2:18]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[N:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]=1[S:26][C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)[CH3:19]
Reactant: CCc1c(Br)n(COc2ccccc2)c(=O)[nH]c1=O
Reactant: Sc1cccnc1
Product: CCc1c(Sc2cccnc2)n(COc2ccccc2)c(=O)[nH]c1=O

Procedure:
Likewise, 6-bromo-5-ethyl-1-(phenoxymethyl)-uracil and 3-pyridinethiol can be reacted according to the present method in order to yield a 5-ethyl-1-(phenoxymethyl)-6-(3-pyridylsulfanyl)uracil.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]=[C:11]1[N:15](C(OC(C)(C)C)=O)[CH:14]([CH2:23][O:24]C(OC(C)(C)C)=O)[CH2:13][S:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[OH:24][CH2:23][CH:14]1[CH2:13][S:12][C:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[N:15]1
Reactant: CC(C)(C)OC(=O)N=C1SCC(COC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC(CO)CS1
Temperature: 20 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
10 cm3 of aqueous 1N sodium hydroxide are added to a solution of 2 g of tert-butyl 2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]methyl-1,3-thiazolidine-3-carboxylate in 20 cm3 of methanol and the mixture is then stirred at a temperature in the region of 20° C. for 4 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is taken up in 30 cm3 of water, filtered and washed with ethyl acetate and then with water. 0.37 g of tert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]-carbamate is obtained in the form of a white solid [mass spectrum: DCI m/z=233 MH30 m/z=177 (M—C4H7)+].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:16][C:17]([O:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=1)=[O:22])([CH3:19])[CH3:18]>>[C:17]([O:20][C:21](=[O:22])[NH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([NH:15][C:13]2[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=[C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[N:11]3[N:12]=2)=[O:32])=[CH:29][CH:30]=1)([CH3:19])([CH3:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)Nc2nc3cccc(-c4ccoc4)n3n2)cc1

Procedure:
The title compound was prepared following procedure and work up described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 75 mg; 0.37 mmol; 1.0 eq.) and boc-(4-aminomethyl)-benzoic acid (113 mg; 0.45 mmol; 1.2 eq.) as a white foam (35.4 mg, 22%). HPLC, Rt: 3.69 min. (purity 88.9%). LC/MS, M+(ESI): 434.1, M−(ESI): 432.1.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH:20]1([C:23]([N:17]2[CH2:16][CH2:15][N:14]([C:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=3)[CH2:19][CH2:18]2)=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(O)C1CC1
Reactant: O=[N+]([O-])c1cnc(N2CCNCC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2ncc([N+](=O)[O-])c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Treat a solution or slurry of 4-nitro-1-piperazin-1-yl-isoquinoline (Preparation 26, 517 mg, 2 mmol), cyclopropanecarboxylic acid (258 mg, 3 mmol) and catalytic DMAP (24 mg, 0.2 mmol) in dichloromethane (20 mL) with EDCI (575 mg, 3 mmol). Agitate the resulting mixture at ambient temperature overnight, then wash with saturated aqueous sodium bicarbonate solution. Dry the organic layer over sodium sulfate and concentrate under reduced pressure. Subject residue to silica gel chromatography using a gradient of 0-2% 2M ammonia-methanol in dichloromethane and a gradient of 0-70% ethyl acetate in hexanes to give a yellow solid after two purifications. (513 mg, 79% yield, LCMS ES+ (m/z) 327 [M+H]).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][N:13]=[C:14](S(C)(=O)=O)[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[OH-:20].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][C:10]3=[N:12][NH:13][C:14](=[O:20])[N:9]3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: CS(=O)(=O)c1nnc2n1C=Cc1cc(Cl)ccc1C2
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=c1[nH]nc2n1C=Cc1cc(Cl)ccc1C2
Temperature: 95 °C

Procedure:
To 2.3 g of 8-chloro-3-methylsulfonyl-11H-s-triazolo[3,4-b][3]benzazepine in 20 ml of dioxane was added 10 ml of 2N-potassium hydroxide and the mixture was heated on a water bath at 95° C. for 30 minutes. The solvent was evaporated off and water was added to the residue. The mixture was made acidic with 2N-HCl and the resultant crystalline precipitate was recovered by filtration and dried. By the above procedure was obtained 8-chloro-2,11-dihydro-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Recrystallization from chloroform-methanol yielded colorless platelets, m.p. 281°-283° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1.ClC(Cl)C(O)=O.[I:35]N1C(=O)CCC1=O>C(#N)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[C:11]=1[I:35]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: O=C(O)C(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(I)c2=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a suspension of methyl 3-[4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (2.53 g, 6.55 mmol) and dichloroacetic acid (0.27 mL, 3.27 mmol) in acetonitrile (20 mL) was added N-iodosuccinimide (1.62 g, 7.20 mmol). Stirred at ambient temperature for 3.5 h. Cooled reaction mixture (0° C.), filtered solid, washed with cold acetonitrile, and dried in vacuo overnight. Obtained product as white solid (2.72 g, 81%). 1H NMR (CD3OD/400 MHz) δ8.24 (s, 1H), 8.07 (m, 1H), 7.93 (s, 1H), 7.63 (q, 1H, J=8.4 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.01 (t, 2H, J=8.4 Hz), 5.57 (s, 2H), 3.90 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 513.0143 (M+H calculated for C20H16F2IN2O4 requires 513.0117).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:10](Cl)(=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][CH3:9])[C:10](=[O:13])[CH:11]=[CH2:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: C=CC(=O)Cl
Solvent: Cc1ccccc1
Product: C=CC(=O)N(CCCC)CCCC
Temperature: 25 °C

Procedure:
In a 2 liter 3-necked flask were combined 129 g (1 mol) di-(n-butyl)amine (Fisher Scientific) and 0.1 l dry toluene and cooled to 5° C. 46 g (0.5 mol) acryloyl chloride dissolved in 50 ml toluene were added slowly so the temperature remained below 10° C. After the addition the flask was warmed to 25° C. and the precipitate removed by filtration. 1 g DNPD was added, and after concentration on a rotary evaporator the product was distilled at 20 m torr and 61°-63° C. Yield 77 g (84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCNCC1
Reactant: COc1cccc(C2(c3cccc(OC)c3)Oc3ccc(C(=O)O)cc3O2)c1
Product: COc1cccc(C2(c3cccc(OC)c3)Oc3ccc(C(=O)N4CCCCC4)cc3O2)c1

Procedure:
This compound was prepared from 2,2-bis-(3-methoxy-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and piperidine according to Example 269f; waxy solid, MS: m/e=446 ([M+H]+].