Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]2[O:19][CH2:18]2)=[CH:11][C:10]=1[N:20](C(OC(C)(C)C)=O)[S:21]([CH3:24])(=[O:23])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([NH:39][C@H:40]1[CH2:45][CH2:44][C@H:43]([C:46]2[CH:56]=[CH:55][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>C(O)C>[CH2:32]([N:39]([CH2:18][C@H:17]([OH:19])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH:11]=1)[C@H:40]1[CH2:41][CH2:42][C@H:43]([C:46]2[CH:47]=[CH:48][C:49]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:55][CH:56]=2)[CH2:44][CH2:45]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1ccc([C@H]2CC[C@H](NCc3ccccc3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N(c1cc(OC[C@@H]2CO2)ccc1OCc1ccccc1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc([C@H]2CC[C@H](N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 818 mg (1.82 mmol) of 4-benzyloxy-3-(N-(tert-butoxycarbonyl)-N-(methylsulfonyl)amino)-1-((2S)-2,3-epoxypropoxy)benzene and of 450 mg (1.82 mmol) of ethyl trans-4-[4-(benzylamino)cyclohexyl]benzoate in the base form is heated at reflux in 15 ml of absolute ethanol for 16 h. The mixture is cooled, 3 ml of a saturated ethanolic hydrochloric acid solution are added thereto and the mixture is heated at 50° C. for 6 h. The solvent is evaporated and the residue is taken up with a mixture of 50 ml of a saturated sodium bicarbonate solution and 50 ml of ethyl acetate. The organic phase is washed with a saturated aqueous NaCl solution. The organic phase is dried and filtered, and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a methylene chloride/methanol/NH4OH (95/5/0.5) mixture. The title compound is obtained in the form of a white solid. [M+H+]=687.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[O:23][CH3:24].[CH:25]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH:25]1([CH2:30][C:31]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH3:11])[CH:6]=[C:5]3[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[O:23][CH3:24])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
A mixture of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.57 g.), cyclopentylacetic acid (0.23 g.), 4-(dimethylamino)pyridine (0.22 g.), and 1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride (0. 343 g.), was dissolved in dichloromethane (25 ml.), under an atmosphere of nitrogen, and stirred at room temperature for 18 hours. The mixture was poured into 1M hydrochloric acid (25 ml.), the separated aqueous layer extracted with dichloromethane (3×25 ml.), the combined organic extracts washed with water, brine, dried (MgSO4) and evaporated. The residual oil was crystallized from ethyl acetate to give the title compound (0.555 g. 73%) as a white powder; m.p. 180°-181° C.; partial NMR (250 MHz, DMSO-d6): 1.17(m,2H); 1.4-1.8 (m,6H); 2.25(m,3H); 3.70(s,3H, NMe); 3.82(s,3H, OMe); 3.92(s,3H, OMe); 3.97(s,2H, ArCH2); 9.62(br s,1 H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]COC)=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])O)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:18])=[C:4]([CH2:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1c(Cl)cccc1C(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1Cc1cccc(Cl)c1O

Procedure:
(3-Chloro-2-methoxymethoxyphenyl)(2-methoxyphenyl)methanol (15.27 g, 49 mmol) was combined with 15.97 g (100 mmol) of triethylsilane in 150 ml of methylene chloride and to this was added at ambient temperature with stirring under nitrogen 14.8 g (130 mmol) of trifluoroacetic acid. The mixture was stirred for 4 hours and was then poured into saturated aqueous sodium bicarbonate. Additional methylene chloride was added and the organic phase was recovered, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by preparative liquid chromatography eluting with a 1:99 mixture of acetone and hexane to obtain 3.98 g (33 percent of theory) of the title compound. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23]>C1COCC1>[CH3:1][N:2]([CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][C:11]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH:10][C:9]2=[O:23])[CH3:3]
Reactant: CNC
Reactant: O=c1cc(-c2ccc(O)cc2)oc2ccc(CBr)cc12
Solvent: C1CCOC1
Product: CN(C)Cc1ccc2oc(-c3ccc(O)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 68 %

Procedure:
Dimethylamine (1 M solution in THF, 1.2 mL) was added to 6-bromomethyl-2-(4-hydroxyphenyl)chromen-4-one (206 mg, 0.62 mmol) dissolved in dry THF (10 mL). The reaction mixture was stirred at rt for 17 hr. Most of the solvent was then removed in vacuo and the yellowish residue was suspended in 20 mL of water. The resulting suspension was stirred at rt for 30 min and the solid was removed by filtration, washed with water, ether, and air-dried to afford 6-((dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one (125 mg, 68%). MS (ES) m/z: 296.98 (M+1), 295.97 (M); Mp. 99-102° C.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[CH3:13][NH:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl>[CH3:13][NH:14][S:15]([N:3]([CH3:2])[O:4][CH3:5])(=[O:17])=[O:16]
Reactant: CNOC
Reactant: CNS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)N(C)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.5 %

Procedure:
5.75 g (58.9 mmol) of N,O-dimethylhydroxylamine hydrochloride was suspended in 300 ml of dichloromethane, and 11.9 g (118 mmol) of triethylamine was added thereto. Then, the mixture was cooled with ice, and a dichloromethane solution of 7.63 g of methylsulfamoyl chloride was dropwise added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure. To the residue, 200 ml of benzene was added, and insoluble substance was filtered off. Then, the solvent was distilled off again under reduced pressure. By the distillation under reduced pressure, 4.4 g of N,N'-dimethyl-N'-methoxysulfamide was obtained (boiling point: 85°-88° C./1.9 mmHg).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[Cl:13]
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CN(C)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.2 %

Procedure:
25 g of N,N-dimethyl-3-nitroaniline is dissolved in 225 ml of DMF. 20 g of N-chlorosuccinimide dissolved in 190 ml of DMF is slowly added dropwise and the solution is stirred at RT. After 24 hours, the solvent is evaporated. About 500 ml of ice is added to the red residue. The suspension is extracted three times with about 200 ml of diethylether. The ether phases are dried over Na2SO4, filtered, and evaporated down. 30.4 g of N,N-dimethyl-2-chloro-3-nitroaniline is obtained as a red oil. The crude product is used further without any additional purification.
Reaction SMILES: OO.[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)(=[O:5])[CH3:4].C=O.[C:20]([OH:23])(=[O:22])[CH3:21]>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]([O:23][C:20](=[O:22])[CH3:21])[CH2:10][CH2:9][CH2:8][CH2:7][O:6][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)O
Reactant: CC(=O)OCCCCCc1ccccn1
Agent: C=O
Agent: OO
Product: CC(=O)OCCCCC(OC(C)=O)c1ccccn1
Temperature: 95 °C
Reaction time: 16 h

Procedure:
Aqueous hydrogen peroxide (13 mls of 30% solution) was added over 2 hours to a solution of 5-(2-pyridyl)-pentan-1-yl acetate (13.0 gms) in acetic acid (50 mls) at 75° C. After 16 hours and mixture was heated to 95° C and paraformaldehyde (1.8 gms) was added. After a further 2 hours the solvent was evaporated in vacuo and the residual oil was added to acetic anhydride (50 mls) and heated at 95° C for 6 hours. The solvent was evaporated and the product was poured onto ice, neutralised with potassium carbonate and extracted into diethyl ether. Evaporation of the ether and distillation of the residual oil yielded 1-(2-pyridyl)-1,5-diacetoxy pentane, b.p. 140°-141° C/1 mm (8 gms; 40%). Characterised by the following spectral data:
Reaction SMILES: [Si]([O:18][C:19]1[CH:60]=[CH:59][C:22]([O:23][CH2:24][C@@H:25]([OH:58])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[C:40]4=[N:41][CH:42]=[CH:43][CH:44]=[C:39]4[N:38]=[C:37]3[C:45]3[CH:50]=[CH:49][C:48]([N:51]4[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]4)=[CH:47][C:46]=3[Cl:57])=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[Cl:57][C:46]1[CH:47]=[C:48]([N:51]2[CH:55]=[CH:54][C:53]([CH3:56])=[N:52]2)[CH:49]=[CH:50][C:45]=1[C:37]1[N:36]([C:33]2[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][CH:25]([OH:58])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:60][CH:59]=3)=[CH:31][CH:32]=2)[C:40]2=[N:41][CH:42]=[CH:43][CH:44]=[C:39]2[N:38]=1
Reactant: Cc1ccn(-c2ccc(-c3nc4cccnc4n3-c3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)c(Cl)c2)n1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccn(-c2ccc(-c3nc4cccnc4n3-c3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)c(Cl)c2)n1
Yield: 62 %

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-[(4-{2-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)phenyl]-3H-imidazo[4,5-b]pyridin-3-yl}phenethyl)amino]-2-propanol (0.18 g, 0.216 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.08 g, 0.134 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:15][C:14]([OH:17])([CH3:16])[CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:16][C:14]1([OH:17])[CH2:15][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13]1
Reactant: CC1(O)CN(C2CN(C(=O)OC(C)(C)C)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-hydroxy-3-methyl-[1,3′]biazetidinyl-1′-carboxylic acid tert-butyl ester (0.09 g, 0.37 mmol) in DCM/TFA (2 mL/2 mL). The reaction mixture was stirred for 90 min at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 3-Methyl-[1,3′]biazetidinyl-3-ol as a colourless oil (0.04 g, 76%). 1H NMR (300 MHz, CDCl3): δ 3.68-3.51 (m, 6H), 3.25 (d, J=7.6 Hz, 2H), 3.15 (d, J=7.6 Hz, 2H), 1.49 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH:12]([CH3:18])[C:13]([OH:15])=[O:14])[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)Oc1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(Oc1cccc2cccnc12)C(=O)O
Temperature: 27 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of ethyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.4 mmol) in EtOH (1 ml) was added a solution of NaOH (24 mg, 0.6 mmol) in H2O (0.5 ml) at 27° C. The mixture was stirred for 30 min at 27° C. The mixture was then concentrated and the residue treated with water (5 mL) and extracted with ethyl acetate (2×5 mL). The water layer was then treated with 2N HCl until pH 3 before being extracted with ethyl acetate (2×5 ml). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title product (70 mg, 80.5%) as a white solid which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH3:22][C:23](=O)[CH2:24][CH3:25]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:22][CH2:23][CH2:24][CH2:25][CH2:22][CH2:23][CH2:24][CH2:25][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][CH3:7])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1OC

Procedure:
A mixture of 28.5 g 3-methoxy-4-(hydroxy)benzoic acid methyl ester, 25.94 g of finely powdered potassium carbonate, 0.070 g potassium iodide and 285 ml of 2-butanone is heated at reflux temperature for 41 hours. The reaction is cooled and filtered. The filtrate is concentrated in vacuo and recrystallized from hexane to give 40.8 g of the desired product as white crystals.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6](OS(C(F)(F)F)(=O)=O)[N:5]=[C:4]2[S:21][CH:22]=[CH:23][C:3]=12.C([O-])([O-])=O.[K+].[K+].[CH2:30]([SH:32])[CH3:31]>CN(C=O)C.O>[CH2:30]([S:32][C:6]1[N:5]=[C:4]2[S:21][CH:22]=[CH:23][C:3]2=[C:2]([CH3:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:31]
Reactant: CCS
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2sccc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SCC)nc2sccc2c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.8 %

Procedure:
To a solution of ethyl 4-methyl-6-(trifluoro-methyl-sulfonyloxy)thieno[2,3-b]pyridine-5-carboxylate (1.84 g, 4.9 mmol, 1 eq.) in DMF (30 ml) were added K2CO3 (2.70 g, 19.6 mmol, 4 eq.) and ethanethiol (3.73 ml, 49.8 mmol, 10 eq.) at RT. The reaction mixture was stirred at 80° C. for 2 h. Afterwards the mixture was diluted with water (50 ml) and was extracted with EtOAc (2×50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over Na2SO4 and evaporated. The crude product was purified by CC (EtOAc/hexane 1:49) to yield ethyl 6-(ethylthio)-4-methylthieno[2,3-b]pyridine-5-carboxylate (0.26 g, 0.92 mmol, 19%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])[CH:19]=[CH:20][C:21](O)=O>>[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=1[F:27])/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(F)c(F)c3)nc2n(CC)c1=O
Yield: 48.6 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.79 g (15.2 mmol) of 3,4-difluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.12 g (yield 49%) of Compound 111 as gray plates.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].Cl[C:9]1[CH:10]=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1.[O-]CC.[Na+].O>C(O)C>[CH2:3]([O:4][C:9]1[CH:10]=[C:11]([CH3:19])[C:12]2[N:13]([C:15]([NH2:18])=[N:16][N:17]=2)[N:14]=1)[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(Cl)nn2c(N)nnc12
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C)c2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
6-Chloro-8-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine trifluoroacetate (W2.002b; 50 mg) was dissolved in ethanol (3.5 ml) while stirring at RT. Thereafter, sodium ethoxide was added dropwise while cooling with ice (25 mg dissolved in 1.5 ml of ethanol). After stirring at RT for 2.5 h, the mixture was heated to 60° C. and, after 2.5 h, a further equivalent of sodium ethoxide solution was added. After standing overnight, the mixture was heated again to 60° C., two further equivalents of sodium ethoxide solution were added and the mixture was stirred for 4 h. Subsequently, the mixture was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 27 mg of the title compound were obtained. LC-MS rt: 0.67 min [M+H]+: 194.1 (met. a)
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[CH3:14][O:15][C:16]1[CH:40]=[CH:39][C:19]([CH2:20][N:21]2[C:25]([NH:26][CH:27]=[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29](OCC)=[O:30])=[CH:24][CH:23]=[N:22]2)=[CH:18][CH:17]=1>C(O)C>[OH:30][C:29]1[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:27][N:26]=[C:25]2[N:21]([CH2:20][C:19]3[CH:39]=[CH:40][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[N:22]=[CH:23][C:24]=12
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccc(OC)cc1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1O
Temperature: 45 °C

Procedure:
Diphenyl ether (180 ml) was heated to about 230° C. (Internal temperature 200-210° C.) under inert atmosphere in a round bottom flask fitted with distillation set and a solution of diethyl ({[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]amino}methylidene)propanedioate (85 gm, 0.227 mol) (example 2) in absolute ethanol (130 ml) was added dropwise. The reaction mixture was heated for about 2 hours. Volatile solubles were distilled out. The mixture was cooled to 45° C. and methanol (150 ml) was added dropwise. Solid, which precipitated out was filtered and washed with methanol and hexane and dried under vacuum.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]12([NH2:14])[CH2:13][CH:11]([CH2:12]1)[CH2:10]2.[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>CN(C=O)C>[C:9]12([NH:14][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[O:16])[CH2:13][CH:11]([CH2:12]1)[CH2:10]2
Reactant: NC12CC(C1)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC12CC(C1)C2)n1ccnc1

Procedure:
Triethylamine (0.1 mL, 0.5 mmol) was added to a solution of bicyclo[1.1.1]-pentan-1-amine hydrogen chloride (19 mg, 0.16 mmol) and 1,1′-carbonyldiimidazole (32 mg, 0.192 mmol) in DMF (2 mL) (clear solution turned into suspension). The suspension was used for the synthesis of compound 1 without further isolation of compound 1b.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]([Cl:19])=[N:17][S:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>>[ClH:19].[Cl:19][C:18]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][S:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nsnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 202.2 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (10 g, 32 mmol, 1.0 eq, prepared as Example 1a) and 4M HCl/Dioxane. The reaction was allowed to stir at room temperature for 2 hour. The resulting precipitate was filtered, washed with EtOAc three times, dried in vacuo to give 4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine hydrochloride (7.8 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([C:21]([F:24])([F:23])[F:22])[CH:10]=3)[S:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:34])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[C:11]([C:21]([F:22])([F:23])[F:24])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2nc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Yield: 72.1 %

Procedure:
To a solution of 6-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (120 mg, 0.325 mmol) in CCl4 (3.5 ml) is added NBS (64 mg, 1.1 eq.). The mixture is heated to reflux for 15 minutes before AIBN (5 mg, 0.1 eq.) is added. The reaction is refluxed overnight, filtered through celite and washed with CCl4. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane=9/95). 6-Bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (105 mg, 72%) is isolated.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[N:6]=[C:5]2[N:13]([NH2:19])C(OCC)=O.CN(C)[CH:22]=[O:23]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[C:22](=[O:23])[NH:19][N:13]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N(N)c1nc(O)nc2ccc(F)cc12
Reactant: CN(C)C=O
Product: O=c1[nH]nc2c3cc(F)ccc3[nH]c(=O)n12
Temperature: 25 °C

Procedure:
3.7 g (0.014 mol) of ethyl 6-fluoro-2-hydroxy-quinazolin-4-yl-carbazate in 75 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, washed with acetone and dried in a vacuum. Yield: 1.7 g (56%) of 9-fluoro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. >350° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:16]([O:20][C:21]([NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26](O)=[O:27])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:25][C:26](=[O:27])[NH:2][NH:1][C:3]1[N:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:7]2[CH:6]=[CH:5][N:4]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: NNc1nccc2nc(C(F)(F)F)nn12
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNc1nccc2nc(C(F)(F)F)nn12)Cc1cc(F)c(F)cc1F

Procedure:
By the procedure of Example 9, Step A, 5-hydrazino-2-(trifluoromethyl)[1,2,4]triazolo[1,5-c]pyrimidine (Intermediate 42) was acylated with (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (Intermediate 3). Purification by flash chromatography on silica gel (1-5% methanol in dichloromethane) afforded the title compound as a light tan solid, mp 159-161° C. LC-MS 534 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:21][N:22]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.NO>CN(C)C=O.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([NH:22][OH:21])=[O:20])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)NO)cc1
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To N-{[4-(2-butynyloxy)phenyl]sulfonyl}-beta-alanine (0.80 g, 2.69 mmol) in dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (0.436 g, 3.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.67 g, 3.5 mmol). After one hour 50% hydroxylamine in water (1.3 mL) was added. The reaction mixture was stirred overnight and concentrated in vacuo. Ethyl acetate was added and the organic phase washed with water (2×) and brine then dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave a white solid that was triturated with ethyl acetate to give 3-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)-N-hydroxypropanamide (0.30 g) as a white solid,. mp 118-128° C. Electrospray Mass Spec 313.3 (M+H)+.