Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])(C)C)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.I[C:15]1[CH:19]=[CH:18][S:17][CH:16]=1.[CH3:20][C:21](C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.O>[S:17]1[CH:18]=[CH:19][C:15]([N:4]2[CH2:3][CH2:2][N:1]([C:7]([O:9][CH2:10][CH2:13][CH2:20][CH3:21])=[O:8])[CH2:6][CH2:5]2)=[CH:16]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Ic1ccsc1
Reactant: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC(=O)N1CCN(c2ccsc2)CC1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (0.300 g, 1.61 mmol) in 10 mL of toluene under an atmosphere of nitrogen was added 3-iodothiophene (0.390 g, 1.86 mmol), sodium tert-butoxide (0.310 g, 3.22 mmol), tris (dibenzylidenacetone)palladium (0) (0.295 g, 0.322 mmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 0.307 g, 0.644 mmol). The mixture was heated to 100° C. for 18 h, cooled to rt, and treated with water. The solution was extracted 3× with ethyl acetate, and the combined organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography, eluting with 0-70% ethyl acetate, to provide text-butyl 4-(3-thienyl)piperazine-1-carboxylate that gave a proton NMR spectra consistent with theory.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34]([OH:36])=O)[C:23]=6[CH:37]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.C1C=CC2N(O)N=[N:50]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[Cl-]>CN(C=O)C.O.CCN(CC)CC>[F:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:38]([CH3:43])[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34]([NH2:50])=[O:36])[C:23]=6[CH:37]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: On1nnc2ccccc21
Reactant: CN(c1cc2oc(-c3ccc(F)cc3)c(C(=O)O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc2oc(-c3ccc(F)cc3)c(C(N)=O)c2cc1-c1ccc2c(n1)-c1cc3c(F)cccc3n1CO2)S(C)(=O)=O
Reaction time: 2 h
Yield: 90.8 %

Procedure:
5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylic acid (200 mg, 0.33 mmol), HOBT (50 mg, 0.37 mmol) and EDCI (140 mg, 0.73 mmol) were dissolved in dry DMF (5 mL). The resulting solution was stirred for 2 hours. And then NH4Cl (100 mg, 1.87 mmol) and Et3N (0.5 mL) were added to the mixture. The mixture was stirred at room temperature overnight. Then H2O was added, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using column chromatography (dichloromethane:MeOH=40:1) to provide 5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (180 mg, yield: 90%). 1H-NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 7.98˜8.03 (m, 2H), 7.69 (s, 1H), 7.48˜7.54 (m, 2H), 7.19˜7.24 (m, 4H), 7.12 (d, J=8.4 Hz, 1H), 6.83˜6.88 (m, 1H), 6.01 (s, 2H), 5.70˜5.86 (m, 2H), 3.39 (s, 3H), 2.74 (s, 3H). MS (M+H)+: 601.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@@H:9]([N:11]=[N+]=[N-])[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([C@@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@H](N=[N+]=[N-])c1cccc(C#N)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: C[C@H](N)c1cccc(C#N)c1

Procedure:
(S)-1-(3-cyanophenyl)-1-azidoethane (1.42 mmol) was dissolved in benzene (4 mL), H2O (500 μL) was added followed by triphenylphosphine (2.90 mmol). The resultant mixture was heated to 80° C. for 3.5 h. 25 mL of 2N HCl was added and the mixture washed 3×20 mL diethyl ether. These washes were discarded and the aqueous phase made strongly basic by the addition of 5N NaOH. This basic aqueous phase was then extracted 3×25 mL diethyl ether, these extracts combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was used without further purification (150 mg). 1H NMR (500 MHz, CDCl3): δ 7.70 (m, 1H); 7.62 (d, J=7.8 Hz, 1H); 7.54 (m, 1H); 7.44 (t, J=7.8 Hz, 1H); 4.20 (q, J=6.6 Hz, 1H); 1.40 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl.CN.[C:4]([C:6]1[CH:7]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5].[CH2:16]([N:18](CC)CC)[CH3:17]>O1CCCC1.O.C(OCC)(=O)C>[C:4]([C:6]1[CH:7]=[C:8]([S:12]([NH:18][CH2:16][CH3:17])(=[O:14])=[O:13])[CH:9]=[CH:10][CH:11]=1)#[N:5]
Reactant: CCN(CC)CC
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
Methylamine hydrochloride (736 mg, 10.9 mmol) was added to a solution of 3-cyano benzene sulfonyl chloride (2.0 g, 9.9 mmol) and triethylamine (3.45 ml, 24.7 mmol) in tetrahydrofuran (30 ml) and the resulting mixture left to stir at room temperature under a nitrogen atmosphere for 16 h hours. The reaction mixture was diluted with water (30 ml) and ethyl acetate (50 ml). The organic phase was separated and dried (sodium sulfate) and reduced in vacuo to give the title compound as a colourless solid (1.68 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].C([Li])CCC.CN(C)[CH:23]=[O:24].O>O1CCCC1>[F:1][C:2]1[C:7]([CH:23]=[O:24])=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: CN(C)C=O
Reactant: CC(C)S(=O)(=O)Nc1ccc(F)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(C=O)c1F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To propane-2-sulfonic acid (2,4-difluoro-phenyl)-amide (48, 2.35 g, 9.95 mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooled with a dry ice/acetone bath was added 1.60 M of n-butyllithium (1.60 M in hexane, 6.53 mL, 10.45 mmol). The reaction was stirred for 40 minutes, and then another portion of n-butyllithium (1.60 M in hexane, 6.84 mL, 10.94 mmol). The reaction was stirred for 1 hour and N,N-dimethylformamide (0.92 mL, 11.9 mmol) was added. The reaction was allowed to warm to room temperature overnight. The reaction was poured into water extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol 5%) to give the compound (49, 1.4 g, 53.4%). MS (ESI) [M−H+]−=263.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].N(C(C)C)C(C)C>ClCCl.[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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[C:11][CH:10]([OH:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: C#CC(C)O
Reactant: Clc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(O)C#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a solution of 4-chloro iodobenzene (10 g, 42 mmol), 3-butyn-2-ol (6.6 mL, 84 mmol, 2 eq.), and iPr2NH (14.8 mL, 105 mmol, 2.5 eq.) in 200 mL dichloromethane was added CuI (1.6 g, 8.4 mmol, 0.2 eq.) followed by Pd(PPh3)2Cl2 (1.5 g, 2.1 mmol, 5 mol %). The mixture was stirred for 1.5 hr at room temperature, concentrated and diluted with ether. The insoluble components of the mixture were filtered off and the filtrate washed with 1N HCl and brine, dried over MgSO4, filtered, concentrated and chromatographed with 20% ethyl acetate-hexane to provide 7.6 g of 4-(4-chloro-phenyl)-but-3-yn-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[N:35]1[CH:40]=[CH:39][C:38](CO)=[CH:37][CH:36]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)=[CH:18][CH:17]=1
Reactant: OCc1ccncc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccncc4)cc3)c2cc1OC
Yield: 28.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 4-pyridylmethanol (28 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (21 mg, yield 23%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]3[O:17][CH2:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)=[C:4]2[CH2:3]1.[Br-].C1C(C(OOC(C)(C)C)=O)=CC=CC=1.O>C1C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[S:10][CH:11]=[CH:12][C:6]=2[N:5]2[CH:13]=[N:14][C:15]([C:16]3[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=3)=[C:4]2[CH2:3]1
Reactant: COC(=O)[C@@H]1COC(c2ncn3c2CN(C)C(=O)c2sccc2-3)=N1
Agent: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1coc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)n1
Yield: 25.1 %

Procedure:
A solution of 5.92 g (0.0171 mol) of methyl (S)-2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepin-3-yl)-4,5-dihydro-oxazole-4-carboxylate in 300 ml of benzene was treated with 2.69 g (0.0188 mol) of copperl bromide and 4.97 ml (0.0256 mol) of tert-butyl perbenzoate according to the method described in Tetr. Letters 1994, 35, 2481. The mixture was boiled at reflux for 1 hr., cooled and treated with 100 ml of water. The mixture was filtered, extracted with benzene and chromatographed over silica gel with ethyl acetate as the eluent. There were obtained 1.48 g (25%) of methyl 2-(5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]-diazepin-3-yl)-oxazole-4-carboxylate as a yellowish solid. An analytical sample was recrystallized from hot ethyl acetate and gave white crystals; m.p. 254°-255°.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=2[C:4]#[N:5])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1c(F)ccc(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)ccc(F)c2C#N)CC1
Reaction time: 0.5 h
Yield: 32.3 %

Procedure:
To 1.0 g (6.36 mmol) of 2,3,6-trifluorobenzonitrile dissolved in 10 mL DMF was added 1.05 g (1.2 eq., 7.63 mmol) potassium carbonate and 1.18 g (1 eq., 6.36 mmol) piperazine-1-carboxylic acid tert-butyl ester. The mixture was stirred 30 minutes to completion, partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduce d pressure. Column chromatography, eluting with ethyl acetate/hexanes provided 665 mg of 4-(2-cyano-3,6-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:22]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 144.7 %

Procedure:
A mixture of thymidine (400 g, and 1.65 mol), 4-dimethylaminopyridine (0.8 g, 6.5 mmol) and t-butyldiphenylchlorosilane (347.2 g, 1.26 mol) in anhydrous pyridine (3.0 lt) was stirred at room temperature for 48 hr. To the stirred reaction mixture two lots of t-butyldiphenyl chlorosilane (129.4 g, 0.47 mol and 22.7 g, 0.082 mol) were added 12 hr. apart and stirring continued for an additional 48 hr. The reaction mixture was concentrated under vacuum and the residue redissolved in ethanol (2.5 lt). The product was precipitated by pouring the reaction mixture into a cold stirred ice-water (5.0 lt) suspension. The aqueous suspension was stirred at room temperature for 3 hr. to quench traces of unreacted chlorosilane. The granular white precipitate was filtered and washed with distilled water (5×1 it) and air dried to furnish 876 g of 5'-O-t-butyldiphenylsilyl thymidine (slightly contaminated with bissilyated product, about 5%).
Reaction SMILES: [OH:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>CC(C)=O>[CH3:26][N:27]([CH3:31])[C:28]([O:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19])=[S:29]
Reactant: CN(C)C(=S)Cl
Reactant: Cc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc2c(c1OC(=S)N(C)C)CCN(C(=O)C(F)(F)F)CC2
Yield: 89.5 %

Procedure:
Dissolve 6-hydroxy-7-methyl-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 3.66 mmol) in acetone (50 mL). Add potassium carbonate (1.517 g, 10.98 mmol) and dimethylthiocarbamoyl chloride (0.904 g, 7.32 mmol). Heat the mixture at reflux overnight. Remove the solvent in vacuo and partition the residue between water and DCM. Dry the organic phase over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0 and 9:1) to obtain the desired intermediate as a solid (1.18 g, 90%). MS (ES+) m/z: 361 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH2:24])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:25]([O-])=O.[Na+]>CC(O)=O.O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][N:17]4[C:18]5[CH:23]=[CH:22][N:21]=[CH:20][C:19]=5[N:24]=[N:25]4)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=N[O-]
Reactant: Nc1cnccc1NCc1nnc2ccc(-c3ccccc3)nn12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc(-c2ccc3nnc(Cn4nnc5cnccc54)n3n2)cc1
Reaction time: 1 h

Procedure:
To a solution of N4-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)pyridine-3,4-diamine (0.0640 g, 0.202 mmol) in HOAc (5 mL) was added sodium nitrite (0.0153 g, 0.222 mmol) in water (2 mL). Stirred for 1 h. Concentrated. Took up in DMSO and purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate and removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=329.2[M+1]+. Calc'd for C17H12N8: 328.3.
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].C(O)(=O)C.O.[H][H]>O1CCOCC1.[Pd]>[NH2:1][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(N2CCC(N=[N+]=[N-])CC2)cc1
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1

Procedure:
To a solution of ethyl 4-(4-azidopiperidin-1-yl)benzoate (7.62 g, 27.8 mmol) in dioxane (190 mL) was added acetic acid (27 mL) and water (54 mL). Then, 10% Pd/C (0.750 g) was added and the mixture was hydrogenated under 1 atmosphere of hydrogen for 5 hours. The mixture was filtered through Celite, concentrated, and 0.5 M HCl (500 mL) was added. The solution was washed with ethyl acetate (2×300 mL) and the aqueous phase basified with ammonium hydroxide, to pH 12. The aqueous phase was saturated with sodium chloride, extracted with CH2Cl2 (2×300 mL), dried over anhydrous MgSO4, filtered, and concentrated, to afford ethyl 4-(4-aminopiperidin-1-yl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[CH3:25][O:26][CH2:27]Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH2:25][O:26][CH3:27])=[O:5]
Reactant: COCCl
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)[O-])c(Cl)cc3F)c1=O)CCC2
Agent: [Na+]
Product: COCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl

Procedure:
using sodium 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and chlorodimethyl ether there is obtained methoxymethyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.93 ppm (d, 1H), 7.36 ppm (d, 1H), 5.45 ppm (s, 2H), 3.54 ppm (s, 3H), 3.41 ppm (s, 3H), 2.95 ppm (m, 2H), 2.81 ppm (m, 2H), 2.17 ppm (m, 2H),
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>CN(C=O)C.O>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)CC1CCNCC1
Reactant: Brc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCN(c2ccccn2)CC1
Temperature: 130 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
To a stirred solution of ethyl 2-(piperidin-4-yl)acetate, hydrochloride (2.0 g, 9.63 mmol) in DMF (40 mL) was added K2CO3 (3.99 g, 28.9 mmol) followed by 2-bromopyridine (1.521 g, 9.63 mmol) and stirred at 130° C. for 16 h. Reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with water (2×100 mL), brine (100 mL) and dried over Na2SO4 filtered and concentrated under reduced pressure. The residues was purified by column chromatography using 100-200 silica gel by eluting with 20% ethyl acetate in petroleum ether to afford ethyl 2-(1-(pyridin-2-yl)piperidin-4-yl)acetate (600 mg, 19.86% yield) as color less liquid. LCMS (ES) m/e 249.20 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:24])[CH2:5][CH:6]([OH:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])#[N:2].CO[C:27](OC)([CH3:29])[CH3:28].CS(O)(=O)=O>CC(C)=O>[C:1]([CH2:3][C@H:4]1[O:24][C:27]([CH3:29])([CH3:28])[O:23][C@@H:6]([CH2:7][C:8]([N:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH2:5]1)#[N:2]
Reactant: N#CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Reactant: COC(C)(C)OC
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CC1(C)O[C@H](CC#N)C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude [R-(R*,R*)]-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide, approximately 0.18 mol, is dissolved in 2,2-dimethoxypropane (160 mL, 1.5 mol) and acetone (300 mL). Methanesulfonic acid (0.5 mL) is added, and the solution is stirred for 2 hours at room temperature. The reaction is quenched by the addition of aqueous sodium bicarbonate (800 mL) and ethyl acetate (500 mL). The ethyl acetate solution is concentrated by vacuum distillation to give 62.5 g of (4R-cis)-6-(cyanomethyl)-2,2-dimethyl-N,N-diphenyl-1,3-dioxane-4-acetamide as an off-white crystalline solid (mp 98°-100° C., uncorrected).
Reaction SMILES: [Br:1][C@@H:2]([C@H:6]([OH:8])[CH3:7])[C:3]([OH:5])=O.[Cl-].[CH3:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][NH2+:17][CH2:18][S:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>>[CH3:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][N:17]([CH2:18][S:19][C:20]([CH3:21])([CH3:23])[CH3:22])[C:3](=[O:5])[C@@H:2]([Br:1])[C@H:6]([OH:8])[CH3:7])=[CH:14][CH:13]=1
Reactant: COc1ccc(C[NH2+]CSC(C)(C)C)cc1
Reactant: C[C@@H](O)[C@H](Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1ccc(CN(CSC(C)(C)C)C(=O)[C@@H](Br)[C@@H](C)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.83 g (10 mmol) of (2S,3R)-2-bromo-3-hydroxybutyric acid, manufactured analogously to a method prescribed by Shimohigashi et al., Bull. Chem. Soc. Japan 52, 949 (1979), there are added in succession, at room temperature, 2.76 g (10 mmol) of N-p-methoxybenzyl-N-tert.-butylthiomethylammonium chloride, 2.06 g (10 mmol) of dicyclohexyl carbodiimide and, dropwise, 1.40 ml (10 mmol) of triethylamine. The resulting reaction mixture is stirred at room temperature for 2 hours. The dicyclohexylurea which has separated out is filtered off with suction, and the filtrate is diluted with methylene chloride and washed with water and phosphate buffer solution of pH 8. The organic phase is dried over sodium sulphate and concentrated by evaporation, and the oily residue is chromatographed over silica gel with toluene/ethyl acetate. The title compound is obtained in the form of a colourless, viscous oil. Rf (toluene/ethyl acetate 1:1): 0.55; IR (in methylene chloride): 3550-3200, 2950-2850, 1632, 1608, 1508, 1457, 1438, 1407, 1360, 1242, 1202, 1175, 1150, 1028 cm-1.