Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][NH:8][C:7]1=[O:11].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21]Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[C:6]1[CH2:10][CH2:9][N:8]([CH2:21][CH2:20][O:19][CH3:18])[C:7]1=[O:11]
Reactant: COc1ccccc1C=C1CCNC1=O
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN1CCC(=Cc2ccccc2OC)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The intermediate 3-(2′-methoxybenzylidene)-2-pyrrolidone (5.0 g) obtained in Example 317 was dissolved in dimethylformamide (50 ml) and sodium hydride (0.99 g) was added under ice-cooling. The mixture was stirred at room temperature for 30 min. To the reaction mixture was again added 2-methoxyethyl chloride (2.3 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hr and at 70° C. for 1 hr. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily title compound (2.8 g).
Reaction SMILES: OP([O-])([O-])=O.[K+].[K+].[F:8][C:9]1[C:10]([CH3:28])=[N:11][C:12]2[C:17]([N:18]=1)=[C:16](B1OC(C)(C)C(C)(C)O1)[CH:15]=[CH:14][CH:13]=2.Br[C:30]1[NH:34][C:33]2[C@@H:35]([CH3:39])[NH:36][C:37](=[O:38])[C:32]=2[CH:31]=1>CN(C=O)C.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:8][C:9]1[C:10]([CH3:28])=[N:11][C:12]2[C:17]([N:18]=1)=[C:16]([C:30]1[NH:34][C:33]3[C@@H:35]([CH3:39])[NH:36][C:37](=[O:38])[C:32]=3[CH:31]=1)[CH:15]=[CH:14][CH:13]=2
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1F
Reactant: C[C@H]1NC(=O)c2cc(Br)[nH]c21
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1F
Yield: 42.6 %

Procedure:
Argon was bubbled into a slurry of potassium phosphate dibasic (Aldrich; 0.164 g, 0.944 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Aldrich; 0.019 g, 0.027 mmol), 3-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxaline (618) (0.155 g, 0.539 mmol), (R)-2-bromo-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (287) (0.058 g, 0.270 mmol) in 1.5 mL DMF and 0.5 mL water for 1 min. The reaction was sealed and placed in a 70° C. oil bath for 45 min. Additional 1 equiv boronic ester and 5 mg catalyst added, and the reaction was heated 30 min additional. The reaction was partitioned between water and EtOAc. The aq. layer was extracted 1× EtOAc, and the combined organic layers were washed with water 2 times, saturated aq. NaCl once, and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (24 g column) using 0-100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford (R)-2-(3-fluoro-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (287f; 0.034 g, 0.115 mmol, 42% yield) as a orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (1H, s), 8.07 (1H, d, J=7.6 Hz), 7.94 (1H, d, J=8.2 Hz), 7.78-7.88 (1H, m), 7.69 (1H, s), 7.01 (1H, d, J=1.6 Hz), 4.58 (1H, q, J=6.7 Hz), 2.71 (3H, s), 1.41 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 297.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C=O)C>[C:8]1([CH2:7][O:6][C:5]([NH:4][CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]2)=[O:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCCBr)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(CCNC(=O)OCc2ccccc2)CC1
Yield: 93.3 %

Procedure:
A mixture of phenylmethyl (2-bromoethyl)carbamate (12.9 g, 50 mmol) (prepared from phenylmethyl (2-bromoethyl)carbamate and phenylmethyl chloridocarbonate according to the method of A. J. Brouwer and R. M. J. Liskamp, European Journal of Organic Chemistry (2005), (3), 487-495), 1,1-dimethylethyl 4-piperidinylcarbamate (10 g, 50 mmol), potassium carbonate (6.9 g, 50 mmol), acetonitrile (100 ml) and DMF (30 ml) was heated at 40° C. for 2.5 days. The solvents were decanted from inorganic residues and evaporated. The residue was partitioned between ethyl acetate and dilute brine. The organic extract was dried (MgSO4) and evaporated affording a white solid (17.6 g, 93%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=O.[C:29]([O:32][CH2:33]C)(=[O:31])C>CO>[CH3:33][O:32][C:29]([C:2]1[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1)=[O:31]
Reactant: CCOC(C)=O
Reactant: Nc1ncc(Br)nc1-c1ccc(OC(F)(F)F)cc1
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cnc(N)c(-c2ccc(OC(F)(F)F)cc2)n1
Yield: 73 %

Procedure:
To a solution of 10.20 g (0.029 mol) 5-bromo-3-(4-trifluoromethoxy-phenyl)-pyrazin-2-ylamine in 100 ml methanol and 40 ml ethyl acetate was added 0.500 g (0.0006 mol) PdCl2 dppf CH2Cl2 ([1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct, Cas Registry No. [95464-05-4]) and 8.113 ml (5.9 g, 0.058 mol) triethylamine and the mixture was stirred at 110° C. under 70 bar carbon monoxide pressure for 4 h. The solvents were evaporated and the residue was purified by chromatography on silica gel with a gradient of 100% heptane to 100% ethyl acetate to yield 6.800 g (73% yield) of the title compound as off white crystalline solid. MS (ISP) (M+H+)=314.0.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1>C(O)(=O)C.O>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[NH:16][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: NNc1ccc(Br)cc1
Reactant: O=CCCCCCl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: ClCCCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 24.5 %

Procedure:
5-Chloropentanal (ca. 70% pure, 8.0 g) was added to a suspension of 4-bromophenylhydrazine hydrochloride (13.4 g) in aqueous acetic acid (50%, 300 ml). The mixture was heated rapidly to boiling with vigorous stirring and maintained at reflux for 7 hours. The resulting dark brown solution was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (4×150 ml). The combined extracts were washed with water (200 ml) and saturated aqueous sodium hydrogen carbonate (4×250 ml), dried (MgSO4), filtered and evaporated to a dark brown oil (14.7 g), which was purified on a silica column (Kieselgel 60, 200 g) eluted with ethyl acetate:light petroleum (b.p. 60°-80°) (1:2) followed by bulb to bulb distillation twice in vacuo to give the title compound as a yellow oil (4 g) b.p. 200° C., 0.5 mm, which rapidly darkened on storage.
Reaction SMILES: O[C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]([NH:18][NH:19][C:20](=O)[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)=[N:14][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O=P(Cl)(Cl)[Cl:30]>C(#N)C>[Cl:30][C:2]1[N:3]=[C:4]2[CH:17]=[CH:16][C:15]3=[N:18][N:19]=[C:20]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[N:14]3[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(NNc1ccc2nc(O)c(-c3ccccc3)nc2n1)c1cccnc1
Solvent: CC#N
Product: Clc1nc2ccc3nnc(-c4cccnc4)n3c2nc1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of N′-(2-hydroxy-3-phenylpyrido[2,3-b]pyrazin-6-yl)nicotinohydrazide (3-4) (5.8 g, 16.2 mmol) in acetonitrile (1.3 mL) was added POCl3 (7.5 mL, 81 mmol), and stirred at 100° C. for overnight. The solvent was removed under reduced pressure, and to the residue was added CHCl3 and water. The organic layer was separated, dried (Na2SO4), filtered, and evaporated in vacuo. To the residue was added CHCl3, and the resulting solid was collected by filtration to yield 3-chloro-2-phenyl-9-(3-pyridinyl)[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazine (3-5) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[CH:8]=[C:7]2[OH:15].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12][CH2:13][CH3:14])[CH:8]=[C:7]2[O:15][CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCSc1cc(O)c2cccc(Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSc1cc(OCc2ccc(OC)cc2)c2cccc(Cl)c2n1
Temperature: 65 °C
Yield: 72.3 %

Procedure:
8-Chloro-2-ethylsulfanyl-quinolin-4-ol (10.26 g, 42.8 mmol) was dissolved in anhydrous dimethylformamide (100 mL). Cesium carbonate (27.9 g, 85.6 mmol) was added, followed by p-methoxybenzyl chloride (8.0 g, 51.36 mmol). The mixture was then heated at 65° C. for 2 hours and then cooled to room temperature and diluted with ethyl acetate. The diluted reaction mixture was washed with brine 2 times, dried over Mg2SO4 and concentrated in vacuo. The residue was recrystallized from EtOAc/Hexanes to afford 8-chloro-2-ethylsulfanyl-4-(4-methoxy-benzyloxy)-quinoline (11.14 g, 67% yield). LCMS found 360.21 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C)C=O>[O:10]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[CH:9])[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CC(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CC(O[Si](C)(C)C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 5.0 g (37.9 mmol) of 1-phenyl-2-propyne-1-ol in 20 ml of dimethyl formamide were added 6.9 g (45.8 mmol) of t-butyl dimethylsilyl chloride and 6.2 g (91.1 mmol) of imidazole, and the resulting mixture was stirred at room temperature for 3 hours, 50 ml of water was added and the mixture was extracted with a pentane-ether (1:1) mixture (4×30 ml). The organic layer was washed with water (30 ml) and saturated brine, dried over anhydrous magnesium sulfate (30 mg) and thereafter concentrated. The residue was purified by column chromatography (silica gel 100 g, cyclohexane-ethyl acetate) and further distilled (dp 98° C./1 mm Hg) to give 5.7 g (24.7 mmol, 65%) of the subject compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(#N)C>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=[C:2]2[CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc(Br)ccn1
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
0.6 g (3.47 mmol) of 2-amino-4-bromopyridine, 1.55 g (7.15 mmol) of ethyl bromopyruvate and 4 mL of acetonitrile are placed in a 20 mL screw-topped tube equipped with a magnetic bar. The top is then screwed on and the tube is stirred at room temperature for 1 hour, and then heated at 150° C. with stirring for 30 minutes. After this time and cooling to room temperature, the precipitate obtained is filtered off, rinsed with acetonitrile and dried. The filtrate is concentrated to dryness and then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. The solid obtained after evaporating off the solvent is dried under reduced pressure. 530 mg of the expected product are obtained in total.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:6][CH:7]=1.[Br:22]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[C:11]=2[Br:22])=[CH:6][CH:7]=1
Reactant: COc1cc(COc2ccc(N)nn2)cc(OC)c1OC
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(COc2ccc(N)nn2)c(Br)c(OC)c1OC
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
3-Amino-6-(3,4,5-trimethoxybenzyloxy)pyridazine (Intermediate 1, 2.91 g, 10 mMol) in acetic acid (20 ml) was treated dropwise with a solution of bromine (1.59 g, 10 mMol) in acetic acid (2 ml) over 5 minutes. After 0.5 hours, the mixture was filtered to give a cream solid which was suspended in water and basified with sodium hydroxide solution. The mixture was extracted with chloroform and the extracts were washed with water, dried (Na2SO4) and evaporated in vacuo to yield a cream solid which was recrystallised from toluene to give the title compound (2.76 g) as cream needles, m.p. 160°-161° C., NMR δH(CDCl3) 6.93(1H,s,ArH) 6.91(1H,JAB,8.8 Hz,5H), 6.80(1H,JAB,8.8 Hz,4H), 5.49(2H,s,CH2), 4.95(2H, brs,NH2), 3.91(3H,s,OCH3), 3.90(3H,s,OCH3) and 3.89(3H,s,OCH3 ).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[C:29]=1[CH3:36].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:8]([NH:10][C:11]([NH:32][C:31]1[CH:33]=[CH:34][C:28]([O:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=2)=[C:29]([CH3:36])[C:30]=1[CH3:35])=[S:12])=[O:9]
Reactant: O=C(N=C=S)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(Cl)c4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Commercially available 3-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 87%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:6]([CH2:7][OH:8])[O:5][C@H:4]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18].N1C=CC=CC=1.[C:25]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])([CH3:27])[CH3:26]>C(OCC)(=O)C>[O:8]([CH2:7][C@H:6]1[O:5][C@@H:4]([N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[NH2:18])[C@@H:3]1[CH2:2][OH:1])[Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:31])[CH3:30]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]1CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a round-bottom flask were placed 10 g of 9-((2R, 3R, 4S)-3,4-bis-hyroxymethyl-oxetan-2-yl)-adenine and 100 mL of pyridine. To the system was added 6.4 g of tert-butylchlorodimethylsilane, and the reaction mixture was stirred under nitrogen at room temperature for 1 day. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated with a rotary evaporator. The residue was purified by column chromatography to afford 9-((2R,3R,4S)-4-t-butyldimethylsiloxymethyl-3-hydroxymethyl-oxetan-2-yl)adenine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:21])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:24])[CH2:9][N:10]([CH3:20])[S:11]([C:14]2[S:15][C:16]([Br:19])=[CH:17][CH:18]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(CN(C)S(=O)(=O)c1ccc(Br)s1)c1ccc(F)cc1
Reaction time: 0.75 h

Procedure:
To a solution of 5-bromothiophene-2-sulfonic acid [2-(4-fluorophenyl)-2-hydroxyethyl]-methyl-amide (the compound of Preparation Example 71) (210 mg) in N,N-dimethylformamide (2 mL) was added 60% sodium hydride (32 mg). After stirring for 45 minutes, methyl iodide (100 μL) was added. Water was added, the solution was extracted with ethyl acetate. After washing the organic layer with saturated sodium chloride water, and then was dried with anhydrous sodium sulfate, the residue that was obtained upon removal of the solvent by evaporation was purified by silica gel column chromatography (hexane/ethyl acetate), and the title compound (110 mg) was obtained as a colorless oily matter.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:30]1(/[CH:36]=[CH:37]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>COC>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:37]=[CH:36]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:17]=2)=[N:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Cc1nc(-c2cncc(Cl)n2)sc1C(=O)NCc1ccccc1
Agent: COC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(-c2cncc(/C=C/c3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 64.6 %

Procedure:
To a solution of 2-(6-chloro-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (40 mg, 0.12 mmol, 1.0 equiv) in dimethyl ether (0.6 mL) was added Na2CO3 (25 mg, 0.23 mmol, 2.0 equiv), trans-2-phenylvinyl boronic acid (43 mg, 0.29 mmol, 2.5 equiv), CombiPhos Pd-6 (6.0 mg, 0.01 mmol, 0.1 equiv) and water (0.2 mL) in a sealed tube. The reaction was heated in the microwave oven at 100° C. for 25 min. After cooling, the solvent was removed in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 5:95, v/v] to give 4-methyl-2-[6-((E)-styryl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (32 mg, 67%). 1H NMR (400 MHz, CD2Cl2) δ 9.17 (s, 1H), 8.64 (s, 1H), 7.83 (d, J=16.0 Hz, 1H), 7.62-7.64 (m, 2H), 7.28-7.43 (m, 8H), 7.19 (d, J=16.0 Hz, 1H), 6.25 (bs, 1H), 4.61 (d, J=1.0 Hz, 2H), 2.74 (s, 3H); HRMS (M+H)+=413.14.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([CH3:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([CH3:28])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:25][CH2:24][CH:21]2[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]3[CH:26]=[CH:27][CH:28]=[C:13]([CH3:12])[CH:14]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C(=O)N2CCC(CO)CC2)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
53.3 g (0.28 mol) of 4-methylbenzenesulphonyl chloride in 60 ml of pyridine are added to a solution of 52 g (0.22 mol) of 1-(3-methylbenzoyl)-4-piperidinemethanol in 100 ml of pyridine. The mixture is stirred at 20° C. for 4 h, and then poured into ice. The phase is extracted with dichloromethane, and the organic phase washed with 5N aqueous hydrochloric acid solution and dried over magnesium sulphate. The solvents are evaporated off under reduced pressure and 70 g of white solid are obtained.
Reaction SMILES: [N:1]([CH:4]([O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)[CH2:5][CH2:6][NH:7]C(=O)C(F)(F)F)=[N+:2]=[N-:3].CO.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:7][CH2:6][CH2:5][CH:4]([N:1]=[N+:2]=[N-:3])[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(COC(CCNC(=O)C(F)(F)F)N=[N+]=[N-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(COC(CCN)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-[(1-azido-3-trifluoroacetamidopropoxy)methyl]benzoate (220 mg; 0.61 mmol) was added to methanol (2.3 mL) and a solution of potassium carbonate (200 mg; 1.4 mmol) in H2O (1.1 mL). The mixture was vigorously stirred at room temperature for 3 h, diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtrated and evaporated. The residue was purified by silica column chromatography (DCM:MeCN 1:1+5% MeOH+1% TEA) to provide methyl 4-[(3-amino-1-azidopropoxy)methyl]benzoate as a liquid in a yield of 110 mg (68%). 1H-NMR (500 MHz, CDCl3): δ=1.78-2.02 ppm (m, 2H), 2.85 ppm (t, J=7.0 Hz, 2H), 3.91 ppm (s, 3H), 4.60 ppm (t, J=6.5 Hz, 1H), 4.62 ppm (d, J=12.5 Hz, 1H), 4.87 ppm (d, J=12.5 Hz, 1H); 13C-NMR (500 MHz, CDCl3): δ=37.79 (in [D6]DMSO this peak splits in two distinct signals with δ=37.92 ppm and 38.93 ppm), 52.21, 70.16, 90.40, 127.55, 129.80, 129.89, 142.17, 166.84 ppm. HRMS [+Scan]; calculated m/z for C12H17N4O3 265.1295; observed mass: 265.1292.
Reaction SMILES: Cl.[H][H].[N+:4]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)([O-])=O>>[NH2:4][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2
Reactant: [H][H]
Reactant: O=[N+]([O-])C12CC3CC(CC(O)(C3)C1)C2
Agent: Cl
Product: NC12CC3CC(C1)CC(O)(C3)C2
Yield: 95 %

Procedure:
An autocrave was charged with 10 ml of methanol were added 10 mmol of the 1-nitro-3-adamantanol obtained by the method of Preparation Example 4, 5% Pd-C (10 mol % as Pd, relative to a substrate) and 1 ml of hydrochloric acid, and the mixture was stirred in a hydrogen atmosphere at a temperature of 80° C. for 2 hours. And, as a result, the 1-nitro-3-adamantanol was converted into a 1-amino-3-adamantanol (yield:95%) with a conversion of 99%.