Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([OH:9])[NH:8][C:4]=2[CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+]>OS(O)(=O)=O>[N+:12]([C:11]1[C:2]([Br:1])=[CH:3][C:4]2[N:8]=[C:7]([OH:9])[NH:6][C:5]=2[CH:10]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc(Br)cc2[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2[nH]c(O)nc2cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
The procedure of Cheesman, G. W. H., J. Chem. Soc. 1170 (1962), was adapted. To a stirred suspension of 5-bromo-2-hydroxybenzimidazole (105 mg, 0.49 mmol) in concentrated H2SO4 (1 mL) at 0° C. for 30 min was added KNO3 (58.5 mg, 0.58 mmol, Baker) in one portion. The mixture was stirred at 0° C. for 3 h then at room temperature for one day. The mixture became a red solution. Then it was poured into ice (30 g) resulting in the separation of a brown precipitate, which was collected by filtration and washed with distilled water (2×1 mL) followed by ethanol (2×1 mL) to give 141 mg of crude title compound (contains minor impurities by NMR). Crystallization from DMSO/H2O gave 103 mg of pure title compound (80.5%) as bright yellow needles: mp 290°-4° C. (dec.), changed color from 200° C. IR (KBr, cm-1): 3406, 3181, 1712, 1537. 1H NMR (DMSO-d6): δ 7.244 (s, 1H), 7.558 (s, 1H), 11.227 (s, 1H), 11.321 (s, 1H). HRMS: calcd for C7H4N3O3Br (M+) m/z 256.9433; found: 256.9439.
Reaction SMILES: [NH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].Cl.[N:15]([O-])=O.[Na+].N(O)=O.N([O-])=O>>[N:15]1[N:4]2[C:5]3[C:10]([C:11](=[O:13])[NH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: O=NO
Agent: [Na+]
Product: O=c1[nH]c2nnnn2c2ccccc12
Reaction time: 1 h

Procedure:
2-Hydrazino-quinazolin-4-one (IIIb) (17.6 g; 0.1 mole), was suspended in 2 N-hydrochloric acid (78 ml; 0.156 mole) in a 600 ml beaker equipped with a thermometer and efficient stirrer. 15% w/v aqueous NaNO2 solution was added at such a rate that the temperature remained between 20° and 25° C., cooling with a water bath when necessary, until a small permanent excess of nitrous acid was present. The volume of the nitrite solution used was 63 ml (=9.45 g NaNO2 ; 0.137 mole). The reaction mixture was then stirred for 1 hour, filtered, and the solid washed acid free with water. After pulling as dry as possible on the filter, the product was dried completely in a vacuum desiccator over phosphorus pentoxide.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].[C:11]1([CH2:17][CH2:18][CH:19]=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[C:4]1([CH2:3][CH2:2][CH:19]([OH:20])[CH2:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=CCCc1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCc1ccccc1)CCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2-(bromoethyl)benzene (1.73 g; 9.33 mmol) in diethylether (10 mL) was added to a stirred slurry of magnesium turnings (250 mg; 10.18 mmol) in 5 mL of ether. The reaction was initiated with a heat gun, and after the addition was complete the mixture was heated on an oil bath for 30 minutes. 3-Phenyl-1-propanal (1.25 g; 9.33 mmol) was added in 10 mL of ether, and reflux was continued for 1 hour. The reaction was cooled and quenched with saturated ammonium chloride, extracted into 2× ethyl acetate, and the combined organic portions were dried and concentrated. Chromatographic purification on a silica gel column (10% ethyl acetate in hexane) delivered 1.42 g (63%) of the diphenyl alcohol, 1H NMR (300 MHz, CDCl3): δ 1.84 (m, 4H); 2.61-2.76 (m,4H); 3.65 (m, 1H); 7.19-7.29 (m, 10H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH2:17])[C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[N+](=[CH2:20])=[N-].CCCCCC>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[CH2:20][CH2:17]2)[C:5]2[O:12][C:9]3([CH2:10][CH2:11]3)[CH2:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: C=Cc1cc(Br)cc2c1OC1(CC1)CC2(C)C
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(Br)cc21

Procedure:
Following general procedure O and using A 6-bromo-3,4-dihydro-4,4-dimethyl-8-vinylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 41, 1.36 g, 4.6 mmol), a solution of diazomethane in diethyl ether and palladium (II)acetate (˜30 mg) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound was obtained as a clear oil (1.38 g, 100%).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:17][CH:18]=1.[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2N)cn1
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)cn1
Reaction time: 1 h

Procedure:
0.3 g of isoamyl nitrite was added to a mixture of 0.83 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine, 0.34 g of copper(I) chloride, 0.69 g of copper(II) chloride and 3 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 1 hour. 0.3 g of isoamyl nitrite was added to the mixture, and stirred for 20 minutes. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.52 g of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine [present compound 7-17].
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[C:20]([OH:22])(=[O:21])[CH3:19].[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]1
Reactant: [H][H]
Reactant: CCOC(=O)COCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)COCC1CCNCC1
Yield: 201.7 %

Procedure:
In a similar manner to Example 2, starting material step (c), the product from step (a) (1.4 g), ethanol (100 ml), glacial acetic acid (0.25 g), 10% Pd on C (140 mg) and hydrogen gas were reacted to give ethyl piperidin-4-ylmethoxyacetate, acetate salt (1.1 g), as a brown oil: NMR Spectrum (DMSO-d6) 1.12 (2H, m), 1.20 (3H, t), 1.62 (3H, m), 1.84 (3H, s), 2.48 (2H, m), 2.96 (2H, m), 3.29 (2H, d), 4.05 (2H, s), 4.12 (2H, q).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2].FC(F)(F)C(O[C:21]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[C:23]([F:30])[C:22]=1[F:31])=O>>[F:27][C:26]1[C:21]([O:14][C:13]([C:8]2[NH:9][C:10]3[C:6]([CH:7]=2)=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)=[O:15])=[C:22]([F:31])[C:23]([F:30])=[C:24]([F:29])[C:25]=1[F:28]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Yield: 57 %

Procedure:
Compound 105 was prepared from compound 104 with pentafluorophenyl trifluoroacetate according to the procedure for 3, and purified by chromatography (toluene-EtOAc 35:1). Yield: 57%.
Reaction SMILES: [C:1](/[C:4](=[CH:23]\[C:24](\[CH3:39])=[CH:25]\[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[CH2:5][CH:6]([CH3:22])[C:7]([O:9][CH:10]1[C:14](=[O:15])[O:13][CH:12]([C:16]([OH:18])=[O:17])[CH:11]1[C:19]([OH:21])=[O:20])=[O:8])([OH:3])=[O:2].C1C[O:43]CC1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1](/[C:4](=[CH:23]\[C:24](\[CH3:39])=[CH:25]\[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[CH2:5][CH:6]([CH3:22])[C:7]([O:9][CH:10]([C:14]([OH:43])=[O:15])[CH:11]([C:19]([OH:21])=[O:20])[CH:12]([OH:13])[C:16]([OH:18])=[O:17])=[O:8])([OH:3])=[O:2]
Reactant: C1CCOC1
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OC1C(=O)OC(C(=O)O)C1C(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OC(C(=O)O)C(C(=O)O)C(O)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(Step 1) To Compound 1 (1.33 g, 2.41 mmol), THF (20 mL), water (20 mL), and sodium carbonate (1.02 g, 9.62 mmol) were added, and the resulting mixture was stirred at room temperature for 30 minutes. The solvent in the reaction mixture was evaporated under reduced pressure. The resulting residue was purified by Diaion (registered trademark) HP-20ss (Mitsubishi Chemical Corporation) column chromatography (water/methanol), and to the residue, water (20 mL) and Dowex 50 (registered trademark) (Muromachi Technos, 50WX8, 50-100 mesh, H+ form) (10 g) were added, and the resulting mixture was gently stirred at room temperature for 30 minutes. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by high performance liquid chromatography (column: Waters SunFire (registered trademark) C18, 19×250 mm, Cat. No. 186002669; mobile phase: acetonitrile containing 0.1% TFA/water containing 0.1% TFA), whereby 1-{(4Z,6E)-4-carboxy-2,6,8,10,12,14-hexamethylhexadec-4,6-dienoyloxy}-3-hydroxypropane-1,2,3-tricarboxylic acid (174 mg) was obtained.
Reaction SMILES: C[Mg]I.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2(C#N)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].CC[O:21][CH2:22][CH3:23]>>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:22](=[O:21])[CH3:23])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)c(Cl)c2)CCCC1
Agent: C[Mg]I
Product: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methylmagnesium iodide (3M solution in ether; 100 ml) was added dropwise at 0° C. under nitrogen to a stirred solution of 1-(3,4-dichlorophenyl)cyclopentanecarbonitrile (48 g) in ether (100 ml), then the mixture was stirred at ambient temperature for 24 hours. The resulting solid was collected by filtration, washed well with ether, and added in portions to an ice-cold mixture of water (200 ml) and concentrated hydrochloric acid (125 ml). The mixture was heated at 95° C. with occasional stirring for 1 hour, then it was allowed to cool to ambient temperature. The product was extracted into ether (5×100 ml), then the combined extracts were washed with water (2×100 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was distilled to give 1-[1-(3,4-dichlorophenyl)cyclopentyl]ethanone as a pale yellow oil (31.9 g), b.p. 124-128° C/0.5 mbar.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16][S:17][C:18]1[N:19]=[CH:20][C:21]2[C:26](=O)[O:25]C(=O)[N:23]([CH2:29][C:30]3[CH:38]=[CH:37][C:36]4[O:35][CH2:34][O:33][C:32]=4[CH:31]=3)[C:22]=2[N:39]=1.Cl>O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:23]([CH2:29][C:30]2[CH:38]=[CH:37][C:36]3[O:35][CH2:34][O:33][C:32]=3[CH:31]=2)[C:22]2[N:39]=[C:18]([S:17][CH3:16])[N:19]=[CH:20][C:21]=2[C:26]=1[OH:25])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CSc1ncc2c(=O)oc(=O)n(Cc3ccc4c(c3)OCO4)c2n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(O)c2cnc(SC)nc2n(Cc2ccc3c(c2)OCO3)c1=O

Procedure:
To a solution of sodium ethoxide (1.6 g., 0.03 g. atom of sodium in 50 ml. of absolute ethanol) was added 4.8 g. (0.03 mole) of diethyl malonate. The ethanol was removed under suction in a rotary evaporator. To the residue was added 50 ml. of dry dimethyl formamide followed by 3.5 g. (0.01 mole) of 7-methylthio-1-piperonyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione. The reaction mixture was heated under reflux for 2 hours, cooled in ice and poured into 400 ml. of water. The reaction mixture was acidified with conc. hydrochloric acid. The resulting precipitateable amounted to 5.0 g.--m.p. 173°-178° C. Recrystallization from dimethyl formamide gave 3.4 g. of pure product--m.p. 187°-188° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][NH:30][C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:20]([N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[C@@H:29]([CH:33]([CH3:35])[CH3:34])[CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)[C@H]1CN(Cc2ccccc2)CCN1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(Cc4ccccc4)C[C@@H]3C(C)C)nc(-c3ccccc3O)nc2c1
Temperature: 85 °C
Yield: 64 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (200 mg, 0.74 mmol) in 10 mL DMF was added (S)-1-benzyl-3-isopropylpiperazine followed by the addition of triethylamine (206 μL). The reaction was heated at 85° C. for two hours. The reaction was quenched with water after cooling it to room temperature. The aqueous layer was extracted twice with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and concentrated. The reaction was purified via silica gel chromatography using 1:1 hexanes:CH2Cl2 solvent system to yield 2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (230 mg, 64%). LC/MS: m/z 453.5 (M+H)+ at 2.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1>>[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]([N:11]2[C:5]3=[N:6][C:7]4[C:2]([C:3](=[O:18])[N:4]3[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]2=3)=[CH:1][CH:10]=[CH:9][CH:8]=4)=[O:27])[CH2:22][CH2:21]1
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Reactant: CC1CCC(C(=O)Cl)CC1
Product: CC1CCC(C(=O)n2c3ccccc3n3c(=O)c4ccccc4nc23)CC1

Procedure:
6-(4-Methylcyclohexanoyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and 4-methylcyclohexanoyl chloride.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C=O>[CH:25]1[CH:24]=[CH:23][C:22]([N:15]([C:9]2[CH:10]=[CH:11][C:12]([Br:1])=[CH:13][CH:14]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
Into a 200 ml three-necked flask, 8.0 g (45 mmol) of N-bromosuccinimide and 10.0 g (41 mmol) of triphenylamine were placed, followed by 150 ml of N,N-dimethylformamide. The mixture was stirred overnight at room temperature. Next, N,N-dimethylformamide was removed from the reaction, and the resulting solid matter was extracted with carbon tetrachloride. Then, carbon tetrachloride was removed, and the reaction product was recrystallized twice from ethanol to give a white solid, 4-bromotriphenylamine in an amount of 8.2 g (yield: 61.7%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[CH:18]=[C:17]([C:19](O)=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[CH3:29][NH:30][CH3:31]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[C:13]4[CH:18]=[C:17]([C:19]([N:30]([CH3:31])[CH3:29])=[O:20])[S:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CNC
Reactant: O=C(O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1
Agent: Cl
Product: CN(C)C(=O)c1cc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2s1

Procedure:
45 mg of 2-(1H-indazol-4-yl)-4-morpholinothieno[2,3-d]pyrimidine-6-carboxylic acid 14 was coupled to dimethylamine HCl via General Procedure B. The product was purified via reverse phase HPLC to give 33 mg of 130. MS (Q1) 409.2 (M)+.
Reaction SMILES: [H-].[Na+].[C:3]1([S:9]([NH2:12])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:31]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:30]3[CH:38]=[CH:39][C:40]([C:42](O)=[O:43])=[CH:41][C:29]=3[N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[N:31]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:30]3[CH:38]=[CH:39][C:40]([C:42]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[S:9]([NH2:12])(=[O:11])=[O:10])=[O:43])=[CH:41][C:29]=3[N:28]=2)=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccccc1C(=O)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
A suspension of compound 49 (0.060 g, 0.14 mmol) and thionyl chloride (0.051 mL) in benzene (2 mL) was refluxed for 2 h under an argon atmosphere. The reaction mixture was cooled to rt and concentrated on a rotary evaporator. The residue was coevaporated with benzene (2×) to afford the acid chloride as a white solid (0.062 g, 100%). Sodium hydride (0.0101 g, 0.252 mmol, 60% dispersion in oil was added to a solution of phenylsulfonamide (0.0425 g, 0.270 mmol) in dimethylformamide (1 mL) at rt under an argon atmosphere. After 1 h, dichloromethane was added (1 mL), followed by the acid chloride of 49 at 0° C. The reaction was warmed to rt. After 1 h, the reaction was diluted with dichloromethane and quenched with 1 N hydrochloric acid. The aqueous layer was washed with dichloromethane (3×). The combined organic layers were dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified by column chromatography (silica gel, 25% acetone/toluene (v/v)). This material was further purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford 55 as a white solid (0.0219 g, 54%). 1H NMR (CDCl3) δ 8.71 (d, 1H, J=1.1 Hz), 8.05 (m, 3H), 7.82 (d, 1H, J=8.8 Hz), 7.69 (d, 2H, J=9.1 Hz), 7.58 (m, 1H), 7.51-7.36 (m, 7H), 7.21 (d, 2H, 8.8 Hz), 5.16 (s, 2H), 4.52 (m, 1H), 2.32 (br m, 2H), 2.01 (br m, 4H), 1.80 (br m, 1H), 1.35 (br m, 3H); ESI-MS m/e 566.4 (M+1); HPLC purity (ELSD)>95%.
Reaction SMILES: [C:1](=[N:4][O:5][CH2:6][CH2:7][OH:8])([CH3:3])[CH3:2].[Br:9][CH:10]([CH3:14])[C:11](Br)=[O:12]>>[Br:9][CH:10]([CH3:14])[C:11]([O:8][CH2:7][CH2:6][O:5][N:4]=[C:1]([CH3:3])[CH3:2])=[O:12]
Reactant: CC(Br)C(=O)Br
Reactant: CC(C)=NOCCO
Product: CC(C)=NOCCOC(=O)C(C)Br

Procedure:
by using 2-isopropylideneaminooxy-ethanol and 2-bromopropionyl bromide there is obtained 2-isopropylideneaminooxy-ethyl 2-bromopropionate, nD20 1.4710.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH2:15][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. Ethanolamine (1.1 mL, 18.6 mmol) and and N,N-diisopropylethylamine (3.9 mL, 22.3 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4-chloromethyl N-(2-hydroxyethyl)benzenesulfonamide. The resulting oil was dried in vacuo (3.7 g, 68%). ES-MS m/z 250 (M+H) and 294 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=2)=[CH:10][O:9][N:8]=1.CC1O[N:27]=[C:26](C2C=CC=CC=2)[C:25]=1[CH2:35][O:36][C:37]1N=CC(C(O)=O)=N[CH:42]=1.NC1CCOCC1>>[O:36]1[CH2:35][CH2:25][CH:26]([NH:27][C:20]([C:17]2[CH:16]=[N:15][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[CH:19][N:18]=2)=[O:22])[CH2:42][CH2:37]1
Reactant: Cc1onc(-c2ccccc2)c1COc1cnc(C(=O)O)cn1
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccccn2)cn1
Agent: NC1CCOCC1
Product: O=C(NC1CCOCC1)c1cnc(OCc2conc2-c2ccccn2)cn1
Yield: 87 %

Procedure:
As described for example 2b, 5-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (75.4 mg, 2.5 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid, was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (SiO2, heptane:ethyl acetate 1:1 to 0:1, 83.8 mg, 87%) which was obtained as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([N:26]([CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[CH:20]=[CH:19]2)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[NH2:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([N:26]([CH2:38][P:39](=[O:46])([O:40][CH2:41][CH3:42])[O:43][CH2:44][CH3:45])[S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[CH:20]=[CH:19]2
Reactant: CCOP(=O)(CN(c1ccc2cc(NC(=O)OC(C)(C)C)ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(CN(c1ccc2cc(N)ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C

Procedure:
1 ml trifluoroacetic acid is pipetted into 130 mg diethyl {[(6-tert.-butoxycarbonylamino-naphthalen-2-yl)-(3,5-dichloro-phenylsulphonyl)-amino]-methyl}-phosphonate in 3 ml methylene chloride. The reaction mixture is stirred for two and a half hours at ambient temperature, then made alkaline with 1 N sodium hydroxide solution and extracted with methylene chloride. The combined organic phases are washed with saturated sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with cyclohexane/ethyl acetate (40:60 to 0:100).