Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[CH2:20][C@@H:19]1[CH2:35][C:36]([O:38]C)=[O:37]>O1CCOCC1.O.C(OCC)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[C:8]2[CH2:15][CH2:16][CH2:17][C@@H:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[C:26][C:27]2[CH:28]=[C:29]([F:34])[CH:30]=[C:31]([F:33])[CH:32]=2)[CH2:20][C@@H:19]1[CH2:35][C:36]([OH:38])=[O:37]
Reactant: COC(=O)C[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CC#Cc4cc(F)cc(F)c4)C[C@@H]3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 88.2 %

Procedure:
0.83 cm3 of 5N aqueous sodium hydroxide solution was introduced with stirring, at a temperature in the region of 20° C., into a solution of 0.525 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetate in 5 cm3 of dioxane and then the mixture was heated for 3 hours at a temperature in the region of 60° C. After cooling to approximately 20° C., the mixture was stirred for 3 days and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 15 cm3 of water and then the solution was extracted with 5 cm3 of ethyl acetate. The aqueous phase was brought to a pH in the region of 5-6 by addition of 4.1 cm3 of 1N aqueous hydrochloric acid and then extracted, first with 30 cm3 of dichloromethane and then with 10 cm3 of the same solvent. The organic extracts were combined, washed with 2 times 5 cm3 of water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in diethyl ether and then concentrated under the same conditions as above until a constant weight was obtained. 0.45 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid was obtained in the form of a solid with a light beige color.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[C:17]([Cu])#[N:18]>C1C=CC=CC=1>[C:17]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2)#[N:18]
Reactant: N#C[Cu]
Reactant: ClC1c2ccccc2COc2ccccc21
Solvent: c1ccccc1
Product: N#CC1c2ccccc2COc2ccccc21
Yield: 92 %

Procedure:
11-Chloro-6,11-dihydrodibenz[b,e]oxepin (32.69 g; 0.14 mole) is dissolved in dry benzene (300 ml) and placed under a dry nitrogen atmosphere. To this solution is added in one portion, CuCN (32.04 g; 0.35 mole). The reaction is heated to reflux for 31/2 hours and filtered while hot. After washing the salts with benzene, the filtrate is removed in vacuo to give a solid. This solid is triturated several times with isopropyl ether and finally hexane to give a solid (92%) of 11-cyano-6,11-dihydrodibenz[b,e]oxepin m.p. 65°-66.5° C.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8](=[O:20])[C:7]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])=[CH:6][C:5]=1[C:35](=[O:38])[CH2:36][CH3:37]>C1COCC1>[Br:1][CH:36]([CH3:37])[C:35]([C:5]1[CH:6]=[C:7]([C:21]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=2)=[O:22])[C:8](=[O:20])[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:4]=1[CH3:3])=[O:38]
Reactant: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Reactant: BrBr
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(C)Br)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Bromine (84 μl, 1.61 mmol) in THF (5 ml) was added to a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-propionyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (700 mg, 1.34 mmol) in TEF (10 ml). After 2 h, the yellow colour had disappeared. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was separated, dried and evaporated under reduced pressure to give the title compound (800 mg, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:15](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(c1ccc(Br)cc1)C1CCNC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(=O)c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
To a solution (4-bromo-phenyl)-pyrrolidin-3-yl-methanone (2.24 g, 8.81 mmol) in methanol (44 mL), add acetic acid (1.01 mL, 17.6 mmol) and formaldehyde (2.15 g, 26.4 mmol, 37% aqueous solution). After 15 min, add sodium triacetoxyborohydride (5.60 g, 26.4 mmol) and allow the mixture to stir at RT for one hour. Concentrate the reaction mixture. Add water and adjust the solution to pH=10 with 2 N NaOH. Extract the aqueous with ethylacetate. Dry the combined organic layers over Na2SO4, filter, and concentrate. Purify the crude material by flash chromatography, eluting with 5-10% MeOH (2N NH3)/CH2Cl2 to give 1.61 g (68%) of the title compound. LC-MS/ES m/z (79Br) 268.0 [M+H]+.
Reaction SMILES: CN(CC)C.Br[C:7]1[S:8][CH:9]=[C:10]([Br:12])[CH:11]=1.[O:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[Br:12][C:10]1[CH:11]=[C:7]([N:15]2[CH2:16][CH2:17][O:13][C:14]2=[O:18])[S:8][CH:9]=1
Reactant: O=C1NCCO1
Reactant: Brc1csc(Br)c1
Agent: [Cu]I
Agent: CCN(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1OCCN1c1cc(Br)cs1
Temperature: 110 °C
Reaction time: 16 h
Yield: 15.5 %

Procedure:
N,N-Dimethylethylamine (0.22 mL, 2.0 mmol), 2,4-dibromothiophene (5.0 g, 20.6 mmol) and oxazolidinone (2.1 g, 24.8 mmol) were added to a mixture of copper(I) iodide (0.39 g, 2.0 mmol) and cesium carbonate (13.4 g, 41.3 mmol) in dry dioxane under nitrogen. The reaction mixture was stirred at 110° C. for 16 h. The reaction was filtered through the Celite™ reagent and rinsed with methylene chloride. The filtrate was concentrated in vacuo to a residue. Purification of the crude product on silica gel using a stepwise gradient of 6:1 to 3:1 hexane:ethyl acetate as the eluent gave 3-(4-bromo-thiophen-2-yl)-oxazolidin-2-one (790 mg, 15%) as the desired product contaminated with 10% of the 3-(5-bromo-thiophen-3-yl)-oxazolidin-2-one isomer. MS (ES) m/z 249 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1)=O>>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][CH:15]=[C:16]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[N:9]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: CCOC(=O)c1ccc(-c2coc(-c3ccc(C(F)(F)F)cc3)n2)cc1
Yield: 21 %

Procedure:
In the same manner as in Example 1, 4-trifluoromethylbenzamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-trifluoromethylphenyl)-4-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 21%. Pale yellow prisms. Melting Point: 168 to 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:12][C:13]=1[C:14]#[N:15].S(=O)(=O)(O)[OH:23]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:12][C:13]=1[C:14]([NH2:15])=[O:23]
Reactant: N#Cc1sc(N2CCOCC2)nc1-c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(O)O
Solvent: O
Product: NC(=O)c1sc(N2CCOCC2)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
4-(2,4-dichlorophenyl)-2-morpholin-4-yl-1,3-thiazole-5-carbonitrile (30 mg, 0.088 mmol) was dissolved in sulfuric acid (0.200 mL, 3.75 mmol) and the mixture was stirred at rt for 1 hour. Water (1 mL) was added and the mixture was quenched with an excess of saturated NaHCO3. Precipitate was filtered off, washed with water and dried to afford the title compound (27 mg, 80%). LCMS: (FA) ES+, 358. 1H NMR (400 MHz, d6-DMSO) δ: 7.67 (d, 1H), 7.47 (d, 1H), 7.43 (dd, 1H), 3.72-3.69 (m, 4H), 3.44-3.42 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:15]([OH:17])=[O:16]>CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:15]([OH:17])=[O:16]
Reactant: COc1cc2ccccc2c(C(=O)O)c1OC
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(c(C(=O)O)c1OC)CCCC2
Reaction time: 11 h
Yield: 72 %

Procedure:
A mixture of 2,3-dimethoxy-1-naphthalenecarboxylic acid (2.21 g, 9.52 mmol) and 10% Pd/C (0.53 g) in HOAc (50 mL) was hydrogenated on a Parr apparatus at 60° C. and 50 psi for 11 h. After filtration through diatomaceous earth, the solvent was removed under reduced pressure, and water was added. The precipitate was filtered and washed with water to give the product as a white solid (1.62 g, 72%). 1H NMR (DMSO-d6) δ 12.99 (s, 1H), 6.77 (s,1H), 3.77 (s, 3H), 3.68 (s, 3H), 2.67 (s, 2H), 2.50 (s, 2H), 1.68 (m, 4H); MS m/z 235 (m−H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1>>[F:27][C:28]1[CH:29]=[C:30]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]([F:23])([F:24])[F:25])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and 3-fluoro-phenylhydrazine according to the method described for example 43. MS: M=431.1 (M+H)+
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][O:2][C:1]([C:4]23[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:6][CH2:5]3)=[O:3])[CH2:26][CH2:25]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: BrCC1CC1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCC3CC3)(CC1)CC2
Yield: 58.7 %

Procedure:
In a similar manner to Example 8, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (20.0 mg) and cyclopropylmethyl bromide (12.8 mg) were used to obtain (2S,4S)-1-[[N-(4-cyclopropylmethyloxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (13.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19](O)=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5].Cl.[CH2:36]([NH2:38])[CH3:37].C1C=CC(P(OC2C(F)=C(F)C(F)=C(F)C=2F)(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[F:34])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[CH:7]=[C:8]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]([NH:38][CH2:36][CH3:37])=[O:20])[CH:17]=2)[CH:9]=[CH:10][C:11]=1[CH3:12])=[O:5]
Reactant: CCN
Reactant: Cc1ccc(-c2cn(CC(=O)O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: Cl
Agent: O=P(Oc1c(F)c(F)c(F)c(F)c1F)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Cn1cc(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of compound 111 (39 mg, 0.08 mmol) in DMF (1.0 mL) was added ethylamine hydrochloride (20 mg, 0.08 mmol), FDPP (43 mg, 0.11 mmol), and DIEA (68 μL, 0.4 mmol). The flask was flushed with argon and the reaction mixture was stirred at RT for 72 h and then poured into a mixture of water (4 mL), HCl (4N, 2 mL), and EtOAc. The phases were separated. The organic phase was concentrated on silica in vacuo. The crude product was purified by chromatography eluting with EtOAc/petroleum ether (40-60) 50:50 to 100:0 as the eluent to afford the title compound as white foam. 13C NMR (DMSO-d6) δ 194.9, 164.8, 149.3, 145.2, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.6, 126.4 (dd), 125.0, 124.2 (dd), 123.0, 114.8, 111.9 (dd), 111.8, 105.0 (dd), 51.7, 33.6, 19.4, 14.4
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1([CH:27]=[CH2:28])O.S(=O)(=O)(O)[OH:31]>O1CCOCC1>[CH3:29][C:2]1([CH3:1])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:27][CH2:28][OH:31]
Reactant: C=CC1(O)c2cc(OC)ccc2CC(N(C)S(=O)(=O)c2ccc(C)cc2)C1(C)C
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 2.5 h
Yield: 70 %

Procedure:
A stirred mixture of 149 g of 2,2-dimethyl-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydro-1-vinyl-1-naphthol, 1200 ml of dioxane and 1380 ml of 0.5 N sulphuric acid is heated until, after 40 minutes, a temperature of 90° C. is reached. The mixture is kept at that temperature during 2.5 hours whereafter it is cooled and extracted three times with chloroform. The chloroform solution is washed with plenty of water and then, after being dried, evaporated in vacuo. The residue is dissolved in acetone. From this solution the product separates as white crystals melting at 142°-144° C. Yield 70%.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:26])[CH:11]=[C:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2.CO.[Li+].[OH-].Cl>O>[CH:14]1[C:13]2[C:12](=[CH:11][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:27])=[O:2])=[O:26])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCNC(=O)C=C1c2ccccc2Sc2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCNC(=O)C=C1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.8 %

Procedure:
6-(2-(9H-thioxanthen-9-ylidene)acetamido)hexanoic acid methyl ester (381 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture was neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (249 mg, 68% yield) as a white solid. LC-MS (m/z) 368 (M+1).
Reaction SMILES: C([O:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.B(Cl)(Cl)Cl.O>ClCCl>[OH:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9]([NH2:18])=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Nc1nc(-c2ccccc2)c(CCO)c2ncnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 28.8 g (0.1 mole) of 8-(2-ethoxyethyl)-7-phenyl-1,2,4-triazolo[2,3-c]pyrimidine-5-amine was added 200 ml of 1 N boron trichloride in dichloromethane. The mixture was then stirred at room temperature overnight, after which 500 ml of water was added. After three hours, the resultant precipitate was collected by filtration. The aqueous phase of the filtrate was separated and neutralized with aqueous sodium carbonate, giving a second precipitate. The combined solids were purified by column chromatography, giving the title compound, m.p. 194°-195°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[Cl:26][C:27]1[CH:38]=[C:31]2[C:32](OC(=O)[NH:36][C:30]2=[CH:29][CH:28]=1)=[O:33]>O1CCCC1>[NH2:36][C:30]1[CH:29]=[CH:28][C:27]([Cl:26])=[CH:38][C:31]=1[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1)=[O:33]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: Nc1ccc(Cl)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-5-chloropyridine (787 mg, 6.1 mmol) in tetrahydrofuran (5 ml) was added 0.5M potassium bis(trimethylsilyl)amide in toluene (20 ml, 10.1 mmol) dropwise at −78° C. After stirred for additional 0.5 hr at −78° C., the mixture was added 5-chloroisatoic anhydride (1 g, 5.1 mmol) at −78° C. The mixture was warmed up to r.t gradually and stirred overnight. After concentrated, the crude was washed with saturated ammonium chloride solution and extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide as yellow solid (1.39 g. 99%). MS found for C12H9Cl2N3O M+=282, (M+2)+=284.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH2:15][CH3:16])[C:13](=[O:17])[C:12]([CH3:19])([CH3:18])[C:11]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].C1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH2:15][CH3:16])[C@H:13]([OH:17])[C:12]([CH3:19])([CH3:18])[C:11]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H]1[C@H](O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 2-chloro-4-(5-ethyl-3,3-dimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (60 mg) and lithium tri(sec-butyl)borohydride-THF solution (0.307 mL, 1 mol/L), and in the same manner as in Example 5, the title compound was obtained as a colorless solid (yield: 50 mg, 84%).
Reaction SMILES: CS(C)=O.[Cl-].[CH3:6][C:7]1[N:12]2[N:13]=[C:14]([CH2:16][OH:17])[N:15]=[C:11]2[N:10]=[C:9]2[CH2:18][CH2:19][CH2:20][C:8]=12.C(N(CC)CC)C>ClCCl.O>[CH3:6][C:7]1[N:12]2[N:13]=[C:14]([CH:16]=[O:17])[N:15]=[C:11]2[N:10]=[C:9]2[CH2:18][CH2:19][CH2:20][C:8]=12
Reactant: Cc1c2c(nc3nc(CO)nn13)CCC2
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1c2c(nc3nc(C=O)nn13)CCC2
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 88.8 %

Procedure:
To a round bottomed flask was loaded 0.17 ml of DMSO and 1 ml dichloromethane. The mixture was cooled to −50˜−60° C. Then a mixture of 0.1 ml oxallyl chloride and 2 ml dichloromethane was injected in into the flask all at once. The mixture was stirred at the same temperature for another 5 minutes. Then 0.174 grams of (8-Methyl-6,7-dihydro-5H-cyclopenta[d][1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-methanol in 2 ml dichloromethane was added within 2 minutes. The mixture was stirred at −50˜−60° C. for fifteen minutes and 0.7 ml triethylamine was next added. After another five minutes the reaction media was warmed up to 23° C. and a mixture of 20 ml water and 200 ml dichloromethane was added. The organic layer was dried over magnesium sulfate. Filter off the drying agent and concentrate the filtrate yielded 0.153 grams of product (89%). MS: 203.1 (M+H). H-NMR (CDCl3): δ 10.24 (s, 1H), 3.49 (m, 2H), 3.15 (m, 2H), 2.67 (s, 3H, CH3), 2.44 (m, 2H, CH2).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:22][C:23]3[C:24]([CH3:32])=[N:25][C:26]([CH2:29][CH2:30]O)=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrC(Br)(Br)Br.[OH-].[Na+].S(O)(O)(=O)=O.[CH3:64][S:65]C(=N)N>C(Cl)Cl.CO>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([NH:22][C:23]3[C:24]([CH3:32])=[N:25][C:26]([CH2:29][CH2:30][S:65][CH3:64])=[CH:27][CH:28]=3)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CSC(=N)N
Reactant: COc1c(Nc2ccc(CCO)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: BrC(Br)(Br)Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1c(Nc2ccc(CCSC)nc2C)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.3 %

Procedure:
To an ice-cooled solution of 4-{6-[6-(2-hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester (40.2 mg, 90.2 μmol) and triphenylphosphine (31 mg, 118 pmol) in 2 mL methylene chloride, perbromomethane (77.0 mg, 232 μmol) were added and solution was stirred at room temperature. After 18 h, the mixture was concentrated, re-dissolved in 1.5 mL MeOH, and added to a well stirred mixture of sodium hydroxide (120 mg, 3.0 mmol) and 2-methyl-2-thiopseudourea sulfate (208 mg, 0.70 mmol) in 2 mL MeOH. After stirring at room temperature for 17 h, mixture was concentrated and extracted with water and methylene chloride. Organic phases were concentrated and purified by HPLC to give 4-{5-methoxy-6-[2-methyl-6-(2-methylsulfanyl-ethyl)-pyrdin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylic acid isopropyl ester (TFA salt, 10.0 mg, 19%) as a white solid. 1HNMR (MeOH-d4, 400 MHz) δ 1.21-1.23 (d, J=6.2 Hz, 6H), 1.72-1.78 (m, 2H), 1.94-2.01 (m, 2H), 2.12 (s, 3H), 2.65 (s, 3H), 2.90-2.93 (t, J=7.2 Hz, 2H), 3.24-3.27 (t, J=7.2 Hz, 2H), 3.39-3.46 (m, 2H), 3.69-3.76 (m, 2H), 3.91 (s, 3H), 4.80-4.86 (m, 2H), 5.32-5.38 (m, 1H), 7.75-7.77 (d, J=8.6 Hz, 1H), 7.96 (s, 1H), 8.57-5.59 (d, J=8.6 Hz, 1H). Exact mass calculated for C23H33N5O4S 475.23 found 476.2 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]23[O:20][CH2:19][CH2:18][O:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1>>[C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][N:27]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:26][CH2:25]2)[C:11](=[O:16])[C:10]23[O:17][CH2:18][CH2:19][O:20]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Nc2ccc(-c3ccccc3)cc2C12OCCO2
Reactant: ClCCN1CCN(Cc2ccccc2)CC1
Product: O=C1N(CCN2CCN(Cc3ccccc3)CC2)c2ccc(-c3ccccc3)cc2C12OCCO2

Procedure:
Following the general method of Example 14, 5'-phenylspiro[1,3-dioxolane-2,3'-[3H]indol]-2'(1'H)-one and 1-(2-chloroethyl)-4-(phenylmethyl)piperazine were reacted together to give the title compound. 13C Nmr (d6 -acetone) 173.9, 144.5, 141.0, 139.6, 136.6, 130.7, 129.7, 129.6, 128.9, 127.9, 127.6, 127.3, 126.2, 124.1, 110.6, 102.7, 66.5, 63.3, 55.6, 54.0, 53.8 and 38.0 ppm.