Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.Br[CH2:11][CH2:12][C:13]#[N:14].[H-].[Na+]>>[C:13]([CH2:12][CH2:11][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][CH:9]=2)#[N:14]
Reactant: c1ncc2[nH]cnc2n1
Reactant: N#CCCBr
Agent: [H-]
Agent: [Na+]
Product: N#CCCn1cnc2cncnc21

Procedure:
More specifically, a purine compound is alkylated with 3-bromopropionitrile in the presence of NaH to give N9-cyanoethyl purine intermediate. Reaction of this intermediate with a methyliodo-ester and lithium 2,2,6,6-tetramethylpiperidine affords a mixture of N7-alkylated and N9-alkylated ester-containing products. Reduction of the ester in N9-alkylated product gives another intermediate, which is converted to a desired purine compound of formula (I) by an alkylation reaction or by reacting with a phosphonate in the presence of tert-butoxide. Similarly, reduction of the ester in N7-alkylated product gives a compound, which reacts with a phosphonate to produce an N7-substituted phosphonate-purine.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[S:7])[CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[NH:3]1.[C:12](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:1][N:2]1[C:6]([S:7][CH3:12])=[CH:5][C:4]([C:8]([F:11])([F:9])[F:10])=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: Cn1[nH]c(C(F)(F)F)cc1=S
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSc1cc(C(F)(F)F)nn1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
3.87 g of compound (8-5) and 4.40 g of potassium carbonate were suspended in 100 ml of acetonitrile. The suspension was stirred at room temperature for 15 minutes. A solution of 3.62 g of methyl iodide in 10 ml of acetonitrile was added dropwise, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure. After water was added to the residue, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to produce 3.60 g of 1-methyl-5-methylthio-3-(trifluoromethyl)pyrazole (14).
Reaction SMILES: ClC1C=CC(N2CCN(S(N)(=O)=O)CC2)=CC=1.Cl[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[C:27]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[S:38](=[O:40])(=[O:39])[NH:37][CH2:36][CH2:35]2)=[CH:29][CH:28]=1>>[C:27]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:28]=[CH:29][C:30]([CH2:33][N:34]2[S:38](=[O:40])(=[O:39])[N:37]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:36][CH2:35]2)=[CH:31][CH:32]=1
Reactant: O=S1(=O)NCCN1Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Product: CC(C)(C)OC(=O)CN1CCN(Cc2ccc(-c3ccccc3)cc2)S1(=O)=O

Procedure:
Proceeding as described in Example 7, Step 2 above, but substituting potassium tert-butoxide and [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine with tert-butyl chloroacetate and 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine gave tert-butyl 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH:17]=[CH2:18])[N:8]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2/[CH:17]=[CH:18]/[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:8]=1
Reactant: Brc1cccnc1
Reactant: C=Cc1cccc2nc(NCc3ccccc3OC)ccc12
Product: COc1ccccc1CNc1ccc2c(/C=C/c3cccnc3)cccc2n1

Procedure:
(2-Methoxy-benzyl)-(5-vinyl-quinolin-2-yl)-amine (150 mg, 0.517 mmol) was reacted with 3-bromopyridine (108 mg, 0.688 mmol) as described in example 2 step B. The title compound was obtained as a light brown solid (93 mg, 49%), MS: m/e=368.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]1([CH3:27])[CH:26]=CC=C[CH:22]=1>C(OC(OC(C)(C)C)N(C)C)(C)(C)C.CCOCC>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:4][C:3]([O:20][C:21]([CH3:22])([CH3:26])[CH3:27])=[O:2])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(CC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
A solution of 3.50 g of (S)-4-carboxymethyl)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester in 40 mL of dry toluene and 10 mL of dimethylformamide di-t-butyl acetal was heated to a bath temperature of 80° C. for 4 hours. After cooling, the mixture was diluted with 100 mL of ether and was washed with water and saturated sodium chloride solution and was dried over magnesium sulfate. The residue obtained after filtration and evaporation was chromatographed over 150 g of silica gel, eluting with 20% ethyl acetate-hexane to give 2.663 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[2-(1,1-dimethylethoxy)2-oxoethyl]benzenepropanoic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>ClCCl>[Cl:26][CH2:27][C:28]([N:8]1[CH2:9][CH2:10][CH:5]([O:4][C:3]2[C:11]([F:18])=[C:12]([F:17])[C:13]([F:16])=[C:14]([F:15])[C:2]=2[F:1])[CH2:6][CH2:7]1)=[O:29]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1

Procedure:
A chilled (ice bath temperature) solution of 10.0 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine and 5.72 ml of triethylamine in 100 ml of dichloromethane was treated, dropwise, with a solution of 3.26 ml of chloroacetyl chloride in 40 ml of dichloromethane, and then stirred at room temperature for four hours. The reaction mixture was then washed with water followed by a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 13.35 g of 1-(2-chloroacetyl)-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[S:44][CH:45]=[CH:46][N:47]=2)=[CH:38][C:37]=1[CH3:48].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:48])=[CH:38][C:39]([C:43]6[S:44][CH:45]=[CH:46][N:47]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc(-c2nccs2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nccs6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-bromo-3,5-dimethyl-phenyl)-thiazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=1.29 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13](I)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:40]=[CH:39][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)=[CH:26][CH:25]=2)O1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:24]4[CH:25]=[CH:26][C:27]([CH2:28][N:29]5[CH2:30][CH2:31][CH:32]([C:35]([F:38])([F:36])[F:37])[CH2:33][CH2:34]5)=[CH:39][CH:40]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1(C)OB(c2ccc(CN3CCC(C(F)(F)F)CC3)cc2)OC1(C)C
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 85 °C
Yield: 6.9 %

Procedure:
A degassed mixture of 6-bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.64 g, 1.7 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-4-trifluoromethyl piperidine (1.14 g, 3.1 mmol) and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II) (0.21 g, 0.26 mmol) in 2-methyl-THF (26 mL) and saturated aqueous sodium carbonate solution (12 mL) was heated at 85° C. for 16 h. The cooled reaction mixture was filtered through celite and partitioned between DCM and water and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated then the residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-15% methanol in DCM). Trituration of the resultant residue with acetonitrile afforded the title compound as a tan solid (57 mg, 7%). NMR (CD3OD, 300 MHz): 8.84 (d, J=2.2 Hz, 1H), 8.70-8.67 (m, 2H), 8.27 (d, J=1.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, 2H), 3.11-3.02 (m, 2H), 2.14-2.02 (m, 3H), 1.94-1.84 (m, 2H), 1.76-1.59 (m, 2H. LCMS (Method B): RT=2.55 min, M+H+=489.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22].Cl[C:24]1C=CC(B(O)O)=C(F)[C:25]=1[O:34]C>C(C(C)=O)C(C)C>[C:25]([NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22])(=[O:34])[CH3:24]
Reactant: COc1c(Cl)ccc(B(O)O)c1F
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Solvent: CC(=O)CC(C)C
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl

Procedure:
An embodiment of the present disclosure includes a method of producing methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate. The method comprises adding methyl isobutyl ketone to an aqueous solution comprising 4-chloro-2-fluoro-3-methoxyphenylboronic acid to form an organic phase comprising the 4-chloro-2-fluoro-3-methoxyphenylboronic acid and an aqueous phase. The organic phase and the aqueous phase are separated. The 4-chloro-2-fluoro-3-methoxyphenylboronic acid is reacted with methyl 4-(acetylamino)-3,6-dichloropyridine-2-carboxylate in methyl isobutyl ketone to produce methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate, which is deacetylated to produce methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1[CH:4]=[C:5]1[S:9]C(=S)N[C:6]1=[O:11].[OH-:18].[Na+]>>[F:1][C:2]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:3]=1/[CH:4]=[C:5](\[SH:9])/[C:6]([OH:18])=[O:11]
Reactant: [OH-]
Reactant: COc1ccc(F)c(C=C2SC(=S)NC2=O)c1
Agent: [Na+]
Product: COc1ccc(F)c(/C=C(\S)C(=O)O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
5-(2-Fluoro-5-methoxybenzylidene)-2-thioxo-1,3-thiazolidin4-one (8.00 g, 9.7 mmol) was added in one portion to 25% w/v sodium hydroxide solution (40 mL). This was allowed stir at reflux for 1 h. After this time the reaction was allowed to cool to room temperature and poured onto water (50 mL). This was washed with dichloromethane (50 mL), and the aqueous layer acidified to pH 2 with aqueous hydrochloric acid (2 N, 50 mL) to give a white suspension. Product was extracted with ether (2×60 mL), dried (MgSO4) and solvent removed in vacuo to give a white solid (6.71 g, 100%); δH (300 MHz, CD3OD) 7.85 (1H, s, Ar), 7.46-7.35 (1H, m, Ar), 7.11 (1H, t, Ar), 7.01-6.75 (2H, m, CH═, and SH), 3.80 (3H, s, OCH3).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:16]=[CH:15][N:14]=2)[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:2]1.Br[C:29]1[O:30][CH:31]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:33]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[C:8]([O:7][C:6]([N:5]([CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:13]1[CH:18]=[C:17]([C:29]2[O:30][CH:31]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:33]=2)[CH:16]=[CH:15][N:14]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: CCOC(=O)c1coc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1coc(-c2ccnc(N(CC3CC3)C(=O)OC(C)(C)C)c2)n1
Temperature: 80 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of tert-butyl (cyclopropylmethyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate (48.3 g), ethyl 2-bromo-1,3-oxazole-4-carboxylate (25.8 g), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (4.79 g), potassium carbonate (32.4 g) and DME (489 mL)/water (98 mL) was stirred at 80° C. for 4 hr, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (33.3 g).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].O.[N+:20]([O-])([OH:22])=[O:21]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: Cc1c(F)ccc(O)c1C(=O)Oc1ccccc1
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: Cc1c(F)cc([N+](=O)[O-])c(O)c1C(=O)Oc1ccccc1
Temperature: 26 °C
Reaction time: 20 h
Yield: 109.3 %

Procedure:
A 30 L 4-neck flask equipped with mechanical stirrer, thermometer and addition funnel was charged with a solution of compound 63 (1100 g, 4.47 mol) in CH2Cl2 (8.0 L) followed by water (8.1 L) and tetrabutyl ammonium bromide (144 g, 0.45 mol). Aqueous HNO3 (591 mL, 68 w %, 8.94 mol) was added to the stirred two-phase reaction mixture at 24˜27° C. over 3 min and the mixture was stirred at 24-28° C. for 20 h. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (4×1.0 L). The organic layers were then combined and successively washed with water (3×1.0 L) and brine (2×2 L). The organic layer was dried over Na2SO4 and filtered and concentrated under reduce pressure to give 1423 g (>100%) of compound 64 as dark brown solid.
Reaction SMILES: Cl[C:2](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH:3]([CH3:5])[CH3:4].[Cl:11][C:12]1[C:13]([NH:19][NH2:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[N:19]([C:13]2[C:12]([Cl:11])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=2)[N:20]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:6]=1[C:9]#[N:10]
Reactant: CC(C)C(Cl)=C(C#N)C#N
Reactant: NNc1ncc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nn(-c2ncc(Cl)cc2Cl)c(N)c1C#N
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A solution of (1-chloro-2-methylpropylidene)methane-1,1-dicarbonitrile (35.6 g, 230 mmole) in THF (875 mL) was treated with 3,5-dichloropyridylhydrazine (40.9 g, 230 mmole) followed by triethylamine (23 g, 230 mmole). The reaction was then heated to reflux for 18 hours. The reaction was then cooled to room temperature and partitioned between EtOAc (1 L) and 1M aqueous NaOH (500 mL). The aqueous layer was extracted with EtOAc (2×500 mL), and the combined organic layers were washed with 10% citric acid (500 mL), saturated aqueous NaHCO3 (750 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to yield the desired product (56 g, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([F:11])[C:3]=1F.[O:13]1[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([F:1])[C:3]=1[N:20]1[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)c(N2CCC3(CC2)OCCO3)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 1,2,3-trifluoro-5-nitrobenzene (4.0 mL, 34.3 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (6.59 mL, 51.4 mmol) and potassium carbonate (5.68 g, 41.1 mmol) in DMSO (35 mL) was heated at 100° C. for 3 hours and then cooled to room temperature. The mixture was partitioned between water and EtOAc, and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-20% EtOAc in hexanes to give a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1.[CH2:14]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15]1.NC1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([N:19]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:25][CH:24]=2)[C:5]2[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:6]=2[N:7]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CCO
Solvent: Nc1ccccc1
Product: Cc1sc2nc(Cl)nc(Nc3ccc(N4CCOCC4)cc3)c2c1C
Yield: 112.5 %

Procedure:
To 240 mg (1.02 mmol of 2,4-dichloro-5,6-dimethyl-thieno[2,3-d]pyrimidine in 50 ml of ethyl alcohol were added 220.20 mg (1.23 mmol) of 4-(4-morpholino)aniline and 130.90 mg (1.23 mmol) of aniline, and then the mixture was stirred under reflux. After completion of the reaction, the reaction solvent, ethyl alcohol, was evaporated under reduced pressure, and the residue was crystallized from ethyl alcohol and filtered, yielding 430 mg (quantitative) of 2-chloro-5,6-dimethyl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. 220 mg (0.53 mmol) of the obtained product was dissolved in 20 ml of 1-butanol in a sealed tube, and 223 μl (1.59 mmol) of triethylamine and 45.9 mg of piperazine were added thereto, and the mixture was stirred at 120° C. After completion of the reaction, the resulting solid was filtered and the filtrate was concentrated under reduced pressure and then crystallized from ethyl acetate, yielding 30 mg (15% yield) of 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine. To 9 mg (0.02 mmol) of the obtained compound and 5,6-dimethyl-2-piperazin-1-yl-thieno[2,3-d]pyrimidin-4-yl-4-morpholin-4-yl-phenylamine in 5 ml of dimethyl chloride were added 3.5 μl (0.02 mmol) of triethylamine and 4.1 mg (0.02 mmol) of picolinoyl chloride hydrochloride, and then the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solvent, dimethyl chloride, was evaporated under reduced pressure, and the residue was crystallized from dimethyl chloride, thus obtaining 6 mg (30% yield) of the title product.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=O)[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N+:20]([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][O:28][C:29]([NH:31][CH2:32][CH2:33][SH:34])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:34][CH2:33][CH2:32][NH:31][C:29]([O:28][CH2:27][C:26]2[CH:35]=[CH:36][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:30])=[O:18])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: O=C(NCCS)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)SCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 87 %

Procedure:
1.00 9 (3,48 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone and 1.07 g (4.8 mmole) of 2-(p-nitrobenzyloxycarbonyl-amino)ethanethiol were dissolved in 20 ml of benzene. To this solution were added 861 mg (4.18 mmole) of dicyclohexylcarbodiimide and 10 mg (0.082 mmole) of 4-dimethylaminopyridine, at room temperature with stirring. The mixture was stirred for 2 hours, after which the insolubles which had formed were filtered off and the resulting filtrate was concentrated to dryness by evaporation under reduced pressure, The residue was purified by column chromatography through 40 g of silica gel, to give 1.59 g (yield 87%) of the desired product as an oil from the fractions eluted with a 1:1 volume mixture of benzene and ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:12])[C:4]=2[N:3]=1.[I:13]N1C(=O)CCC1=O>C(#N)C>[I:13][C:8]1[C:9]2[CH:10]=[CH:11][C:2]([CH3:1])=[N:3][C:4]=2[C:5](=[O:12])[NH:6][CH:7]=1
Reactant: Cc1ccc2cc[nH]c(=O)c2n1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Cc1ccc2c(I)c[nH]c(=O)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
2-Methyl-7H-[1,7]naphthyridin-8-one (10.0 g, 62.4 mmol) was suspended in 300 ml acetonitrile and N-iodosuccinimide (16.9 g, 74.9 mmol) was added. The suspension was stirred for 3 hours at reflux. The reaction mixture was cooled to room temperature and filtered. The solid was washed with acetonitrile and dried for 30 minutes at 50° C. and <20 mbar, to get the desired compound as a brown solid (14.3 g, 80%), MS: m/e=287.0 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([CH3:29])[CH:16]=2)[NH:7][N:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[CH2:35][OH:36]>>[CH3:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]4[CH2:34][CH2:33][CH2:32][C@@H:31]4[CH2:35][OH:36])[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: OC[C@H]1CCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2C)cn1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC[C@@H]5CO)c34)cc2C)cn1
Yield: 13 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-2-pyrrolidinemethanol to give the title compound in 13% yield; NMR Spectrum: 1.50-1.54 (m, 1H), 1.61-1.67 (m, 2H), 1.77-1.82 (m, 1H), 2.19 (s, 3H), 2.32-2.36 (m, 1H), 2.43 (s, 3H), 2.55-2.60 (m, 1H), 2.77-2.80 (m, 1H), 3.15 (br t, 1H), 3.25-3.29 (m, 2H), 3.37-3.42 (m, 1H), 4.40 (t, 2H), 6.95 (d, 1H), 7.18-7.24 (m, 2H), 7.63-7.66 (m, 2H), 8.16 (s, 1H), 8.28 (s, 1H), 8.31 (s, 1H); Mass Spectrum: 476 (MH+).
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH2:7]([S:9](Cl)(=[O:11])=[O:10])[CH3:8]>>[CH2:7]([S:9]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])(=[O:11])=[O:10])[CH3:8]
Reactant: O=C1NCCN1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCNC1=O

Procedure:
The starting material required is prepared as follows: A mixture of 29.2 g of ethyleneurea and 43.7 g of ethane sulphonyl chloride is heated at 110° for 3 hrs under nitrogen. The reaction mixture is triturated with 30 ml methanol and filtered. The filtrate is evaporated off and the residue is dissolved in chloroform and chromatographed on a column of 750 g of silica gel. The fraction which eluted with 5% methanol in chloroform, is recrystallized from a mixture of methylene chloride and hexane to afford 1-ethylsulphonyl-2-oxo-tetrahydroimidazole which melts at 114°-116°.