Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11](=[O:20])[CH2:12][C@@H:13]([OH:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(B(CC)OC)C.[BH4-].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C@@H:11]([OH:20])[CH2:12][C@@H:13]([OH:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C[C@H](O)CC(=O)/C=C/c1ccc(Cl)cc1Cl
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)C[C@H](O)C[C@H](O)/C=C/c1ccc(Cl)cc1Cl

Procedure:
For instance, methyl (3R,6E)-3-[(tert-butyldimethylsilyl)oxy]-7-(2,4-dichlorophenyl)-5-oxo-6-heptenoate (which is one of the compounds of the formula (1)) is subjected to the tert-butyldimethylsilyl removing step using hydrogen fluoride in the manner as described in Japanese Patent Provisional Publication H5(1993)-178841, to give methyl (3R, 6E)-7-(2,4-dichlorophenyl)-3-hydroxy-5-oxo-6-heptenoate. The obtained ester is then subjected to Syn reduction using diethylmethoxyborane and sodium borohydride (NaBH4), to give methyl (3R,5S,6E)-7-(2,4-dichlorophenyl)-3,5-dihydroxy-6-heptenoate. Subsequently, thus obtained ester is treated with sodium hydroxide and hydrochloric acid in the manner as described in Journal of Medicinal Chemistry, 1985, vol.28, No.3, pp.347-358, to give (+)-trans-(E)-6-[2-(2,4-dichlorophenyl)-ethenyl] 3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-on which has the 3-hydroxy-3-methylglutaryl Coenzyme A reductase preventive action.
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>O>[CH2:27]([CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH2:20]
Reactant: C=CCCCCCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
Sodium hydride (60%, 6.3 g, 156.96 mmol) was added to anhydrous tetrahydrofuran (200 ml) under argon atmosphere and cooled to 0° C. To this mixture, diethyl malonate (23.8 ml, 156.95 mmol) was slowly added dropwise, followed by stirring for 1 hour at room temperature. After cooling to 0° C., 8-bromo-1-octene (20 g, 104.64 mmol) was slowly added to the reaction mixture, followed by stirring for 12 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30) to give diethyl 2-(7-octenyl)malonate (16 g, Yield 56.56%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:27]/[C:26]2[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(/C=C/C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 11.9 %

Procedure:
A suspension of (E)-4-(4-methoxyphenyl)-but-3-en-2-one (615 mg, 3.5 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (965 mg, 7.0 mmol) in H2O (5 mL) was added and the reaction mixture was stirred for further 10 min at 0° C. After the dropwise addition of 4-(trifluoromethoxy)-benzaldehyde (528 μl, 3.7 mmol), the pale yellow suspension was stirred for further 4 h at 0° C. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW350 as a pale yellow solid (145 mg, 12%). mp: 105-107° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[NH:37]([CH3:39])[CH3:38]>>[CH3:38][N:37]([CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:39]
Reactant: CNC
Reactant: O=Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: CN(C)Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
N-(4-Dimethylaminomethyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide was prepared from N-(4-formyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Step G) and Me2NH, using essentially the same procedure described in Example 1, Step H, yielding a White solid. MS (ESI) m/z 528 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1
Reactant: NCc1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: NCc1ccc(O)cc1
Yield: 85 %

Procedure:
10% Palladium-carbon catalyst (water content 50%, 50 mg) was added to a solution of 4-benzyloxybenzylamine (530 mg, 2.485 mmol, 1.0 eq) in THF (10 ml), and the mixture was stirred for 3 hours at room temperature in a stream of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (n-hexane/ethyl acetate=1/1) to give 4-hydroxybenzylamine (260 mg, 85.0%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[CH2:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([CH3:10])=[C:5]([I:11])[CH:6]=1)[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1ccc(C)nc1N
Solvent: CN(C)C=O
Product: CCc1cc(I)c(C)nc1N
Reaction time: 15 h
Yield: 81.3 %

Procedure:
To a solution of 2-amino-3-ethyl-6-methylpyridine (3.00 g, 21.6 mmol) in DMF (100 mL) was added N-iodosuccinimide (4.86 g, 21.6 mmol). The mixture was stirred in the dark for 15 hours and then partitioned between Et2O and H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated to yield a brown solid (4.6 g, 79%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 2.35 (q, J=7.4 Hz, 2 H), 2.49 (s, 3 H), 4.44 (s, 2 H), 7.52 (s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]2[C:22](=[O:23])[N:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]3=[N:19][C:18]=2[CH3:28])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].C(O)CO>O>[CH3:28][C:18]1[N:19]=[C:20]2[CH:27]=[CH:26][CH:25]=[CH:24][N:21]2[C:22](=[O:23])[C:17]=1[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:8]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[N:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:29]=2)[CH2:10][CH2:11]1
Reactant: Cc1nc2ccccn2c(=O)c1CCN1CCN(C(=NNc2ccccc2)c2ccccc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: Cc1nc2ccccn2c(=O)c1CCN1CCN(c2nn(-c3ccccc3)c3ccccc23)CC1
Reaction time: 8 h
Yield: 25.5 %

Procedure:
A mixture of 2.5 parts of 3-[2-[4-[(2-fluorophenyl)(2-phenylhydrazono)methyl]-1-piperazinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 1 part of potassium carbonate and 27.8 parts of 1,2-ethanediol was stirred overnight at reflux temperature. The reaction mixture was cooled and then poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 0.7 parts (25.5%) of 2-methyl-3-[2-[4-(1-phenyl-1H-indazol-3-yl)-1-piperazinyl]ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 260.0° C. (decomp.) (compound 4).
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28].[OH-].[Na+]>O1CCCC1.C(Cl)Cl>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([OH:29])(=[O:8])=[O:28].[C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=S(=O)(O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.1 mole of benzoin and 0.12 mole of β-naphthalenesulfonyl chloride are dissolved at room temperature in 500 ml of tetrahydrofuran. After addition of 0.15 mole of 30% sodium hydroxide solution the mixture is stirred for 8 hours at room temperature. The reaction solution is diluted with 200 ml of methylene chloride and the organic phase is washed once with NaHCO3 solution and once with water. The organic solution is dried over MgSO4, dried and concentrated by evaporation. The residue is crystallised from hexane/ethyl acetate. The resultant sulfonate melts at 107°-109° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11]1[N:15]=[C:14]([NH2:16])[O:13][N:12]=1)([CH3:10])[CH3:9])(C)(C)C.[ClH:18].O1CCOCC1>C(O)C>[ClH:18].[NH2:7][C:8]([C:11]1[N:15]=[C:14]([NH2:16])[O:13][N:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1noc(N)n1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(N)c1noc(N)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [1-(5-amino-[1,2,4]oxadiazol-3-yl)-1-methyl-ethyl]carbamic acid tert-butyl ester (1.6 g, 6.6 mmol) in ethanol (30 mL) was added HCl in dioxane (4 M, 6.6 ml, 26.4 mmol) and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was concentrated in vacuo and dried by applying high vacuum at 40° C. for 4 hours to give the title compound as off-white solid (1.2 g, quant.); LC-MS (UV peak area/ESI) 99.9%, 143.0927 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH2:21]([C@H:9]1[CH2:10][NH:11][CH2:12][CH2:13][NH:8]1)[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1ccc(CC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine (S)-1,4-dibenzyl-2-phenethyl-piperazine (5.15 g, 13.90 mmol), ammonium formate (4.38 g, 69.49 mmol), 5% Pd/C (672.5 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify by silica gel chromatography using dichloromethane/7N ammonia in methanol (90:10) to give the title compound as a white solid: mp 116–119° C.; mass spectrum (ion spray): m/z=191.2 (M+1); Analysis for C12H18N2: calcd: C, 75.74; H, 9.53; N, 14.72; found: C, 75.90; H, 9.57; N, 14.59.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CC(C)([O-])C.[K+].Cl.Cl[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH3:37]>CC(N(C)C)=O>[CH3:37][N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[CH2:31][CH2:30][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CN1CCCC1CCCl
Reactant: COc1cc(CCc2ccccc2O)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc(CCc2ccccc2OCCC2CCCN2C)cc(OC)c1OC
Yield: 65 %

Procedure:
Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3,4,5-trimethoxyphenyl)ethyl]phenol (prepared as described in Preparation 28), 1.18 g of potassium t-butoxide and 0.958 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.900 g (yield 65%) of the title compound as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:5].Cl.[CH:13]([Cl:16])(Cl)[Cl:14]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:14][C:13]1([Cl:16])[CH2:3][C:4]1([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: C=C(C)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CC1(c2ccccc2)CC1(Cl)Cl
Temperature: 50 °C

Procedure:
A solution of 3 g of triethylbenzylammonium chloride in 500 g of chloroform is added over the course of 5 minutes to 800 g of 50% strength by weight sodium hydroxide solution in a 2 l stirred apparatus equipped with a dropping funnel and internal thermometer, at 50° C., whilst cooling and stirring slowly. A solution of 345 g of α-methylstyrene in 300 g of chloroform is added dropwise over the course of 45 minutes to the preceding mixture with vigorous stirring and cooling at 50° C. After stirring for a further 4 hours at 50° C., the reaction mixture is cooled to 20° C. and neutralised with concentrated hydrochloric acid at 10°-20° C., whilst cooling. It is then diluted with 2 l of water and the organic phase is separated off. The aqueous phase is extracted with 100 g of chloroform. The combined organic phases are washed with 250 g of water and 100 g of 10% strength by weight sodium carbonate solution. The solvent is then distilled off and the residue is subjected to fractional distillation. This gives 561 g=92.9% of theory of 2,2-dichloro-1-methyl-1-phenyl-cyclopropane of boiling point 116°-117° C./17 mm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=1[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[H-].[Na+].Cl[C:35]1[N:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][N:36]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:42][S:41][C:38]1[CH:37]=[N:36][C:35]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[N:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([NH:17][S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])[C:6]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[N:40][CH:39]=1
Reactant: CSc1cnc(Cl)nc1
Reactant: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCO)c1Oc1ccccc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1nc(-c2ncccn2)nc(OCCOc2ncc(SC)cn2)c1Oc1ccccc1OC
Temperature: 75 °C
Yield: 51 %

Procedure:
Ethanesulfonic acid [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (89 mg) was dissolved in THF (6 ml). Sodium hydride (40 mg) and 2-chloro-5-methylsulfanyl-pyrimidine (71 mg) were added and the mixture was heated to 75° C. for 48 h, then poured onto water, acidified with solid citric acid and the precipitate was filtered off. The crude material was purified by crystallization from methanol to give ethanesulfonic acid [6-[2-(5-methylsulfanyl-pyrimidin-2-yloxy)-ethoxy]-5-(2-methoxy-phenoxy)-[2,2′]bipyrimidinyl-4-yl]-amide (58 mg) as a white powder. LC-MS: tR: 4.15, [M+H]+: 572.19.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([N:32]5[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH2:34][CH2:33]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:44]1[CH:48]=[CH:47][CH:46]=[C:45]1[CH2:49][C:50](Cl)=[O:51]>>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:50](=[O:51])[CH2:49][C:45]5[S:44][CH:48]=[CH:47][CH:46]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)=[CH:25][C:26]=1[N:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][S:40]([CH3:43])(=[O:41])=[O:42])[CH2:34][CH2:33]1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1ccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)cc1N1CCN(CCS(C)(=O)=O)CC1
Product: COc1ccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)cc1N1CCN(CCS(C)(=O)=O)CC1
Yield: 47 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-(methyloxy)-3-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}phenyl)-2-pyrimidinamine using 2-thienylacetyl chloride as described in Example 10, Step E to give a light brown solid in 47% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.5 (m, 4H) 2.7 (m, 3H) 2.9 (m, 4H) 3.0 (s, 3H) 3.7 (s, 3H) 3.9 (s, 2H) 6.4 (d, J=5.1 Hz, 1H) 6.8 (d, J=9.1 Hz, 1H) 7.0 (d, J=4.6 Hz, 2H) 7.1 (t, J=6.6 Hz, 1H) 7.3 (m, 3H) 7.4 (d, J=10.4 Hz, 1H) 7.4 (m, 2H) 7.7 (d, J=8.1 Hz, 1H) 7.9 (s, 1H) 8.2 (d, J=5.5 Hz, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.3 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 723 [M+H]+.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([C:12]3[S:13][CH:14]=[CH:15][N:16]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1csc(N2CCC3(CC2)OCCO3)n1
Yield: 60.8 %

Procedure:
4-Piperidone ethylene ketal (2.0 ml, 16 mmol), 2-bromothiazole (2.68 g) and caesium carbonate (8.9 g) in DMF (20 ml) were heated at 90°-100° C. for 16 h . The cooled mixture was diluted with water, extracted twice with ether, the ether layers washed with water six times, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica eluting with 50% ether/hexane to afford the title compound as a pale yellow oil (2.2 g), MS (+EI) 226 (M+), 1H NMR (CDCl3) 7.17 (1H, d, 3.6 Hz), 6.55 (1H, d, 3.6 Hz), 4.00 (4H, s), 3.65-3.61 (4H, m), 1.83-1.80 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([F:10])[CH:3]=1.C(N(CC)CC)C.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1>C(Cl)(Cl)Cl>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][C:4]=2[F:10])=[O:24])=[C:21]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: O=C(Cl)c1ccc(Br)cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(Br)cc1F)c1ccc(Br)cc1[N+](=O)[O-]
Yield: 81.9 %

Procedure:
To a solution of 4-bromo-2-fluorobenzylamine (2.3 g) and triethylamine (1.55 ml) in chloroform (40 ml) was added dropwise a solution of 4-bromo-2-nitrobenzoyl chloride (2.69 g) in chloroform (10 ml) at 0° C. with stirring and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed in turn with diluted aqueous hydrochloric acid and water, and then dried. Evaporation of the solvent followed by recrystallization from diethyl ether gave 4-bromo-N-(4-bromo-2-fluorobenzyl)-2-nitrobenzamide (3.60 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])=[C:15]2[C:10]([N:11]=[C:12](Cl)[N:13]([CH3:26])[C:14]2=[O:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>O1CCOCC1>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])=[C:15]2[C:10]([N:11]=[C:12]([N:31]([CH2:32][CH2:33][CH3:34])[CH2:28][CH2:29][CH3:30])[N:13]([CH3:26])[C:14]2=[O:25])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2c3c(=O)n(C)c(Cl)nc3nn2Cc2ccccc2)c(C)c1
Reactant: CCCNCCC
Solvent: C1COCCO1
Product: CCCN(CCC)c1nc2nn(Cc3ccccc3)c(-c3ccc(C)cc3C)c2c(=O)n1C
Temperature: 100 °C
Yield: 92.1 %

Procedure:
To a solution containing 0.089 g (0.23 mmol) of 2-benzyl-6-chloro-3-(2,4-dimethylphenyl)-5-methyl-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one in 15 ml of dioxane was added 0.06 ml (0.47 mmol) of dipropyl amine. The mixture was heated to 100° C. under a nitrogen atmosphere for 48 h. The reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via biotage eluting with 40% ethyl acetate/hexanes gave 0.094 g (90.2%) of product.
Reaction SMILES: Cl[P:2]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:6])[O:3][CH2:4][CH3:5].[NH2:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])=[O:32])[C:19]1=[O:40]>>[CH2:4]([O:3][P:2]([NH:17][CH:18]1[CH2:23][S:22][C@H:21]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:20]([CH2:30][C:31]([O:33][CH2:34][CH2:35][Si:36]([CH3:38])([CH3:37])[CH3:39])=[O:32])[C:19]1=[O:40])([CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6])[CH3:5]
Reactant: C[Si](C)(C)CCOC(=O)CN1C(=O)C(N)CS[C@@H]1c1ccccc1
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Product: CCOP(=O)(CCCCc1ccccc1)NC1CS[C@H](c2ccccc2)N(CC(=O)OCC[Si](C)(C)C)C1=O

Procedure:
Chloro(4-phenylbutyl)phosphinic acid, ethyl ester is reacted with (R)-dihydro-5-amino-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester according to the procedure of Example 1(f) to yield (R)-dihydro-5-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-4-oxo-2-phenyl-2H-1,3-thiazine-3(4H)-acetic acid, trimethylsilylethyl ester.
Reaction SMILES: C1N(P(N2CC2)(N2CC2)=S)C1.[H-].[Na+].Cl.[OH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:17]12.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:17]12)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1cn2c(n1)C(O)CCC2
Reactant: ClCc1ccccc1
Agent: Cl
Agent: S=P(N1CC1)(N1CC1)N1CC1
Agent: [H-]
Solvent: CN(C)C=O
Product: Cc1cn2c(n1)C(OCc1ccccc1)CCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
This reaction mixture (which contains the free base of the compound of StepA) was added stepwise to an ice cooled, stirred suspension of 1.02 g of 50%dispersion of sodium hydride. The resulting mixture is stirred 30 min. on an ice-water bath. To this cold suspension (which contains the alkoxide ofthe compound of Step A) there was added a solution of benzyl chloride (2.48g) in DMF. The resultant mixture was stirred in an ice bath for 5 min., at room temperature for 5 min., and then in a heating bath at 85°-90° C. for 1.5 hrs. The solvent was evaporated off at reduced pressure. To the residue there was added water and the mixture wasextracted three times with a 1:1 mixture of methylenechloride and ether. The combined extracts were washed with brine, dried over Na2SO4and the solvent evaporated at reduced pressure. The oily residue was chromatographed on silica gel, using a 1:1 mixture of acetone and methylene chloride as eluant. The title compound was obtained as a yellow oil with the following PMR spectrum (DMSO-d6): 2.08(3H,s); 1.7-2.2(4H,m); 3.65-4.1(2H,m); 4.42(IH, deformed triplet); 4.70(2H,s); 6.73(IH,s); 7.30(SH,s).