Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:6])([C@H:7]1[CH2:8][CH2:9][C@H:10]([O:13][S:28]([C:25]2[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=2)(=[O:30])=[O:29])[CH2:11][CH2:12]1)[CH3:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@H](O)CC1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](OS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.400 g trans-2-(4-hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester (residue HH) are dissolved in 10 ml of dichloromethane. Triethylamine (0.42 ml) and 4-dimethylamino pyridine (0.012 g) are added and the solution is cooled to 0° C. 0.419 g of para-toluenesulfonyl chloride are added portionwise and the reaction mixture is then stirred at room temperature for 16 hours. The reaction mixture is poured onto saturated aqueous sodium hydrogencarbonate solution and the layers are separated. The aqueous layer is extracted with dichloromethane and the combined organics are dried over sodium sulphate and concentrated. Flash chromatography (SiO2 60F) of the residue provides the title compound which is identified on the basis of its Rf-value.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].[C:20]([O-])(=O)[CH3:21].[Na+].Cl.C(N)(=N)C>C(O)C>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][C:20]([CH3:21])=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: CC(=O)[O-]
Agent: CC(=N)N
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(C)=NC2=N1

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one (1.56 g), anhydrous sodium acetate (114 g) and acetamidine hydrochloride (142 g) was heated in an oil bath at 150°-160° C. for 2 hours. The mixture was digested with ethanol (2 ml), cooled, filtered and the solid washed with ethanol. Recrystallisation from ethanol gave the title compound, 0.72 g, m.p. 264°-265° C.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[Li]CC[CH2:9][CH3:10].[CH2:11]([Si:13]([CH2:17][CH3:18])([CH2:15][CH3:16])Cl)[CH3:12]>C1COCC1>[CH2:11]([Si:13]([CH2:9][CH3:10])([CH2:15][CH3:16])[O:5][CH2:1][CH2:2][C:3]#[C:4][Si:13]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:11][CH3:12])[CH3:12]
Reactant: [Li]CCCC
Reactant: C#CCCO
Reactant: CC[Si](Cl)(CC)CC
Solvent: C1CCOC1
Product: CC[Si](C#CCCO[Si](CC)(CC)CC)(CC)CC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-butin-1-ol (34.99 g, 0.50 mole) was dissolved in THF (1.2 l) under nitrogen and cooled to −30° C. n-BuLi (640 ml, 1.02 mole, 1.6 M solution in n-hexane) was added dropwise to this solution within 15 minutes at such a rate that the temperature did not exceed −20° C. After 1 hour at −20° C. a solution of triethylchlorosilane (171.4 ml, 1.02 mole) in THF (300 ml) was added dropwise within 30 minutes. The cooling bath was removed and the reaction solution was stirred for 15 hours at RT. The reaction mixture was quenched with aqueous Na2CO3 solution (1%) while cooling in an ice bath and was extracted with hexane (2×500 ml). The combined organic phases were washed with saturated NaCl-Solution (300 ml) and dried over MgSO4. After filtering off the drying agent the solvents were removed on a rotary evaporator and the residue was purified by distillation (p=0.05 mbar, head temperature=115°-110° C.), triethyl(4-(triethylsilyl)but-3-inyloxy)silane (88.9 g, 60%) being obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.C(O)C.[CH3:18][NH:19][NH2:20]>O>[CH3:18][N:19]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1)[NH2:20]
Reactant: CNN
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)n(-c2ccc(N(C)N)nn2)n1

Procedure:
A mixture of 4.17 g (0.02 moles) of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 42 ml of ethanol and 2.3 g (0.05 moles) of methyl hydrazine is heated to reflux for 9 hours, and after cooling the mixture is poured into 100 ml of water. The solution is extracted with 3×50 ml of chloroform and the combined organic phases are dried over magnesium sulphate. After evaporation the residue is recrystallized from a 3:1 mixture of isopropanol and petroleum ether. Yield: 1.9 g (44.5%); m.p.: 93°-94° C.
Reaction SMILES: C([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH2:19][CH:20](Br)[C:13]2=[N:12][C:11]=1[C:22]([O:24]C)=O)(=O)C1C=CC=CC=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>CN(C=O)C>[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH:38][C:22]([C:11]2[N:12]=[C:13]3[CH:20]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH2:19][CH2:18][CH2:17][N:14]3[C:15](=[O:16])[C:10]=2[OH:9])=[O:24])=[CH:35][CH:34]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCC2Br
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCCC2N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate in DMF was added morpholine (3 eq.) and the mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was triturated with diethyl ether. The crude material was dissolved in methanol, 4-fluoro-benzylamine (3 eq.) was added and the mixture was stirred for 1.5 h at 65° C. The solvent was removed under reduced pressure and the product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluents (column: C18). The pooled product fractions were lyophilized and redissolved in 1N HCl. The solvent was removed under reduced pressure and the residue was lyophilized from water/acetonitrile to afford the hydrochloride salt of N-(4-fluorobenzyl)-3-hydroxy-9-morpholin-4-yl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxamide as a slightly pink fluffy material.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1nc(-c2ccccc2)cnc1N
Temperature: 85 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
5-Bromo-3-methoxy-pyrazin-2-ylamine (A) (816 mg, 4 mmol) and phenyl boronic acid (732 mg, 6 mmol) in toluene (5 mL), ethanol (5 mL) and Na2CO3 (8 mmol, 1 M aqueous) was purged with nitrogen for 10 minutes, and was added PdCl2(PPh3)2(140 mg, 0.2 mmol). The reaction mixture was stirred at 85° C. for 4 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 mL). The solution was washed with brine (2×5 mL). The organic extracts was dried with MgSO4, then solvent was removed under vacuum. The residue was purified with flash column to give product B (660 mg, 82%) as yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.08 (1H, s), 7.92 (2H, d), 7.46 (3H, m), 4.94 (2H, bs), 4.12 (3H, s); MS: 202 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[CH:7][C:8]([CH3:14])([S:10]([CH3:13])(=O)=O)[CH3:9])=[O:4].CC(SC)(C)C=NO.CN=C=O>>[CH3:1][NH:2][C:3]([O:5][N:6]=[CH:7][C:8]([CH3:14])([S:10][CH3:13])[CH3:9])=[O:4]
Reactant: CNC(=O)ON=CC(C)(C)S(C)(=O)=O
Agent: CN=C=O
Agent: CSC(C)(C)C=NO
Product: CNC(=O)ON=CC(C)(C)SC

Procedure:
This invention relates to a process for preparing 2-methyl-2-(methylsulfonyl) propionaldehyde O-(methylcarbamoyl) oxime as an aqueous wet cake by reacting 2-methyl-2-(methylthio) propionaldehyde oxime with methyl isocyanate in an aqueous medium to give 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime which is then oxidized in an aqueous medium to give 2-methyl-2-(methylsulfonyl) propionaldehyde O-(methylcarbamoyl) oxime. This invention also relates to an aqueous wet cake composition containing 2-methyl-2-(methylsulfonyl) propionaldehyde O-(methylcarbamoyl) oxime.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1.Cl.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C>[Cl:8][C:9]1[N:10]=[C:11]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:12]2[CH2:17][N:16]([CH:26]([CH3:28])[CH3:25])[CH2:15][C:13]=2[N:14]=1
Reactant: CC(C)=O
Reactant: Clc1nc2c(c(N3CCOCC3)n1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine (intermediate 20) as a HCl salt (455 mg, 1.6 mmol) in anhydrous THF (5 ml) was added anhydrous acetone (500 μl) and glacial acetic acid (two drops). The reaction was stirred at RT for 30 minutes after which time sodium triacetoxyborohydride (696 mg, 3.3 mmol) was added. After stirring for a further 2 hours at RT the reaction was partitioned between water and DCM. The aqueous phase was extracted into DCM and the organic extracts were combined and concentrated in vacuo to afford the title compound as a brown oil which was used without further purification.
Reaction SMILES: C(OC([N:8]1[C@@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.[CH2:22]([C:26]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH2:31][NH:32][CH2:33][CH2:34][C:29]=2[C:28](=[O:35])[O:27]1)[CH:23]([CH3:25])[CH3:24].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[OH:21][C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([C:18]([N:32]3[CH2:33][CH2:34][C:29]4[C:28](=[O:35])[O:27][C:26]([CH2:22][CH:23]([CH3:24])[CH3:25])([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:30]=4[CH2:31]3)=[O:20])[NH:8][CH2:9]2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@@H]1C(=O)O
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@H]1Cc3ccc(O)cc3CN1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a solution of (R)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (102 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and the crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 30% ethyl acetate in hexanes). The purified fractions were re-dissolved in dichloromethane (5 mL), cooled to 0° C. and stirred with TFA (1 mL) for 5 hours at room temperature. The reaction mixture was concentrated to dryness, re-dissolved in dichloromethane (20 mL), washed with sat. NaHCO3 solution (5 mL), brine (5 mL), dried (MgSO4), and concentrated to provide 5-((R)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (55 mg, 67%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.58-1.88 (m, 2H), 2.25-2.54 (m, 5H), 2.65-2.97 (m, 2H), 3.52 (d, J=6.40 Hz, 1H), 3.75-3.95 (m, 2H), 3.98-4.11 (m, 3H), 4.56-4.86 (m, 1H), 6.51 (s, 1H), 6.59-6.73 (m, 1H), 6.95 (t, J=8.48 Hz, 1H), 7.28-7.45 (m, 5H); MS m/z 447 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:28][N:29](C)[C:30](=O)OC(C)(C)C)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[O:21][CH2:22][C:23]([N:25]([CH3:26])[CH3:27])=[O:24])(=[O:14])=[O:13])[CH:10]=[C:9]([CH2:28][NH:29][CH3:30])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CN(C)C(=O)COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2C2=CCCCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(C2=CCCCC2)n(S(=O)(=O)c2cccc(OCC(=O)N(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl ((5-(cyclohex-1-en-1-yl)-1-((3-(2-(dimethylamino)-2-oxoethoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 8c (69 mg, 0.13 mmol) was dissolved in 8 mL of dichloromethane, and the reaction solution was cooled in an ice bath, followed by dropwise addition of 2 mL of trifluoroacetic acid. After removing the ice bath, the reaction solution was stirred at room temperature for 2 h. A saturated sodium bicarbonate solution was added dropwise until the pH of the reaction solution was 7 to 8, and then it was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 2-(3-((2-(cyclohex-1-en-1-yl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N,N-dimethylacetamide 8 (39 mg, a colorless oil) in 69% yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[F:18])(=[O:7])[CH3:6]>CN(C)C=O.C1C=CC=CC=1>[C:5]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:3])=[O:14])=[CH:11][C:10]=1[F:18])(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1F
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1F
Temperature: 25 °C

Procedure:
2.90 ml of thionyl chloride was added to 2.50 g (12.6 mM) of 4-acetoxy-3-fluorobenzoic acid. Under stirring at room temperature, two drops of N,N-dimethylformamide (DMF) was added thereto, followed by refluxing for 40 minutes. After the reaction, dry benzene was added to the reaction mixture, followed by two times of distilling-off of excessive thionyl chloride under reduced pressure to obtain 4-acetoxy-3-fluorobenzoyl chloride.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[O:20]=[C:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1>C1COCC1>[CH2:18]([O:17][C:13]([C:14]#[C:15][C:21]1([OH:20])[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:24]1)=[O:16])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#CC1(O)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.5 %

Procedure:
n-butyl lithium (1.17 mmol, 0.47 ml, 2.5 M) was added dropwise to a solution of diisopropylamine (130 mg, 1.29 mmol, 0.18 ml) in THF (8 ml) at −78° C. The solution was warmed to 0° C., stirred for 15 mins, and cooled back to −78° C. Ethyl propiolate (126 mg, 1.29 mmol, 0.13 ml) was added dropwise and the solution stirred for 1 hr at −78° C. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (200 mg, 1.17 mmol) in THF (2 ml) was added dropwise, stirring continued for 30 mins, and the solution warmed to 0° C. and stirred for a further 15 mins. The reaction was quenched with Sat NH4Cl (20 ml) and extracted into ethyl acetate (20 ml), dried (Na2SO4), and concentrated to give a brown oil. The oil was purified by flash column chromatography eluting with 30% ethylacetate/hexanes to give the title compound as a colorless oil 0.20 g, 64%. 1H NMR (CDCl3, 400 MHz) 1.33 (3H, t), 1.48 (9H, s), 2.92 (1H, s), 4.04 (2H, d), 4.22-4.31 (4H, m).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[CH:6][C:5]=2[C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[CH2:3][CH2:2]1.[O-]CC.[Na+].O.Cl>C(O)C>[C:6]([CH:5]([C:4]([CH:1]1[CH2:2][CH2:3]1)=[O:8])[C:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19])=[O:20])#[N:7]
Reactant: COc1cc(SC)ccc1C(=O)c1cnoc1C1CC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(SC)ccc1C(=O)C(C#N)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Cyclopropyl-4-[2-methoxy-4-(methylsulphenyl)benzoyl]-isoxazole (1.0 g) was added to a solution of sodium ethoxide in ethanol (prepared from sodium (0.12 g) and ethanol). The mixture was stirred at room temperature for 2 hours, poured into water and acidified to pH 1 by addition of hydrochloric acid. The resultant suspension was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with ether and filtered to give 2-cyano-3-cyclopropyl-1-[2-methoxy-4-(methylsulphenyl)phenyl]propan-1,3-dione, COMPOUND 651, (0.88 g) as a cream solid, m.p. 108°-109° C.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])[CH3:16]>C(O)C>[CH2:15]([O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1)[CH3:16]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: CCOc1ccccc1N
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2OCC)[nH]c1=O
Reaction time: 48 h
Yield: 66.2 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (8 g) and 2-ethoxyaniline (6.1 g) are added to ethanol (60 ml), and the mixture is refluxed with stirring for 48 hours. After cooling, the precipitate is collected by filtration, washed with ethanol and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2-ethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (7.5 g). M.p. 220°-221° C.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][C@H:23]2[OH:36])=[CH:18][C:17]=1[F:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[C:58]1[C:63]([C:64]#[N:65])=[CH:62][CH:61]=[CH:60][NH:59]1>O1CCCC1.O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C@@H:23]2[O:36][C:58]2[C:63]([C:64]#[N:65])=[CH:62][CH:61]=[CH:60][N:59]=2)=[CH:18][C:17]=1[F:37]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](O)C1
Reactant: N#Cc1ccc[nH]c1=O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@@H](Oc2ncccc2C#N)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
Diisopropyl azodicarboxylate (1.9 M in toluene, 0.69 mL) was added dropwise to a solution of tert-butyl (6R,7S)-7-(4-chloro-3-fluorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (300 mg), triphenylphosphine (340 mg) and 2-oxo-1,2-dihydropyridine-3-carbonitrile (160 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (250 mg).
Reaction SMILES: [SiH:1]([Cl:4])([CH3:3])[CH3:2].[Si:5]([O:9][CH2:10][CH:11]=[CH2:12])([CH3:8])([CH3:7])[CH3:6]>>[CH3:6][Si:5]([CH3:8])([CH3:7])[O:9][CH2:10][CH2:11][CH2:12][Si:1]([CH3:3])([CH3:2])[Cl:4]
Reactant: C=CCO[Si](C)(C)C
Reactant: C[SiH](C)Cl
Product: C[Si](C)(Cl)CCCO[Si](C)(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A 500 ml Schlenk flask equipped with a stir-bar, a reflux condenser and a rubber septum was charged under nitrogen with 94.6 g of HSiMe2Cl and 5 drops of a 0.1 M solution of the platinum complex Pt(0) 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane complex (a product sold by Aldrich Chemical Co) at room temperature. To this solution 131 g of Me3SiO—CH2—CH═CH2 was added during 30 minutes. After the addition the reaction mixture was gradually heated at 40° C. and mantained at this temperature under stirring for 2 hours, and finally heated at 60° C. for another 5 hours. The desired product can be isolated by distillation under vacuum (25 mbar) at 84° C. Yield 80%. 1H NMR (CDCl3): 0.125 (s, 9H, SiMe3), 0.413 (s, 6H, SiMe2), 0.798–0.890 (m, 2H, CH2), 1.595–1.720 (m, 2H, CH2), 3.585 (t, 2H, CH2).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:17][C:11]1([CH3:16])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:18][C:10]1=2
Reactant: C1COCCN1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: CC1(C)c2cc(N3CCOCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:29]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[O:30].O>CN(C)C=O>[CH3:35][O:34][CH2:33][CH2:32][O:31][C:29](=[O:30])[N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:9]1[N:17]=[C:16]([N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH3:25]
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Reactant: COCCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOC(=O)N(c1ccc(Cl)cc1)c1nc(-n2nc(C)cc2C)nc2c1ncn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
(4-Chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-amine (520 mg, 1.5 mmol) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (60% in mineral oil, 90 mg, 2.2 mmol) was added and mixture was stirred at room temperature for 30 minutes. 2-Methoxyethyl chloroformate (0.26 mL, 2.2 mmol) was added and stirring was continued at room temperature over night. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/methanol as eluent) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-9-methyl-9H-purin-6-yl]-carbamic acid 2-methoxy-ethyl ester (280 mg, 42%) as a white solid.