Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([C:9](=O)[CH3:10])[C:6](=O)[CH3:7])[CH3:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][NH2:20]>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:9]([CH3:10])=[N:20][N:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[C:6]=1[CH3:7])=[O:12])[CH3:2]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nn(-c2ccccn2)c1C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
Dissolve 2-acetyl-3-oxobutyric acid ethyl ester (20.74 g, 0.120 mol) and 2-pyridylhydrazine (14.5 mL, 0.133 mol) in acetic acid (160 mL) and stir the mixture for 18 hr. Concentrate, dilute with DCM, wash with saturated sodium bicarbonate, dry (sodium sulfate), filter and concentrate to give 3,5-dimethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester as an oil (28.6 g, 97%). MS (m/z): 246 (M+1).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:29].[Na+]>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[Si:11]([O:10][C@@H:6]1[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:1][CH:2]=[O:29])[CH2:5]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@H]1CCC[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](O[C@@H]1CCC[C@H](CC=O)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5.5 g of (cis-3-allylcyclohexyloxy)-tert-butyl-diphenylsilane are dissolved in 100 ml of diethyl ether, and 9.4 g of sodium periodate, dissolved in 100 ml of water, are added. At 0° C., 15 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) are added, and the mixture is stirred vigorously at room temperature. After 5 hours, a further 5 g of sodium periodate are added, and the mixture is stirred at room temperature for another 3 hours. The reaction mixture is then diluted by addition of 300 ml of methyl tert-buthyl ether and washed with saturated sodium thiosulfate solution. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. This gives 6 g of [cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]acetaldehyde as a yellow-brown oil. C24H32O2Si (380.61), MS(ESI): 381 (M+H+), Rf(n-heptane:ethyl acetate=5:1)=0.44.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Cl>ClCCl.CN(C1C=CC=CN=1)C>[C:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.7 %

Procedure:
To a solution of p-hydroxybenzoic acid (3 g) and triethylamine (2.4 g) in dichloromethane (30 ml) were added decanoyl chloride (4.3 g) and dimethylaminopyridine (0.2 g). The mixture was stirred at room temperature for about 20 hours. After dilute aqueous hydrochloric acid solution was added to the mixture, an organic layer was separated by a funnel. After the solution was distilled to remove the solvent, the residue was washed with n-hexane and dried to obtain the titled compound (about 5 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH2:5][N:4]([CH2:9][CH2:10][N:11]2[CH2:16][C:15](=[O:17])[NH:14][C:13](=[O:18])[CH2:12]2)[CH2:3]1.[CH2:19]=[O:20].CN([CH:24]=[O:25])C>>[OH:20][CH2:19][N:14]1[C:13](=[O:18])[CH2:12][N:11]([CH2:10][CH2:9][N:4]2[CH2:3][C:2](=[O:1])[N:7]([CH2:24][OH:25])[C:6](=[O:8])[CH2:5]2)[CH2:16][C:15]1=[O:17]
Reactant: O=C1CN(CCN2CC(=O)NC(=O)C2)CC(=O)N1
Reactant: CN(C)C=O
Reactant: C=O
Product: O=C1CN(CCN2CC(=O)N(CO)C(=O)C2)CC(=O)N1CO
Temperature: 130 °C
Yield: 64.7 %

Procedure:
A mixture of 1,2-bis(3,5-dioxopiperazin-1-yl)ethane (2.0 g, 7.9m mol) and DMF (10 ml) was heated at 130° C. for 10 minutes. To the mixture, 37% aqueous formaldehyde solution (2 ml) was added gradually, and then the mixture was successively heated at 130° C. for 1.5 hours. The reaction mixture was allowed to stand in a refrigerator overnight. The resulting precipitates were collected, washed with ethyl acetate and dried under reduced pressure to give the tilted compound (1.6 g; yield 64.7%).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.[C:22](Cl)(Cl)=[O:23].C1(C)C=CC=CC=1>C1COCC1>[N:1]([C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])=[C:22]=[O:23]
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1sc2cccnc2c1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1sc2cccnc2c1N=C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Methyl 3-aminothieno[3,2-b]pyridine-2-carboxylate (0.624 g, 3.00 mmol), prepared as described in (Journal of Heterocyclic Chemistry, 24: 85 (1987), and triethylamine (0.84 mL, 6.0 mmol) in THF (20 mL) at −78° C. was treated with a 1.93M solution of phosgene in toluene (1.7 mL, 3.3 mmol), stirred for 2 hours at −78° C., concentrated, and used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]O)[CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1cccnc1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1cccnc1)c1cc(F)ccc1F
Yield: 57.8 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (120 mg, 0.396 mmol) obtained in Example 5 and 3-pyridylmethanol (50.1 μl, 0.515 mmol) were dissolved in toluene (4 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (124 mg, 0.515 mmol). The resulting mixture was heated under reflux for 18 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=3:7 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (90.3 mg, 0.229 mmol, 58%) was obtained as colorless columnar crystals.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[N:8]([CH:14]3[CH2:16][CH2:15]3)[CH2:9][NH:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1)([OH:3])=[O:2].[C:19]1(O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1.O>CN(C=O)C>[CH:14]1([N:8]2[C:7]3[CH:17]=[CH:18][C:4]([C:1]([O:3][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:2])=[CH:5][C:6]=3[S:11](=[O:13])(=[O:12])[NH:10][CH2:9]2)[CH2:15][CH2:16]1
Reactant: O=C(O)c1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Reactant: Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccccc1)c1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-carbonyldiimidazole (0.6 g) is added to a solution of the compound of Example 78 (3.5 mmol) in DMF (7 mL). After stirring for 1 hour at ambient temperature, phenol (0.5 g) and DBU (0.5 mL) are added. After stirring for 2 hours at ambient temperature, water (40 mL) is added and the mixture is extracted three times with ethyl acetate (30 mL). The organic phases are combined, dried over anhydrous MgSO4 and filtered. The filtrate is evaporated to dryness and the residue is re-dissolved in methanol (5 mL). Water (50 mL) is added to the solution and the precipitate obtained is collected by filtration, washed with water and dried to yield the title product in the form of a white solid.
Reaction SMILES: F[B-](F)(F)F.[N:6]#[O+:7].[CH3:8][C:9]([CH3:15])([CH2:13][CH3:14])[CH2:10][CH:11]=[CH2:12].[C:16](#[N:18])[CH3:17]>>[CH3:8][C:9]([CH3:15])([CH2:13][CH3:14])[CH2:10][C:11]1[N:18]=[C:16]([CH3:17])[N:6]([OH:7])[CH:12]=1
Reactant: C=CCC(C)(C)CC
Reactant: CC#N
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Product: CCC(C)(C)Cc1cn(O)c(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitrosonium tetrafluoroborate 45 g (0.38 mol) was added in three portions to a 0° C. solution of 4,4-dimethyl-1-hexene (43 g, 0.38 mol) in acetonitrile (100 mL). After stirring at ambient temperature for 1 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine, dried (magnesium sulfate), filtered and concentrated in vacuo to afford 4-(2,2-dimethylbutyl)-2-methyl-1H-imidazol-1-ol which was used in the subsequent step without further purification.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C([O-])([O-])=O.[K+].[K+].C(O)CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:28]5[CH:29]=[CH:30][S:26][CH:27]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccsc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCO
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccsc4)ccc32)n1)c1ccccc1

Procedure:
A stirred solution of 2-[(S)-1-phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine (EXAMPLE 271) (37 mg), 3-thiophene boronic acid (16 mg), K2CO3 (35 mg) and Pd(PPh3)4 (0.97 mg) in 1:1 n-propanol:water (4 mL) was stirred under N2 at 100° C. for 16 h. The reaction mixture was cooled and poured into 100 mL EtOAc and washed with water, then brine. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography eluting successively with 10% acetone/hexanes, 20% acetone/hexanes and 30% acetone/hexanes giving 25.3 mg of the title compound. Mass spectrum (ESI): 398.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[C:12](=[O:19])[N:13]([CH3:18])[CH2:14][C:15](=O)[NH:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:27])[CH2:24][N+:25]#[C-:26])[CH3:21].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C)C=O>[CH3:18][N:13]1[C:12](=[O:19])[C:11]2=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[CH:8][CH:9]=[C:10]2[N:16]2[CH:26]=[N:25][C:24]([C:23]([O:22][CH2:20][CH3:21])=[O:27])=[C:15]2[CH2:14]1
Reactant: CCOC(=O)c1cccc2c1C(=O)N(C)CC(=O)N2
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2c1C(=O)N(C)Cc1c(C(=O)OCC)ncn1-2
Temperature: -20 °C

Procedure:
6-Ethoxycarbonyl-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione (10 mmol) was dissolved in 25 ml dry dimethylformamide (DMF). While stirring, K-t-butoxide (12 mmol) was added and the mixture was thereafter cooled to -20° C. A -30° C. cold solution of K-t-butoxide (12 mmol) in dry DMF (15 ml) was charged with isocyano-acetic acid ethylester (12 mmol). This solution was added to the above mentioned solution, and the combined solution was stirred at room temperature for 2 hours. 2 ml of acetic was added, whereafter the solution was evaporated to dryness. The oily residue was subjected to SiO2 -purification with acetone/chloroform (1/3) as eluent. This yielded the title compound as a crystalline powder. M.p. 136.3°-139.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[S:8][C:7]=2[CH:18]=1.C(O[C:23](=[O:25])[CH3:24])(=O)C.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:23]([C:24]3[CH:28]=[CH:29][C:30]([CH2:31][N:26]4[CH2:27][CH2:7][CH2:6][CH2:5]4)=[C:3]([CH3:4])[CH:18]=3)=[O:25])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[S:8][C:7]=2[CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: COc1ccc2cc(-c3ccc(N)cc3)sc2c1
Product: COc1ccc2c(C(=O)c3ccc(CN4CCCC4)c(C)c3)c(-c3ccc(N)cc3)sc2c1
Reaction time: 2 h

Procedure:
A solution of 15.0 g (58.7 mmol) of 6-methoxy-2-(4-aminophenyl)benzo[b]thiophene (Part B) in 350 mL of pyridine was treated with 17.0 mL (180 mmol) of acetic anhydride in a dropwise manner. After stirring for 2 h, the reaction was concentrated in vacuo to give 15.1 g (50.7 mmol; 87%) of the title compound as a yellow solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[S:10][C:9]2[CH:11]([C:15]([OH:17])=[O:16])[CH2:12][C:13](=O)[C:8]=2[CH:7]=1.Cl>O.C1(C)C=CC=CC=1.[Zn]>[CH3:5][C:6]1[S:10][C:9]2[CH:11]([C:15]([OH:17])=[O:16])[CH2:12][CH2:13][C:8]=2[CH:7]=1
Reactant: Cc1cc2c(s1)C(C(=O)O)CC2=O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc2c(s1)C(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
6.5 cc of acetic acid was added to a suspension of 64.1 g (0.98 g at) of zinc powder and 6.4 g (0.024 mole) of mercuric chloride in 65 cc of water and the mixture was stirred for 30 min. Then a solution of 14 g (0.076 mole) of 2-methyl-4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid in 140 cc of toluene, then 60 cc of 10N hydrochloric acid were successively added. The mixture was refluxed for 5 hours then decanted after cooling to ambient temperature. The organic phase was separated. The aqueous phase was extracted with toluene. The organic solutions were collected, washed with water and dried on sodium sulfate. Evaporation of the solvent under reduced pressure provided 9.8 g (yield=71%) of 2-methyl-5,6-dihydro-4H-cyclo-penta[b]thiophene-6-carboxylic acid (mp=105°-107° C.) which was used afterwards without further purification. An analytical sample was obtained by recrystallization in a hexane-ethyl acetate mixture. Mp=107°-109° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(#N)C.I.[Na]>>[F:19][C:18]([F:21])([F:20])[C:16]1[CH:15]=[CH:14][N:13]=[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)[CH:17]=1
Reactant: FC(F)(F)c1ccnc(N2CCc3c(Cl)ncnc3C2)c1
Reactant: COc1cccc(N)c1
Agent: I
Agent: [Na]
Solvent: CC#N
Product: COc1cccc(Nc2ncnc3c2CCN(c2cc(C(F)(F)F)ccn2)C3)c1
Temperature: 160 °C
Yield: 24.9 %

Procedure:
A mixture of 4-chloro-7-(4-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.041 g, 0.00013 mol), 3-methoxyaniline (0.018 mL, 0.00016 mol) in acetonitrile (1.00 mL, 0.0191 mol) and 47% HI (0.11 mL, 0.001 mol) was heated at 160° C. for 10 minutes in in a sealed tube via microwave. After cooling to r.t., the mixture was poured into saturated aqueous sodium bicarbanate (5 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine and dried over magnesium sulfate. Concentrated to leave a brown solid. Residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give a white foam (0.013 g)
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:17](=[O:39])[N:18]([C@H:25]([CH2:36][O:37][CH3:38])[CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:19][CH:20](OC)OC)[CH3:16])(C)(C)C.C([SiH](CC)CC)C.C(N(CC)CC)C>ClCCl>[CH2:29]([O:28][CH2:27][CH2:26][C@H:25]([N:18]1[CH2:19][CH2:20][NH:14][C@@H:15]([CH3:16])[C:17]1=[O:39])[CH2:36][O:37][CH3:38])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC[C@H](CCOCc1ccccc1)N(CC(OC)OC)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@H](CCOCc1ccccc1)N1CCN[C@@H](C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Trifluoroacetic acid (8.03 g, 70.4 mmol) was added at 0° C. to a solution of {(S)-1-[((S)-3-benzyloxy-1-methoxymethyl-propyl)-(2,2-dimethoxy-ethyl)-carbamoyl]-ethyl}-carbamic acid tert-butyl ester (2.20 g, 4.69 mmol) in dichloromethane (40 mL). The reaction mixture was allowed to reach room temperature over 2 h, then triethylsilane (2.73 g, 70.4 mmol) was added. The reaction mixture was stirred for 16 h at room temperature, then cooled to 0° C. and treated with triethylamine (7.24 g, 70.4 mmol). After 10 min the ice bath was removed and the reaction mixture evaporated. The residue was taken up in ethyl acetate/water and neutralized with 2 M aq. sodium carbonate solution. The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. Chomatography (SiO2; dichloromethane-methanol gradient) afforded the title compound (735 mg, 51%). Light yellow oil, MS (ISP)=307.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1.[CH3:17][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([C:8]([OH:15])([CH3:17])[CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C(Cn1ccnc1)c1cc(Cl)ccc1O
Solvent: C1CCOC1
Product: CC(O)(Cn1ccnc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 24.5 %

Procedure:
A suspension of 1-(5-chloro-2-hydroxyphenyl)-2-(1H-1-imidazolyl)-1-ethanone [compound (5-1)] (2.37 g, 10 mmol) in tetrahydrofuran (200 mL) was added to a solution of methylmagnesium bromide in tetrahydrofuran (1 mol/L, 100 mL, 0.1 mol) under cooling with ice, and the mixture was stirred for 17 hours at room temperature. The solvent was removed, a solution of saturated ammonium chloride was added to the resultant mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. The solvent was removed under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography and dried under reduced pressure, to thereby yield 4-chloro-2-(1-hydroxy-2-(1H-1-imidazolyl)-1-methylethyl)phenol as colorless crystals (620 mg, yield: 24.5%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[C:22]2[C:29]([I:30])=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:46][CH2:47][C@@H:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH:49]=[CH2:50]>COCCOC>[Cl:20][C:21]1[C:22]2[C:29]([I:30])=[CH:28][N:27]([CH2:50][CH2:49][C@@H:48]([NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55])[CH:47]=[CH2:46])[C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: C=C[C@@H](CCO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: C=C[C@@H](CCn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Triphenylphosphine (3.25 g) was added to and dissolved in a solution of (R)-tert-butyl (5-hydroxypent-1-en-3-yl)carbamate (2.5 g) obtained in Step 3 and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.31 g) obtained in Step 1 of Example 1 in DME (23 ml) under ice-cooling. Thereafter, diisopropyl azodicarboxylate (2.44 ml) was gradually added thereto. The reaction mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1 hour, and the solvent was then distilled off under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a light-yellow solid (3.49 g).
Reaction SMILES: [C:1]([S@@:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]=[C:18]([CH:20]=O)[N:17]=[CH:16]2)=[CH:11][CH:10]=1.CCOC(C)=O.CCCCCCC>ClCCCl.[O-]S([O-])(=O)=O.[Cu+2]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH:19]=[C:18](/[CH:20]=[N:7]/[S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[N:17]=[CH:16]2)=[CH:13][CH:14]=1
Reactant: O=Cc1cn(-c2ccc(Cl)cc2)cn1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCCCCCC
Product: CC(C)(C)[S@](=O)/N=C/c1cn(-c2ccc(Cl)cc2)cn1
Temperature: 60 °C
Yield: 28.1 %

Procedure:
To a suspension of (S)-(−)tert-Butanesulfinamide (2.35 g, 19.4 mmol) and 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (4 g, 19.4 mmol) in DCE (39 mL) was added CuSO4 (4.63 g, 29.0 mmol). The reaction mixture was heated at 60° C. for 18 hours in a oil bath. A dark brown suspension resulted. The reaction mixture was then cooled to room temperature, filtered through a pad of celite, rinsed with DCM. The solution was then concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (S,E)-N-((1-(4-chlorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (1.69 g, 5.45 mmol, 28.2% yield) as a light brown solid. LCMS m/z 310.0 (M+H)+, Rt 0.75 min.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10][S:11][CH3:12])=[O:6])[CH:2]=[CH2:3].Cl.[C:17](=O)(O)[O-].[Na+]>CO>[CH3:17][O:14][C:13](=[O:15])[C@H:8]([CH2:9][CH2:10][S:11][CH3:12])[NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6]
Reactant: C=CCOC(=O)N[C@@H](CCSC)C(=O)O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCOC(=O)N[C@@H](CCSC)C(=O)OC

Procedure:
A solution of 0.06 mol of N-(allyloxycarbonyl)methionine, prepared as described by H. Kunz and C. Unverzagt in Angew. Chem. Int. Ed. Engl., 1984, 23, 436-437, and 0.066 mol of HCl in 100 mL of CH3OH is stirred at reflux for 8 hours. The solution is then cooled and treated with 0.066 mol of sodium bicarbonate. The solvent is removed by rotary evaporator, and the residue is dissolved in diethyl ether, filtered, driedover MgSO4, and filtered. The solvent is removed by rotary evaporator to give N-(allyloxycarbonyl)methionine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[C:25](O)(=[O:27])[CH3:26].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:25](=[O:27])[CH3:26])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2nc(CC3CCNCC3)ccc2n1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reaction time: 8 h

Procedure:
4-(2-chloro-6-(piperidin-4-ylmethyl)pyrido[3,2-d]pyrimidin-4-yl)morpholine (40 mg) was added to a pre-stirred (15 minutes) solution of acetic acid (5 eq), 1-Hydroxybenzotriazole (HOBt, 1.2 eq.), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5 eq.), DIPEA (5 eq) in N,N-Dimethylformamide (DMF, 0.9 mL). The reaction was stirred overnight then extracted with Ethyl Acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to give quantitative yield of 1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone.