Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:30](=[O:31])[N:4]2[CH:5]([C:10]3[N:14]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[CH:18][CH:17]=4)[N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.N1C=CC=CC=1.[C:38]1([CH2:44][C:45](Cl)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:38]1([CH2:44][C:45]([NH:1][CH:2]2[C:30](=[O:31])[N:4]3[CH:5]([C:10]4[N:14]([CH2:15][C:16]5[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)=[CH:20][CH:21]=5)[N:13]=[N:12][N:11]=4)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]23)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnnn1Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
To a stirred solution of 189 mg of 6-amino-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam in 4 ml of chloroform, is added, at ambient temperature, 0.038 ml of pyridine followed by 0.057 ml of phenylacetyl chloride. Stirring is continued for a further 45 minutes, and then the reaction mixture is diluted with 25 ml of chloroform and then washed with water. The organic phase is dried using anhydrous magnesium sulfate and then evaporated in vacuo. The residue is 209 mg (86% yield) of 6-(2-phenylacetamido)-2,2-dimethyl-3-(1-[4-benzyloxybenzyl]tetrazol-5-yl)penam. The NMR spectrum (in CDCl3) shows absorptions at 7.50-6.70 ppm (multiplet, aromatic hydrogens), 6.4 ppm (doublet, amide hydrogen), 5.80-5.20 ppm (multiplet, benzyl hydrogens and C-5 and C-6 hydrogens), 5.10 ppm (singlet, C-3 hydrogen), 5.05 ppm (singlet, benzyl hydrogens), 3.60 ppm (singlet, phenylacetyl methylene hydrogens), 1.30 ppm (singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[NH:23][CH:24]=[C:25]([CH2:27][CH2:28][OH:29])[N:26]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:23]2[CH:24]=[C:25]([CH2:27][CH2:28][OH:29])[N:26]=[C:22]2[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(CCO)c[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(CCO)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.4 %

Procedure:
Triphenylmethyl chloride (24.5 g, 88 mmol) in DMF (100 ml) was added dropwise over 1 hr to a solution of 2-methyl-4-(2-hydroxyethyl)imidazole (10 g, 80 mmol) and triethylamine in DMF (100 ml). The reaction mixture was stirred at ambient temperature for 18 hours and then the volatiles were removed by evaporation. The resultant solid was triturated with water (3×500 ml) and ether (200 ml), collected by filtration and dried under vacuum at 60° C. to give the title compound (23.7 g, 80%) as a pale yellow solid. NMR 1.43 (d, 3H), 1.62 (s, 3H), 2.53 (s, 1H), 4.80 (q, 1H), 6.59 (s, 1H), 7.13 (m, 6H), 7.37 (m, 9H); m/z 369.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:37][N:38]1[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]1>C(#N)C.O.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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:41]4[CH:40]=[N:39][N:38]([CH3:37])[CH:42]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
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: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(-c2c(-c3cnn(C)c3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 35.1 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (50 mg, 0.095 mmol), tetrakis(triphenylphosphine)palladium(0) (5.51 mg, 4.77 μmol), sodium carbonate (20.23 mg, 0.191 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (12.02 mg, 0.095 mmol) in acetonitrile (1 mL) and water (0.250 mL) was heated at 80° C. under nitrogen, overnight (ca. 18 h). The reaction mixture was then cooled to RT and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-50% ethyl acetate in DCM, to give the title compound (17.5 mg). LCMS (A) m/z: 525 [M+1]+, Rt 1.34 min (acidic).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1.Cl>O>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:2]2[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: O
Product: COCc1cc(Nc2ccc(OC)cc2)nc(-c2cccc(C)c2)n1
Yield: 40.8 %

Procedure:
A mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (100 mg, 0.402 mmol), p-anisidine (50 mg, 0.402 mmol), water (5 ml) and 2N HCl (300 μl) was refluxed overnight. The resulting yellow solid was collected by filtration, washed with water and then dried under vacuum to give the title compound (55 mg, 41%). 1H NMR (CDCl3): 8.28 (d, J=8.7 Hz, 2H), 7.43–7.35 (m, 4H), 6.96 (d, J=9.0 Hz, 2H), 6.83 (s, 1H), 4.64 (s, 2H), 3.85 (s, 3H), 3.45 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:22]=[C:21]([OH:23])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:32])(=O)=O.CCCCCC>C1(C)C=CC=CC=1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:22]=[C:21]([O:23][CH3:32])[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([NH:24][C:25](=[O:27])[CH3:26])[CH:19]=4)[N:14]=3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)Nc1ccc2nc(-c3ccc(C4CCCCC4)cc3)cc(O)c2c1
Reactant: COS(=O)(=O)OC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(C3CCCCC3)cc2)nc2ccc(NC(C)=O)cc12
Temperature: 70 °C
Yield: 96.6 %

Procedure:
Into a 500 mL three-neck round-bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet was added 35.7 g (0.099 moles) of N-[2-(4-cyclohexylphenyl)-4-hydroxy-quinolin-6-yl]-acetamide. The material was suspended in 250 mL of toluene with stirring and then 20.6 mL (0.21 moles) of dimethyl sulfate was added. The resulting suspension was heated with a silicone oil heating bath, to gentle a reflux for 18 hr. After this time the reaction was allowed to cool and hexane was added. The solids were collected by vacuum filtration and washed with hexane. After drying, the solids were suspended in a 2 L Erlenmeyer flask with 1 L of 5% sodium hydroxide solution. The vigorously stirred suspension was then heated to 70° C. for 30 min. This step converted the salt form of the material to the free base and removed some impurities. After cooling the solids were collected by vacuum filtration and then washed with water. The product was dried in a vacuum oven to give 35.8 g (96%) of a material which contained approximately 30% of side products, with the N-methylated material constituting the major impurity. This material was used in the following procedure without further purification.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:15]=[N:16][C:17]=1[O:18][CH3:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.C(N(CC)CC)C.[H][H]>[C].[Pd].C(O)C>[C:20]1([C:14]2[N:15]=[N:16][C:17]([O:18][CH3:19])=[C:12]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:13]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: COc1nnc(-c2ccccc2)cc1C(OC(C)=O)c1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1nnc(-c2ccccc2)cc1Cc1ccccc1
Yield: 100.3 %

Procedure:
600 mg of 10% palladium carbon was added to a mixture of 1.58 g of 5-(α-acetoxybenzyl)-3-phenyl-6-methoxypyridazine, 2.0 ml of triethylamine and 10 ml of ethanol, and the mixture was subjected to hydrocracking in a hydrogen atmosphere. The catalyst was filtered off, and the solvent was removed. Then, the residue was subjected to NH-silica gel (Fuji Silicia) and eluted with ethyl acetate, to give 1.31 g of the target compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)cc(-c2cccc(C(F)(F)F)c2)n1
Product: CSc1nc(Cl)cc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
2-Methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-ol (500 mg) and phosphorous oxychloride (2.5 ml) were heated to reflux for four hours. The reaction mixture was concentrated under reduced pressure and the remaining residue dissolved in ethyl acetate (50 ml) and washed with water (2×30 ml). Organics were separated, dried over sodium sulphate and solvent was removed under reduced pressure to yield 4-chloro-2-methylsulfanyl-6-(3-trifluoromethyl-phenyl)-pyrimidine (478 mg) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Reactant: Nc1ccc(F)cc1
Product: Cc1ccc(Nc2ccc(F)cc2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 4-Fluoroaniline instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=326.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8](C(OCC(Cl)(Cl)Cl)=O)[C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][O:5][C:6]=1[CH3:7].OP([O-])(O)=O.[K+]>[Zn].C1COCC1>[Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1noc(C)c1Br
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)Nc1noc(C)c1Br
Reaction time: 1.5 h

Procedure:
To a dry THF solution (20 mL) of methyl N-(4-bromo-5-methylisoxazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate (1.19 g, 2.47 mmol) and activated zinc (10.1 g, 154 mmol) was added ca. 10 mL of 1 M KH2PO4 (10 mmol) at 0° C. The mixture was stirred for 1.5 hours, filtered through celite, washed with 150 mL ethyl acetate, and concentrated to a small volume. The mixture was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulphate and concentrated in vacuo. The crude product was purified by flash chromatography (20% ethyl acetate/hexane) to afford methyl N-(4-bromo-5-methylisoxazol-3-yl)leucinate.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=2)[CH:11]=[CH:10]1>CCO>[OH:3][NH:2][C:18]([C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][NH:9]2)=[CH:13][CH:14]=1)=[NH:19]
Reactant: NO
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc2cc[nH]c2c1
Reaction time: 36 h
Yield: 106.5 %

Procedure:
Hydroxylamine hydrochloride (4.7 g) and sodium bicarbonate (8.6 g) were added to a solution of 1H-indole-6-carbonitrile (4.8 g) in EtOH (70 mL) successively. The reaction mixture was heated to reflux and stirred for 36 hours. The inorganic percipitate was filtered off. The solid was washed with EtOH (30 mL). The filtrate was concentrated to afford N-hydroxy-1H-indole-6-carboximidamide (D100) (6.3 g) as a yellow solid. No purification was attempted. MS (ES): C9H9N3O requires 175; found 176.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[F:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[F:1][C:2]1[C:3]([F:10])=[C:4]([F:9])[C:5]([F:8])=[CH:6][C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: Fc1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To one liter of concentrated sulfuric acid was added, at 5° C., 100 ml of 1,2,3,4-tetrafluorobenzene. Then a mixture of 100 ml of 70% nitric acid premixed with 200 ml of concentrated sulfuric acid at 0° C. was slowly added. The reaction was stirred at 0° C. for one hour, and then one hour at 25° C. The mixture was poured over ice and extracted with dichloromethane, which was dried and concentrated to give 120 g of a thick residue which was one spot thin layer chromatography. This product was used for the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)C2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1(F)CCN(C2CNC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(3,3-difluoropyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (193 mg, 0.74 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-yl-3,3-difluoropyrrolidine as a white solid (122 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 3.63 (m, 4 H), 3.48 (m, 1 H), 2.87 (t, J=13.1 Hz, 2 H), 2.70 (t, J=7.0 Hz, 2 H) and 2.29 (m, 2 H)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:18]=[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])[S:16][C:15]=1[C:23]([OH:25])=[O:24].[CH2:26]=[O:27].Cl>C1COCC1.C(OCC)(=O)C.O>[OH:27][CH2:26][CH2:13][C:14]1[CH:18]=[C:17]([Si:19]([CH3:20])([CH3:21])[CH3:22])[S:16][C:15]=1[C:23]([OH:25])=[O:24]
Reactant: Cc1cc([Si](C)(C)C)sc1C(=O)O
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)c1cc(CCO)c(C(=O)O)s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Diisopropylamine (9.4 g) was added to a solution of n-Butyllithium (1.6 M in hexane, 43.7 mL) in THF (67 mL) at −78° C. The mixture was stirred for 10 min at 0° C. and then cooled to −78° C. and a solution of 3-Methyl-5-trimethylsilanyl-thiophene-2-carboxylic acid (5.0 g) in THF (40 mL) was added. The mixture was stirred at −78° C. for 30 min and then paraformaldehyde (3.2 g) was added. After warming to room temperature water and ethyl acetate were added. The aqueous phase was slightly acidified with HCl (10%) and then extracted three time with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed in vacuum. The raw product was purified by preparative HPLC. In this way the product was obtained with molecular weight 244.39 (C10H16O3SSi); MS (ESI): 245 (M+H+).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Si:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:30]=[CH:29][C:28]=1[CH:41]1[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>ClC(Cl)C>[CH:10]1([NH:16][C:17](=[O:18])[O:47][C@H:44]2[CH2:43][CH2:42][C@H:41]([C:28]3[CH:29]=[CH:30][C:31]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])=[CH:32][C:27]=3[O:26][Si:19]([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20])[CH2:46][CH2:45]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C=NC1CCCCC1
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](OC(=O)NC3CCCCC3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 40 °C

Procedure:
N,N-Diisopropylethylamine (199 μl) and cyclohexyl isocyanate (128 μl) were added to a stirred solution of 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon. The reaction mixture was heated to 40° C. for 120 h, and was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound as a pale yellow solid (30 mg, 47%); δH(CDCl3) 0.12 (6H, s), 0.18 (6H, s), 0.90 (9H, s), 0.95 (9H, s). 1.00-2.10 (18H, m), 2.70-2.80 (1H, m), 3.36-3.50 (1H, m), 4.40-4.48 (1H, m), 4.50-4.62 (1H, m), 6.20 (1H, d), 6.32 (1H, dd), 6.86 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([NH:12][N:13]=[C:14]([C:23]#[N:24])[C:15]([NH:17][C:18](=O)[O:19]CC)=[O:16])=[CH:4][CH:3]=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:10]2[O:9][CH:8]([CH3:11])[CH2:7][C:6]=2[C:5]([N:12]2[C:18](=[O:19])[NH:17][C:15](=[O:16])[C:14]([C:23]#[N:24])=[N:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1ccc(Cl)c2c1CC(C)O2
Solvent: Cc1ccccc1C
Product: CC1Cc2c(-n3nc(C#N)c(=O)[nH]c3=O)ccc(Cl)c2O1
Temperature: 25 °C

Procedure:
A mixture of 12.5 g of 32B and 600 mL of xylene was stirred at reflux temperature overnight under a Soxhlet extractor filled with 4A molecular sieves to collect the alcohol that was formed. The mixture was cooled to room temperature and filtered; the solid product was dried under reduced pressure to give 2-(7-chloro-2,3-dihydro-2-methyl-4-benzofuranyl)-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile (32C) as a tan solid, m.p.: 244°-245° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]([NH:19][C:20]([C:22]2([C:28]#[N:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])[CH3:18])=[CH:13][CH:12]=1.[CH:30]1[C:34]2[C:35](Cl)=[N:36][CH:37]=[N:38][C:33]=2[NH:32][CH:31]=1>CC(N(C)C)=O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]([NH:19][C:20]([C:22]2([C:28]#[N:29])[CH2:23][CH2:24][N:25]([C:35]3[C:34]4[CH:30]=[CH:31][NH:32][C:33]=4[N:38]=[CH:37][N:36]=3)[CH2:26][CH2:27]2)=[O:21])[CH3:18])=[CH:15][CH:16]=1
Reactant: C[C@@H](NC(=O)C1(C#N)CCNCC1)c1ccc(Cl)cc1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)C1(C#N)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
DIPEA (1.101 mL, 6.17 mmol) was added to (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyanopiperidine-4-carboxamide (Intermediate 44) (720 mg, 2.47 mmol) and 6-chloro-7-deazapurine (379 mg, 2.47 mmol) in DMA (50 mL) at 25° C. The resulting solution was stirred at 90° C. for 3 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7N ammonia/MeOH and pure fractions were evaporated to dryness to afford (R)—N-(1-(4-chlorophenyl)ethyl)-4-cyano-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (46.2%) as an orange solid. This was used in the next step without further purification.
Reaction SMILES: [CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]CC3C=CC=CC=3)=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Pd].C(OCC)(=O)C>[CH3:1][C@H:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[O:17])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC[C@H](C)Oc1ccc(C(=O)Oc2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC[C@H](C)Oc1ccc(C(=O)Oc2ccc(O)cc2)cc1
Reaction time: 6 h
Yield: 63.2 %

Procedure:
{circle around (2)}: A mixture comprising 2.2 g of (S)-4-[4′-(1″-methylheptyloxy)phenylcarbonyloxy)-1-benzyloxybenzene, 0.2 g of palladium/carbon and 10 g of ethyl acetate was stirred for 6 hours under hydrogen atmosphere. Then, palladium/carbon was filtered off, followed by distilling off ethyl acetate from the filtrate. The resultant residue was recrystallized from hexane, whereby 1.1 g of (S)-4-[4′-(1″-methylheptyloxy)phenylcarbonyloxy)phenol was obtained in the form of a colorless crystal.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[C:14]([O:19][CH2:20][CH3:21])(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+]>>[CH3:17][C:16]1[C:15]([C:14]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][NH:11][CH:12]=1
Reactant: C/C=C/C(=O)OCC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1c[nH]cc1C
Yield: 71.1 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (8.55 g), ethyl crotonate (5.0 g) and potassium tert-butoxide (5.90 g), a procedure as in Reference Example 39 was performed to give the title compound as a pale-yellow solid (yield 4.77 g, 71%).
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[O:23]1[CH2:26][C:25](=O)[CH2:24]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])(=[O:14])=[O:15])[CH2:10][N:9]1[CH:25]1[CH2:26][O:23][CH2:24]1)=[O:7])#[N:3]
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: O=C1COC1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C1COC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K1 was reductively aminated with oxetane-3-one (prepared according to G. Wuitschik et al., Angewandte Chemie, International Edition (2006), 45(46), 7736) in analogy to experiment L3 to give to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-oxetan-3-yl-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless foam. MS: 384.1 [M+H]+.
Reaction SMILES: [C:1]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1>N1C=CC=CC=1>[C:18]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:3])[CH3:2])=[CH:11][CH:12]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(c1ccccc1)c1ccc(OC(=O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
42,4 g (200 mmol) of p-cumylphenol and 40 g (220 mmol) nicotinic acid chloride hydrochloride was mixed with 600 ml dry pyridine and stirred for 24 hours at 40° C. After cooling precipitated pyridine hydrochloride was sucked off and the filtrate mixed with 150 ml of water. The precipitated raw product was washed with two 100 ml portions of water and recrystallized from methanol.