Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[OH:20].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:20][CH:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH3:18])[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CC(O)c1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CC(Oc1nc(N)nc(-c2ccco2)c1C#N)c1ccccn1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (RS)-alpha-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([O:7]CC#C)=[O:6].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([OH:7])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1c(F)cc(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To 40 ml of methanol were added 4.5 g of 2-propynyl 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoate and 20 ml of a 15% aqueous sodium hydroxide solution, and the resulting mixture was stirred at room temperature for 8 hours. Thereafter, the reaction mixture was concentrated under reduced pressure. To the residue was added hydrochloric acid to make the mixture acidic. The precipitated solids were collected by filtration, and dried, and 3.7 g of 3-fluoro-5-methoxy-4-(2-propynyloxy)benzoic acid was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[C:20]([Br:28])[CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc4c(N)ncnn34)cc2C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(Br)c4c(N)ncnn34)cc2C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 150 %

Procedure:
To a solution of 7-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.2 g, 6.1 mmol) in THF (30 mL) at −20° C. was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (884 mg, 3 mmol) in four portions. The reaction mixture was allowed to stir at −20° C. for 2 h. The solvent was evaporated and the residue was purified by column chromatography (10-50% EtOAc/Hexane) to provide 2 g (72%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.9 (s, 1 H), 7.85 (d, 2 H), 7.2 (d, 2 H), 4.5 (s, 2 H), 3.5 (t, 2 H), 2.8 (t, 2 H), 1.4 (s, 9 H); ES-MS m/z 444.08 [M+H]+, HPLC RT (min) 3.24.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([S:7]([N:9]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:10]2[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)(Cl)Cl>[C:1]1([CH3:22])[CH:2]=[CH:3][C:4]([S:7]([N:9]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:10]2[C:18]([O:20][CH3:21])=[O:19])(=[O:28])=[O:8])=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1[C@H](c2ccccc2)N1S(=O)c1ccc(C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H]1[C@H](c2ccccc2)N1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Into a 25-mL single-necked round-bottomed flask equipped with a magnetic stir bar were placed 0.63 g (2.0 mmol) of (2S,3S)-(+)-N-(p-toluenesulfinyl)-2-carbomethoxy-3-phenylaziridine (prepared according to Example 1), 1.04 g (3.0 mmol) 3-chloroperoxybenzoic acid (60%, from Aldrich) and 20 mL chloroform. The reaction mixture was stirred at room temperature for 1 h, washed with 20 mL saturated aqueous Na2S2O3 solution, diluted with 50 mL CH2Cl2, washed with saturated aqueous Na2CO3 solution (2×10 mL) and dried (MgSO4). Filtration and removal of the solvent gave a solid residue which was purified by flash chromatography (ethyl acetate:n-pentane, 2:8) to afford the titled compound (0.62 g, 94%): mp. 85°-87° C.; [α]D20 +18.2° (c 1.0, CHCl3); IR (KBr): 3033.3, 1757.2, 1597.5, 1334.1, 1210.1, 1163.6, 1091.7 cm-1 ; 1H NMR (CDCl3) δ2.44 (s, 3H, CH3), 3.49 (s, 3H, CH3), 3.71 (d, J=7.7 Hz, 1H, CH), 4.12 (d, J=7.6 Hz, 1H, CH), 7.20-7.32 (m, 5H, aromatic), 7.35 (d, J=8.4 Hz, 2H, aromatic), 7.92 (d, J=8.3 Hz, 2H, aromatic); 13C NMR (CDCl3) δ164.5, 145.0, 133.8, 130.9, 129.7, 128.3, 128.0, 127.9, 127.2, 52.3, 45.3, 43.3, 21.6. Anal. Calcd for C17H17NO4S: C, 61.61; H, 5.17. Found: C, 61,43; H, 5.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[CH:35][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][C@@:12]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:17][C:16](=[O:18])[N:15]([C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:5][CH:4]=1.C1C[O:40]CC1>>[OH:40][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C@@H:19]([N:15]2[CH2:14][CH2:13][C@:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:36][CH:35]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:17][C:16]2=[O:18])[CH3:20])=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: C=Cc1ccc([C@H](C)N2CC[C@](CCCOCc3ccc(OC)cc3)(c3ccccc3)OC2=O)cc1
Product: COc1ccc(COCCC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(CCO)cc3)C(=O)O2)cc1
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of (R)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-3-((S)-1-(4-vinylphenyl)ethyl)-1,3-oxazinan-2-one (260 mg, 0.536 mmol) in THF (3 mL) was added BH3 THF (1.6 mL, 1 mol/L) at 0° C. under nitrogen atmosphere. The formed mixture was stirred for 2 h. The reaction was quenched with water. Then aqueous NaOH solution (1 mol/L, 2 mL) and H2O2 (1 mL) were added to the above mixture. The resulting mixture was stirred for 1.5 h. The mixture was extracted with EtOAc and the combined organic phase was concentrated to give crude (R)-3-((S)-1-(4-(2-hydroxyethyl)phenyl)ethyl)-6-(3-(4-methoxybenzyloxy)propyl)-6-phenyl-1,3-oxazinan-2-one (260 mg, 96%), which was used for the next step without purification. 1H NMR (CDCl3): δ=1.32 (m, 2H), 1.41 (d, 3H), 1.89 (m, 2H), 2.12 (m, 1H), 2.22 (m, 2H), 2.68 (m, 1H), 2.81 (m, 1H), 3.27 (m, 2H), 3.72 (s, 3H), 4.26 (s, 2H), 5.53 (q, 1H), 6.71-6.88 (m, 5H), 7.13 (m, 2H), 7.26 (m, 4H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:20]#[N:21])[CH2:19][CH2:18]3)=[C:13]([F:22])[CH:12]=2)[CH2:6]1)=[N+]=[N-]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[NH2:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:20]#[N:21])[CH2:18][CH2:19]3)=[C:13]([F:22])[CH:12]=2)[CH2:6]1
Reactant: N#CC1(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: N#CC1(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reaction time: 3 h

Procedure:
A suspension of 5(R)-azidomethyl-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]oxazolidin-2-one (122 mg) and Lindlar catalyst (12 mg) in methanol (5 mL) was hydrogenated at 1 atm for 3 hours at room temperature. After filtration of the catalyst, the filtrate was concentrated in vacuo to give 5(S)-aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]oxazolidin-2-one. To a solution of crude 5(S)-aminomethyl-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]oxazolidin-2-one thus obtained in dichloromethane (2 mL) was added pyridine (96 mg) and methanesulfonyl chloride (70 mg) at 0° C., and the mixture was stirred at the same temperature for 30 min. The mixture was washed with water and 5% hydrochloric acid, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, ethyl acetate) of the residue gave N-[5(S)-3-[4-(1-cyanocyclopropan-1-yl)-3-fluorophenyl]-2-oxooxazolidin-5-ylmethyl]methanesulfonylamide. MS (EI+) m/z: 353 (M+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[O:12]1[CH2:31][CH:13]1[CH2:14][O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([O:26][CH2:27][CH:28]1[O:30][CH2:29]1)=[O:25])=[O:17]>C1C=CC=CC=1>[OH:12][CH:13]([CH2:31][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]1([CH3:11])[CH3:10])[CH2:14][O:15][C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[C:24]([O:26][CH2:27][CH:28]([OH:30])[CH2:29][N:5]1[C:4]([CH3:11])([CH3:10])[CH2:3][CH:2]([OH:1])[CH2:7][C:6]1([CH3:9])[CH3:8])=[O:25])=[O:17]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: O=C(OCC1CO1)C1CCCCC1C(=O)OCC1CO1
Solvent: c1ccccc1
Product: CC1(C)CC(O)CC(C)(C)N1CC(O)COC(=O)C1CCCCC1C(=O)OCC(O)CN1C(C)(C)CC(O)CC1(C)C
Reaction time: 5 h

Procedure:
A mixture of 11.0 g of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 7.0 g of bis(2,3-epoxypropyl)1,2-cyclohexanedicarboxylate was heated, with stirring, at 170°-180° C. for 5 hours. After completion of the reaction, benzene was added to the reaction mixture and then the benzene solution was washed with water and dried over anhydrous potassium carbonate. The solvent was evaporated under reduced pressure from the benzene solution, leaving a residue, which was then purified by column chromatography through silica gel eluted with a 16:2:1:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine, giving the desired Compound No. 90 as a vitreous solid. The Compound had an Rf value of 0.32 on thin-layer chromatography on silica gel developed with a 16:2:3:1 by volume mixture of ethyl acetate, benzene, ethanol and triethylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]3[CH2:8][CH2:9][CH2:10][C:5]3=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][CH:13]=3)[CH:3]=2)[CH2:27][CH2:26]1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(Cl)nc3c2CCC3)cc1
Reactant: CN1CCNCC1
Product: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C)CC3)nc3c2CCC3)cc1
Yield: 14.9 %

Procedure:
Following general procedure B1, ethyl 2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.095 g, 0.29 mmol) was reacted with 1-methylpiperazine (0.043 g, 0.44 mmol) to afford the title compound (0.017 g, 15%) as an orange oil. MW=394.51. 1H NMR (CD3OD, 500 MHz) δ 7.15 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 6.07 (s, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.51 (s, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.46-2.38 (m, 4H), 2.21 (s, 3H), 1.99 (quin, J=7.5 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H); APCI MS m/z 395 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](C3CCCCO3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[CH:14]=[C:13]([F:15])[C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CC(F)(F)CC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1c(F)cc(O[C@H]2CC(F)(F)CC[C@@H]2c2cn[nH]c2)cc1F
Yield: 39.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,6-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.24 mmol) prepared in Example 104a, triethylsilane (0.15 mL), trifluoroacetic acid (1.5 mL), dichloromethane (1.5 mL) and methanol (1.5 mL), to yield the title compound (45 mg, 56%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([S:12][CH2:13][CH:14]([O:18]CC)OCC)[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:9]([C:10]=1[CH3:11])[CH:14]([OH:18])[CH2:13][S:12]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(SCC(OCC)OCC)[nH]c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1nc2n(c1C)C(O)CS2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(2,2-diethoxy-ethylsulfanyl)-5-methyl-1H-imidazole-4-carboxylic acid ethyl ester (10.0 mmol) in aq. HCl (15%, 8.0 mL) is stirred for 1 h at RT and neutralized by addition of aq. Na2CO3 solution. The obtained precipitate is filtered off to give the desired product which is used without further purification.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+:5].[Na+].Cl[CH2:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16].O.[Cl-].[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Na+:5].[CH3:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[CH2:8][S:1]([O-:4])(=[O:3])=[O:2]
Reactant: Cc1cccc(C)c1CCl
Reactant: O=S([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1CS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 83.8 %

Procedure:
Sodium sulfite (442.4 g) was added to a stirred mixture of 2-chloromethyl-1,3-dimethyl-benzene (526.6 g), tetrabutylammonium iodide (6.4 g) and water (3.0 L). The mixture was warmed to reflux for 1 h. As the mixture cooled to room temperature, sodium chloride (526 g) and ethyl acetate (1.4 I) were added. The mixture was stirred and cooled to <10° C. The product was collected by filtration and washed with ethyl acetate (250 mL) and acetone (500 mL). The product was dried in vacuo at 60° C. to constant weight to give (2,6-dimethyl-phenyl)-methanesulfonic acid sodium salt (634 g, 88%). 1H NMR (300 MHz, DMSOd6): δ 7.17-6.91 (m, 3H, ArH), 3.96 (s, 2H, CH2), and 2.29 (s, 6H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11](Cl)[CH:10]=[C:9]([Cl:14])[N:8]=1)[CH3:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:8]=[C:9]([Cl:14])[CH:10]=[C:11]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:12]=1)[CH3:2]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1nc(Cl)cc(Nc2ccc(OC)cc2)n1
Yield: 65.3 %

Procedure:
A stirred mixture of 5.2 g of (4,6-dichloro-2-pyrimidinylthio)acetic acid ethyl ester, 2.4 g of p-anisidine and 2.1 g of sodium carbonate in 100 ml. of ethanol was heated under reflux for 6 hr. The reaction mixture was filtered and the filtrate cooled in ice. A crystalline material was deposited which was purified by recrystallization from ethanol. There was obtained 4.5 g of product, mp. 96°-97.5°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[N:24][N:23]=2)=[C:20]2[C:15]([N:16]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:17](=[O:29])[NH:18][C:19]2=[O:28])=[N:14]1.Br[CH2:35][C:36]#[N:37]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[N:24][N:23]=2)=[C:20]2[C:15]([N:16]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:17](=[O:29])[N:18]([CH2:35][C:36]#[N:37])[C:19]2=[O:28])=[N:14]1
Reactant: N#CCBr
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3nncn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Product: CC(C)Cn1c(=O)n(CC#N)c(=O)c2c(-c3nncn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made by alkylation of 2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione with bromoacetonitrile following conditions in Example 6.d. 504.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[CH2:7][O:6][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][C@H:15]4[O:41]C(OC)=O)[CH2:12][CH2:11]2)[CH3:9])[O:4][CH2:3]1.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H]([C@H]4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3OC(OC)=O)=C[C@H]4OC(OC)=O)CC2)C)OC1>>[CH3:46][C:2]1([CH3:1])[CH2:3][O:4][CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:20][C@@H:21]3[O:29][CH2:30][O:31][CH3:32])=[CH:16][C@H:15]4[OH:41])[CH2:12][CH2:11]2)[CH3:9])[O:6][CH2:7]1
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: COC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 59.3 %

Procedure:
The reaction and workup procedures of Example 140 were repeated except that 120 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxy-7α-(methoxycarbonyl)oxypregn-5 -ene was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3 -dioxan-2-yl)-1α,3β,7α-tris (methoxycarbonyloxy)pregn-5-ene to give 65 mg of 20-(5,5-dimethyl-1,3-dioxan-2yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5-en-7α-ol showing the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][OH:29])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)cn2CCO[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(F)c3)cn2CCO)CC1
Yield: 24.5 %

Procedure:
Combine 4-[1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-4-(3,4-difluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (18.3 g; 0.035 mol; 1.0 equiv), tetrabutylammonium fluoride (20.3 g; 0.07 mol; 2.0 equiv) in THF (100 mL) and stir at RT for 3 h. Concentrate, quench the reaction with water and extract with EA. Evaporate the organic layer to give the title compound (3.5 g; 24.49%). MS (ES+): m/z=408(M+H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][NH:7][C:8]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9].[CH3:31]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:1][C:2]([F:29])([F:30])[C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:6][N:7]([CH3:31])[C:8]([C:10]1[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: CN(C)C=O
Reactant: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: ClCCl
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1ccccc1-c1ccccc1
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 0.63 g (1.50 mmol) biphenyl-2-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 10 ml N,N-dimethylformamide 0.08 g (1.98 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture was stirred for 1 hr. After the addition of 0.15 ml (2.4 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 50 ml H2O, 50 ml brine and 50 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/CH2Cl2 15:1) to give 0.50 g (76%) biphenyl-2-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as colorless solid, m.p. 97-88°.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].C(=O)([O-])[O-].[K+].[K+].[NH2:11][C:12]1[C:16]([C:17]#[N:18])=[C:15]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20]2)[N:14]([CH2:33][C:34]2[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=2[Cl:41])[C:13]=1[C:42]([O:44]CC)=O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[Cl:41][C:35]1[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:34]=1[CH2:33][N:14]1[C:13]2[C:42](=[O:44])[N:2]([CH3:1])[C:3](=[S:4])[NH:11][C:12]=2[C:16]([C:17]#[N:18])=[C:15]1[N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:20]1
Reactant: CN=C=S
Reactant: CCOC(=O)c1c(N)c(C#N)c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n1Cc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cn1c(=S)[nH]c2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3cc(F)ccc3Cl)c2c1=O
Temperature: 130 °C

Procedure:
Methyl isothiocyanate (7.36 ml) and potassium carbonate (14.86 g) were added to a solution (200 ml) of ethyl 3-amino-5-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chloro-5-fluorobenzyl)-4-cyano-1H-pyrrole-2-carboxylate (27.96 g) in pyridine, and the resulting mixture was stirred with heating at 130° C. for 13 hours. After the reaction solution was cooled to 25° C., toluene (50 ml) was added thereto and the resulting mixture was concentrated under reduced pressure. This procedure was repeated three times. The resulting residue was adjusted to pH 2 with an aqueous potassium hydrogensulfate solution and the solid precipitated was collected by filtration and washed with water and then hexane. The solid thus obtained was dried at 45° C. under reduced pressure to obtain the title compound (28.56 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])=[CH:21][CH:20]=1)([CH3:24])[CH3:23]
Reactant: CC(C)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(NC(=O)C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
4-(4-Isopropyl-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.68 g) was dissolved in methylene chloride (50 ml), trifluoroacetic acid (2.75 g) was added at 0° C. and under an argon atmosphere and the mixture was stirred for 12 h at RT. Further trifluoroacetic acid (1.1 g) was added and stirring was continued for 1.5 h to complete the reaction. The reaction mixture was partitioned between methylene chloride and aqueous 1M NaOH, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue was triturated with diethyl ether/heptane to give the desired piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (1 g) as a white solid that was directly used in the next step.