Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[Cl:21][C:11]([C:10]1[CH:9]=[C:8]([CH:16]=[CH:15][CH:14]=1)[CH2:7][S:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:17])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)CCSCc1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Into a 50-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-((3-methoxy-3-oxopropylthio)methyl)benzoic acid (61.6 mg, 0.24 mmol, 1.00 equiv) in dichloromethane (5 mL). This was followed by dropwise addition of oxalyl dichloride (121.76 mg, 0.96 mmol, 4.00 equiv) with stirring at room temperature. Then a few drops of N,N-dimethylformamide were added as catalyst. The resulting solution was heated to reflux for 30 min. The resulting mixture was concentrated under vacuum to yield 60 mg (crude) of methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate as yellow oil. The crude was used directly in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1)=O.[O:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:17][C:16]([F:19])([F:18])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3](/[CH:1]=[C:24]2/[C:23](=[O:25])[NH:22][C:21](=[O:26])[O:20]/2)[CH:4]=1
Reactant: O=Cc1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: O=C1COC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cccc(-c3ccccc3OC(F)(F)F)c2)O1

Procedure:
The title compound was prepared by reacting 3-formyl-(2′-trifluoromethoxy-1,1′-biphenyl) (from Example 56, Step A) with 2,4-oxazolidinedione in toluene in the presence of piperidine and benzoic acid as described in Example 56, Step B.
Reaction SMILES: [CH3:1][OH:2].[Na].C[O-].[Na+].[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1>CN(C=O)C>[Br:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([O:2][CH3:1])[CH:13]=1
Reactant: CO
Reactant: Brc1cncc(Br)c1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 70 °C
Yield: 62 %

Procedure:
A solution of methanol (180 mL) was treated with sodium spheres (4.7 g, 0.20 mol) portionwise, evaporated to dryness, azeotroped with toluene (100 mL), and then concentrated under reduced pressure. The sodium methoxide in dry DMF (130 mL) was treated with 3,5-dibromopyridine (32 g, 135 mmol), from Avocado Chemicals. After heating at 70° C. for 4 hours, the mixture was poured onto ice/water (300 g) and filtered. The filter cake was dried under reduced pressure to provide the title compound (15.6 g, 62% yield). MS (DCI/NH3) m/z 188/190 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[B:10](OC)([O:13]C)[O:11]C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:13])[OH:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(F)c1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
In a separate reaction vessel, 40 mL of tetrahydrofuran was cooled to -78 ° C., and the Grignard reagent of 3,5-difluorophenyl bromide and a solution of 11.3 grams (0.109 mole) of trimethyl borate in 15 mL of tetrahydrofuran were added simultaneously dropwise in an effort to provide an equimolar addition of each. An additional 115 mL of tetrahydrofuran was added during the additions to dilute the thickening reaction mixture. The completion of additions required about 15 minutes. After this time the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. The reaction mixture was then poured into 300 mL of an aqueous dilute solution of hydrochloric acid. The resultant mixture was extracted with two 150 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 13.6 grams of 3,5-difluoro-phenylboronic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:22]1([CH2:28]C#N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]4[C:15]([CH:14]=3)=[C:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:20][N:19]=4)[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: N#CCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1ccc(C2(c3ccc4noc(-c5ccccc5)c4c3)OCCO2)cc1
Yield: 16.3 %

Procedure:
2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (prepared as described in WO 97/21701) (0.0373 mol) was added to a vigorously stirring mixture of benzene acetonitrile (0.041 mol) and NaOH (0.186 mol) in methanol (37.3 ml) (an exothermic effect was observed and the temperature rose to 45° C.) and the mixture was stirred vigorously for 20 h. The mixture was diluted with water and filtered off. The precipitate was washed with water and a few methanol and dried. A part (3.5 g) of the residue (10.59 g, 75%) was purified by column chromatography over silica gel (eluent: DCM). The pure fractions were collected and evaporated. The residue (2.94 g) was crystallized from DIPE, yielding 2.3 g of 5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-3-phenyl-2,1-benzisoxazole, mp. 143.4° C. (intermediate 23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](Cl)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][O-:13].[Na+].Cl>CN(P(N(C)C)(N(C)C)=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C[O-]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(Cl)cc(C(=O)O)c1
Temperature: 170 °C
Yield: 75 %

Procedure:
To a solution of 3,5-dichlorobenzoic acid (1.91 g, 10 mmol, 1.0 equiv.) in 10 mL of HMPA was added NaOMe (1.62 g, 30 mmol, 3.0 equiv.). The mixture was heated in a 170° C. oil bath for 72 h. After cooling to room temperature, the mixture was poured into 50 mL of 1 M aqueous HCl. The precipitates were collected by filtration, and washed twice with 20 mL of water. The white solid was dried under vacuum to give 1.4 g of 38a. 1H-NMR (DMSO-d6): δ 14.0 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 3.82 (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:23]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].O>CN(C=O)C>[CH2:1]([N:8]([C:23]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26])[S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccccc2)cc1
Reactant: N#Cc1cccc(C(F)(F)F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C#N)cccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
To a solution of 3.05 g (11.0 mmol) of the product of Example 121 in 15 mL of DMF was added 0.484 g (12.1 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperature and then 1.89 g (10.0 mmol) of 2-fluoro-3-(trifluoromethyl)benzonitrile in 2 mL of DMF was added. The reaction mixture was stirred at 90° C. for 18 hr, poured into water and extracted with ether. The combined organics were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude solid was triturated with ether to provide 3.33 g (75%) of the desired product as a white solid. Electrospray Mass Spec 447.2(M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[CH2:4][NH:5][C:6](=[O:10])[O:7][CH2:8][CH3:9].[H-].[Na+].Br[CH2:16][CH:17]=[CH:18][CH3:19].O>C1(C)C=CC=CC=1>[CH2:16]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:11][CH3:12])[C:6](=[O:10])[O:7][CH2:8][CH3:9])[CH:17]=[CH:18][CH3:19]
Reactant: CC=CCBr
Reactant: CCOC(=O)NCC(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC=CCN(CC(OC)OC)C(=O)OCC
Reaction time: 1 h

Procedure:
89 g (0.5 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate are added dropwise to 17.5 g (0.58 mol) of NaH (80% strength in paraffin oil) in 500 ml of absolute toluene at 80° C. The mixture is then stirred for one hour and 80 g (0.59 mol) of 1-bromo-2-butene are subsequently added dropwise at 80° C. The mixture is stirred at 80° C. overnight and cooled, the salts are dissolved with water and the aqueous phase is separated off and extracted with toluene. The toluene solutions are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[C:2]([NH:1][C:39]3[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=4[N:35]=[CH:36][N:37]=3)[CH:3]=2)=[CH:9][CH:10]=1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Oc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Oc3ccc(O)cc3)ncnc2n1
Yield: 49 %

Procedure:
The product of Example 37C was reacted with the product of Example 9B using the procedure of Example 37D substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (42 mg, 49%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.66 (s, 3 H) 6.75 (d, J=8.82 Hz, 2 H) 6.89 (t, J=8.27 Hz, 3 H) 7.53 (d, J=8.82 Hz, 3 H) 7.75 (d, J=9.19 Hz, 2 H) 7.86 (dd, J=8.64, 1.65 Hz, 1 H) 8.18 (d, J=1.47 Hz, 1 H) 8.61 (s, 1 H) 8.77 (d, J=8.46 Hz, 1 H) 9.39 (s, 1 H) 10.00 (s, 1 H) 10.30 (s, 1 H); MS (ESI+) m/z 542/544 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].Cl>O.CN(C)C(=O)C>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([C:31]2[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: N#Cc1ccc([C@@H](N)CC(=O)O)cc1
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1ccc([C@H](CC(=O)O)NC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)cc1
Temperature: 150 °C
Yield: 90 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.156 mmol) was combined in an oven-dried flask with 3-(S)-Amino-3-(4-cyano-phenyl)-propionic acid (92 mg, 0.468 mmol) (commercially available from Combi-Blocks SS-1849) and N,N-dimethylacetamide (1.5 mL) was added with stirring. Solid sodium methoxide (25 mg, 0.468 mmol) was added and the reaction was heated to 150° C. in an oil bath for approximately five hours. The reaction was cooled and the solution diluted with five volumes of water. The solution was acidified to pH 3 with 1M hydrochloric acid to induce precipitation. Filtration of the solid followed by vacuum drying provided the desired product in 90% yield. LC-MS ESI−: 477 (M−1)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:35])[CH2:29][C:30]([O:32]CC)=[O:31])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:5]([NH:27][C:28](=[O:35])[CH2:29][C:30]([OH:32])=[O:31])[CH:4]=[N:3]1
Reactant: CCOC(=O)CC(=O)Nc1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1ncc(NC(=O)CC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a stirred solution of ethyl 3-{[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}-3-oxopropanoate (1.3 g) in tetrahydrofuran (30 ml) was added 1N aqueous sodium hydroxide solution (3.1 ml) and the mixture was stirred at room temperature for 3 hours. Tetrahydrofuran was removed in vacuo and the residue was made acidic with diluted aqueous citric acid solution. The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-{[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}-3-oxopropanoic acid (1.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].[F:11][C:12]([F:16])([F:15])CI.[F-].[Cs+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][C:12]([F:16])([F:15])[F:11]
Reactant: Oc1cc(F)c(F)cc1Br
Reactant: FC(F)(F)CI
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CS(C)=O
Product: Fc1cc(Br)c(OC(F)(F)F)cc1F
Temperature: 120 °C
Yield: 52.4 %

Procedure:
A mixture of 2-bromo-4,5-difluoro-phenol (1.0 g, 4.8 mmol), 1,1,1-trifluoro-2-iodo-ethane (706 mg, 7.2 mmol) and CsF (882 mg, 5.8 mmol) in DMSO (20 mL) was heated at 120° C. overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (10:1) to give the title compound (697 mg, 50%). 1HNMR (500 MHz, CDCl3) δ ppm 4.36 (q, J=7.93 Hz, 2 H) 6.85 (dd, J=10.98, 7.02 Hz, 1 H) 7.43 (t, J=8.85 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[OH:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:10]([CH3:11])=[O:12])=[CH:4][C:3]=1[OH:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c(O)c1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Cl)c(O)c1
Temperature: 70 °C

Procedure:
0.05 Mole (7.17 grams) of 2-chloro-5-aminophenol is dissolved in 21 cc of dioxane at 75°C. There is then added, with agitation, 0.05 mole (5.1 grams) of acetic anhydride. At the end of this addition, the reaction medium is maintained for 10 minutes at 70°C and then cooled. The raw product which has crystallized in then filtered and recrystallized in a hydroalcoholic medium. It exhibits a melting point of 212°C.
Reaction SMILES: [P:1]([O:5][CH2:6][C@@H:7]1[C@@H:11]([O:12][P:13]([O:16][CH2:17][C@@H:18]2[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([N:25]3[CH:33]=[N:32][C:31]4[C:26]3=[N:27][CH:28]=[N:29][C:30]=4[NH2:34])[O:19]2)([OH:15])=[O:14])[CH2:10][C@H:9]([N:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][C:36]2=[O:42])[O:8]1)([OH:4])([OH:3])=[O:2].C([N+](CCCC)(CCCC)CCCC)CCC.P(OC[C@@H]1[C@@H](OP(OC[C@@H]2[C@@H](O)[C@@H](O)[C@H](N3C=NC4C3=NC=NC=4N)O2)(O)=O)C[C@H](N2C=CC(N)=NC2=O)O1)(O)(O)=O.[CH3:102][N:103]([CH2:110][C:111](OCC#N)=[O:112])[C:104](=[O:109])[CH2:105][CH2:106][CH:107]=[CH2:108]>O1CCCC1>[CH3:102][N:103]([CH2:110][C:111]([O:23][C@H:22]1[C@@H:21]([OH:24])[C@H:20]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[O:19][C@@H:18]1[CH2:17][O:16][P:13]([O:12][C@H:11]1[CH2:10][C@H:9]([N:35]2[CH:40]=[CH:39][C:38]([NH2:41])=[N:37][C:36]2=[O:42])[O:8][C@@H:7]1[CH2:6][O:5][P:1]([OH:4])([OH:3])=[O:2])([OH:15])=[O:14])=[O:112])[C:104](=[O:109])[CH2:105][CH2:106][CH:107]=[CH2:108]
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: C=CCCC(=O)N(C)CC(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N(C)CC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (Compound 1h) (1.00 g, 1.57 mmol) was dissolved in buffer A (1 l), a solution of cyanomethyl 2-(N-methylpent-4-enamido)acetate (Compound SP704) (2.00 g, 9.51 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction solution was lyophilized, and the resulting residue was purified by reverse-phase silica gel column chromatography (0.5% aqueous trifluoroacetic acid solution/acetonitrile) to afford the title compound (Compound SP705) (139 mg, 11%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:34])(=O)[CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[CH2:35]([NH2:41])[CH2:36][O:37][CH2:38][CH2:39][OH:40].[Cl-].[NH4+]>ClCCCl>[OH:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][NH:41][C:13](=[O:34])[CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC#CCC#CCC#CCSCC(=O)O
Reactant: NCCOCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: CCCCCCCCC#CCC#CCC#CCSCC(=O)NCCOCCO
Temperature: 25 °C
Yield: 74.1 %

Procedure:
3 g of carbonyldiimidazole are added to a solution of 3.18 g of 3-thia-5,8,11-eicosatriynoic acid in 50 cm3 of 1,2-dichloroethane, stirred at ambient temperature under an inert atmosphere. The mixture thus obtained is heated to a temperature of between 40° and 50° C. for 3 hours. The solution is then cooled to about 10° C. and 2.10 g of diglycolamine are added. 2 hours after the end of the introduction, the reaction mixture is poured into a saturated solution of ammonium chloride. The organic phase is separated off, washed with water, then dried over magnesium sulphate and finally treated with animal charcoal. The solvent is removed by evaporation under vacuum. The product obtained crystallizes on cooling. It is recrystallized from isopropyl ether. 3 g of N[(2-hydroxyethyl) oxyethyl]-3-thia-5,8,11-eicosatriynamide are thus isolated in the form of cream-white crystals having a melting point of 56° C. Elemental analysis: C23H35NO3S
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH2:16][C:17]([O:20][Si](C(C)(C)C)(C)C)([CH3:19])[CH3:18])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH:38]2[CH2:43][C:42]([CH3:45])([CH3:44])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]2)[N:32]=1>N1C=CC=CC=1>[CH3:19][C:17]([OH:20])([CH2:16][CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([C:8]([C:35]3[CH:36]=[CH:31][N:32]=[C:33]([NH:37][CH:38]4[CH2:43][C:42]([CH3:45])([CH3:44])[NH:41][C:40]([CH3:47])([CH3:46])[CH2:39]4)[N:34]=3)=[CH:7][NH:6]2)=[CH:10][CH:11]=1)[CH3:18]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CC(C)(CCc1ccc2ccn([Si](C)(C)C(C)(C)C)c2c1)O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Product: CC(C)(O)CCc1ccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c2c1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-6-[3-(tert-butyl-dimethyl-silanyloxy)-3-methyl-butyl]-1H-indole (prepared by Raney-Nickel hydrogenation of (E)-3-(1H-Indol-6-yl)-acrylic acid methyl ester, followed by reaction with MeMgBr (Step A of Method A) and TBDMS protection according to standard procedures) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the TBDMS protecting groups with HF in pyridine. Yield: 57 mg (17%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30].[CH3:34]I.Cl>CN(C)C=O>[CH3:34][N:27]([C:5]1[CH:6]=[C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:16])[F:17])[O:12][N:11]=2)[CH:8]=[CH:9][C:4]=1[Cl:3])[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: O=C(Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl)C(F)(F)F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
Sodium hydride (60% oily) was suspended in N,N-dimethylformamide (15 mL), and thereto was added dropwise a solution of {N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.6 g) obtained by Reference Production Example 24 in N,N-dimethylformamide (15 mL) at room temperature, and then the mixture was stirred at the same temperature for 20 minutes. To the mixture was added methyl iodide (1.52 g), and the mixture was further stirred for 1 hour. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-methyl-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.73 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH2:24][CH3:25]>CN1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH3:25]
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: CCI
Agent: CN1CCCC1
Solvent: CCOC(C)=O
Product: CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Yield: 39.7 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 153 mg, 0.5 mmol) and iodoethane (0.21 mL, 2.6 mmol) in N-methylpyrrolidine (1 mL) was heated at 100° C. in a sealed tube for 17 h. The reaction mixture was purified by preparative HPLC to give a brown semi-solid which was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium thiosulfate (three times) and brine, dried (sodium sulfate), filtered, evaporated, and dried under high vacuum to give (4R,7S)-2-(2,4-difluoro-phenyl)-1-ethyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (66 mg, 39%) as a pale yellow foam. ES(+)-MS (M+H) 333.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]([S:25]([CH3:24])(=[O:27])=[O:26])[C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CNC(=O)N1c1cccc(I)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC(=O)N(c2cccc(I)c2)C1=O

Procedure:
A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (950 mg) and N,N-diisopropylethylamine (1.1 ml) in DCM (20 ml) was treated with methanesulfonyl chloride (0.453 ml) at 20° C. After 2 h the reaction mixture was diluted with DCM and washed with aqueous 2M HCl (3×20 ml) and NaHCO3 and dried (MgSO4). The solvent was removed under reduced pressure to give the title compound (1.15 g). LCMS RT=2.91 min.