Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][CH:14]=1)=O)(C)(C)C.[ClH:25].C(OCC)C>O1CCOCC1>[ClH:25].[CH3:24][O:23][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:14][CH:15]=1
Reactant: COC(=O)/C=C/c1ccc([C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc([C@@H]2CCCN2)cc1
Reaction time: 16 h
Yield: 94 %

Procedure:
To a stirred solution of (S)-2-[4-((E)-2-methoxycarbonyl-vinyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (40.2 g, 115 mmol) was added 120 mL of 4 N hydrochloric acid in dioxane and the reaction mixture was stirred for 16 h. Diethyl ether (500 mL) was added to the suspension and the resulting solid was filtered and washed twice with diethyl ether to yield 29.0 g (94%) of the title compound as a white solid.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=O)C(C)(C)C.C([O:45][CH2:46][C@@H:47]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])[C:48]1[C:49]([C:67]2[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([C:59]#[C:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH:52]=[CH:51]2)(=O)C(C)(C)C>>[C:75]([O:74][C@@H:47]([C:48]1[C:49]([C:67]2[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=2)=[C:50]2[C:55](=[CH:56][C:57]=1[CH3:58])[N:54]=[C:53]([C:59]#[C:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH:52]=[CH:51]2)[CH2:46][OH:45])([CH3:78])([CH3:76])[CH3:77]
Reactant: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(C#Cc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)ethanol (12 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol of Example 29 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(phenylethynyl)quinolin-6-yl)ethyl pivalate instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H29ClNO2: 470.2. Found: 470.2.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:21])(=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:8][CH:7]=1)C.[OH-].[K+]>C(O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][S:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:22])=[O:3])=[CH:7][CH:8]=1)(=[O:20])=[O:21]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Yield: 65.2 %

Procedure:
A solution of [4-(pyridin-2-ylsulfamoyl)-phenyl]-acetic acid ethyl ester (0.26 g, 0.813 mmol) in absolute ethanol (10 mL) was treated with a 1.0M ethanolic potassium hydroxide solution (2.0 mL, 2.0 mmol). The reaction mixture was heated to reflux under argon for 3.5 h. The reaction mixture was then concentrated in vacuo. The residue was dissolved in water and filtered through celite. The filtrate was acidified to pH=4.5 with a 1.0M aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to afford [4-(pyridin-2-ylsulfamoyl)-phenyl]-acetic acid (155 mg, 65%) as an off white solid; 1H NMR (DMSO-d6, 300 MHz) δH 12.26 (broad s, 1H), 7.96 (d, J=4.4 Hz, 1H), 7.77 (d, J=7.7 Hz, 2H), 7.80 (t, J=7.5 Hz, 1H), 7.37 (d, J=7.7 Hz, 2H), 7.13 (d, J=8.8 Hz, 1H), 6.82 (broad s, 1H), 3.62 (s, 2H); LRMS for C13H12N2O4S (M+H)+ at m/z=293.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([F:10])=[CH:5][N:4]=1.[CH3:11][NH2:12].C(Cl)Cl.CO.N>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:12][CH3:11])[C:6]([F:10])=[CH:5][N:4]=1
Reactant: CSc1ncc(F)c(Cl)n1
Reactant: CN
Agent: N
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CNc1nc(SC)ncc1F

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-fluoro-pyrimidine by reacting with methylamine in ethanol at 100° C., Rf value: 0.53 (silica gel; methylene chloride/methanol/conc. aqueous ammonia=20:1:0.1)
Reaction SMILES: CC(CCCCCCCCCCCCC(NCC(NC1C(C(O)CO)OC([NH:33][C:34]2[C:39]3[NH:40][CH:41]=[N:42][C:38]=3[N:37]=[CH:36][N:35]=2)C(O)C1O)=O)=O)C.Cl>>[N:35]1[C:34]([NH2:33])=[C:39]2[C:38]([N:42]=[CH:41][NH:40]2)=[N:37][CH:36]=1
Reactant: CC(C)CCCCCCCCCCCCC(=O)NCC(=O)NC1C(O)C(O)C(Nc2ncnc3nc[nH]c23)OC1C(O)CO
Agent: Cl
Product: Nc1ncnc2nc[nH]c12

Procedure:
By hydrolyzing Spicamycin in an aqueous solution of 1N HCl at 100° C. for one hour, adenine, an unknown amino sugar, and an acidic substance can be obtained. By further hydrolyzing this acidic substance in an aqueous solution of 6N HCl at 110° C. for 48 hours, glycine and a mixture of saturated fatty acids can be obtained. The mixture of saturated fatty acids thus obtained was methylated with diazomethane and analyzed by means of gas chromatography-mass spectrometry (1.5% Silicone-OV-1/Shimalite W 170° C.), whereupon this mixture was found to comprise fatty acids represented by (CH3)2CH(CH2)nCOOH (n=8-14) or CH3 (CH2)mCOOH (m=10-16), typically iso-palmitic acid and isomargaric acid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28]CC4C=CC=CC=4)=[C:21]([C:36]#[N:37])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]>CO.[Pd]>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][OH:28])=[C:21]([C:36]#[N:37])[CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(OCCOCc4ccccc4)c(C#N)c3)cc3ccccc23)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(OCCO)c(C#N)c3)cc3ccccc23)CC1
Yield: 68.5 %

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-[3-cyano-4-(2-benzyloxyethoxy)phenyl]isoquinoline (0.50 g) was dissolved in methanol (20 ml), followed by the hydrogenation in the presence of 10% palladium/carbon catalyst (0.05 g) at room temperature. After the catalyst was filtered off and washed with methanol, the resulting filtrate was concentrated, to give 0.28 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl-].Cl[CH2:3][CH2:4][NH3+:5].[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]=[S:18]>>[CH3:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]=[C:17]1[NH:5][CH2:4][CH2:3][S:18]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: [NH3+]CCCl
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1

Procedure:
2-Chloroethylammonium chloride (Entry 1) was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine, which was reacted with 5-(bromomethyl)bicyclo[2.2.1]hept-2-ene according to Method D2a to give 2-(4-nitrophenylimino)-3-((bicyclo[2.2.1]hept-2-en-5-yl)methyl)-1,3 -thiazolidine.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-:20].[K+]>C(O)(C)(C)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:20])=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCC3=O)cc1
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)cc1
Yield: 5.8 %

Procedure:
Combine 4-(1-Oxo-indan-5-yloxy)-benzonitrile (1.64 g, 6.58 mmol), tert-butyl alcohol (50 ml), and grounded KOH (1.85 g, 32.89 mmol) at room temperature under nitrogen atmosphere. Stir the reaction for 24 hours then concentrate under reduced pressure. Add Ethyl acetate to the reaction mixture and wash with brine. Dry the organic layer over Na2SO4. A yellow-mange solid precipitates out to afford 101.0 mg, 0.38 mmol (5.7% yield) of the title compound: No Characterization—Characterized by sequential reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[N:12]([C:14](OC(C)(C)C)=O)[CH:13]=2)[O:3]1.Cl.[H-].[Na+].CI>C(Cl)Cl.O1CCOCC1>[CH3:14][N:12]1[CH:13]=[C:9]([B:4]2[O:3][C:2]([CH3:1])([CH3:31])[C:6]([CH3:8])([CH3:7])[O:5]2)[CH:10]=[C:11]1[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CI
Solvent: C1COCCO1
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Benzyl 1-tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate (0.5 g) was dissolved in CH2Cl2 (1 mL) and then 4 N HCl in dioxane (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was redissolved in DMF (4 mL). To the resulting solution was added NaH (60% dispersion in mineral oil, 0.08 g, 2.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. Methyl iodide (0.11 mL, 2.0 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with sat. NH4Cl solution and then diluted with EtOAc. After separation of layers, the organic phase was washed with water (twice) and brine; dried over Na2SO4. The solvent was removed to provide the desired crude product which was used in the next step without further purification. LCMS calculated for C19H25BNO4 (M+H)+: m/z=342.2. found: 342.2.
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[N:11](C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:9]1[N:4]2[N:3]=[C:2]([NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc2nc(N)nn12
Product: O=C(Nc1nc2cccc(-c3ccc[nH]3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure and work up described for example 9, but starting from tert-butyl 2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and benzoyl chloride (47 mg; 0.33 mmol; 2.0 eq.) as a white solid (22.7 mg, 45%). HPLC, Rt: 3.23 min. (purity 91.6%). LC/MS, M+(ESI): 304.3, M−(ESI): 302.3.
Reaction SMILES: [C:1](Cl)(Cl)=O.[CH:5]1[C:10]([N+]([O-])=O)=CC=C([Cl-]C([O-])=O)[CH:6]=1.[N:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>>[CH:5]([N:18]([CH:19]([CH3:20])[CH3:1])[CH2:23][CH3:22])([CH3:10])[CH3:6]
Reactant: c1ccncc1
Reactant: O=C(Cl)Cl
Product: CCN(C(C)C)C(C)C

Procedure:
In the second preferred activating procedure, the T-CA is treated with a phosgene equivalent (approx. 1.1 equivalent), e.g., 4-nitrophenylchloroformate, and a tertiary amine (approx. 1.1 equivalent), e.g., diisopropylethylamine, in an aprotic solvent, e.g., pyridine, at between 0° and 25° C. for between 10 min and 2 hrs to give the active T-CA linker.
Reaction SMILES: C([O:3][C:4](=[O:10])[CH2:5][C@H:6]([NH2:9])[CH2:7][CH3:8])C.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu](I)I.C(OCC)(=O)C.O.CN(C)C=O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([NH:9][C@H:6]([CH2:7][CH3:8])[CH2:5][C:4]([OH:3])=[O:10])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C[C@H](N)CC
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: I[Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](CC(=O)O)Nc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 40.3 %

Procedure:
(R)-3-Aminovaleric acid ethyl ester (0.5 g), 4-bromobenzotrifluoride (0.62 g), copper iodide (0.053 g), potassium carbonate (1.14 g) and water (0.5 ml) were added to dimethylformamide (5 ml) and the mixture was sealed under nitrogen atmosphere and stirred at 100° C. for 3 days. The mixture was cooled, water and ethyl acetate were added to the mixture, and the pH of the mixture was adjusted to about 3 or less with addition of 2N HCl. The organic layer was separated, dried over magnesium sulfate and concentrated at reduced pressure. The resulting residue was purified by column chromatography to give the titled compound (0.29 g, yield 40.3%). MS (APCI) m/z: 262 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].C1CCCCC1>CCOCC>[NH2:2][CH2:1][C:3]1([OH:13])[CH:4]2[CH2:12][CH:8]3[CH2:7][CH:6]([CH2:11][CH:10]1[CH2:9]3)[CH2:5]2
Reactant: N#CC1(O)C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CCOCC
Product: NCC1(O)C2CC3CC(C2)CC1C3
Yield: 75.4 %

Procedure:
A solution of 2-cyanoadamantan-2-ol (6.0 grams, 0.03 mol) in ether was added to a suspension of lithium aluminum hydride (3.9 grams, 0.13 mol) in ether. The reaction mixture was refluxed for 6 hours. Following workup, 4.10 grams of 2-aminomethyl-2-hydroxyadamantane were obtained as white crystals, melting point 154°-156° C. (cyclohexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[F:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[F:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 59 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(3,4-difluorophenyl)piperidine-1-carbonyl]-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (57 mg, 0.11 mmol) obtained in step 4 and ethanesulfonamide (58 mg, 0.55 mmol), the title compound (39 mg, 59%) was obtained.
Reaction SMILES: [F:1][C:2]([F:26])([C:10]([F:25])([F:24])[C:11]([F:23])([F:22])[C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.O>N1C=CC=CC=1>[S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:26])([F:1])[C:10]([F:24])([F:25])[C:11]([F:22])([F:23])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])(=[O:35])=[O:34]
Reactant: OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 3 h

Procedure:
2.76 ml of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecan-1-ol is dissolved in 20 ml of absolute pyridine, mixed at 0° C. with 2.48 g of p-toluenesulfonyl chloride and stirred for 3 hours under cold conditions. Then, the reaction mixture is stirred into water, extracted with dichloromethane, dried on magnesium sulfate and concentrated by evaporation in a vacuum. Column-chromatographic purification on silica gel with a hexane-ethyl acetate gradient yields 4.33 g of 7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl tosylate as a clear oil.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][C@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@H:17]([NH:16][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:18]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: O=C(O)c1cc2cccc(Br)c2o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cccc(Br)c2o1

Procedure:
4.0 g (16.59 mmol) of 7-bromobenzofuran-2-carboxylic acid (Example 29A), 3.3 g (16.59 mmol) of (S)-3-aminoquinuclidine dihydrochloride, 7.57 g (19.91 mmol) of HATU, 10.41 ml (59.74 mmol) of N,N-diisopropylethylamine and 21 ml of DMF are reacted by general method C. The solvent is removed under reduced pressure, and the crude product is taken up in 100 ml of ethyl acetate and washed 15 times with a total of 1.5 1 of 1N sodium hydroxide solution. The organic phase is dried over magnesium sulphate and freed of solvent. 5.0 g (85% of theory) of the title compound are isolated.
Reaction SMILES: [ClH:1].C([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C:18]1[N:19]([CH3:31])[C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH3:30])[CH:21]=2)(=O)C>>[ClH:1].[NH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[C:18]1[N:19]([CH3:31])[C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([O:27][CH3:28])=[C:22]([O:29][CH3:30])[CH:21]=2
Reactant: COc1cc(CCNC(C)=O)c(-c2cc3cc(OC)c(OC)cc3n2C)cc1OC
Agent: Cl
Product: COc1cc(CCN)c(-c2cc3cc(OC)c(OC)cc3n2C)cc1OC

Procedure:
A 2N hydrochloric acid solution of 53.0 g of 2-[2-(2-acetamidoethyl)-4,5-dimethoxyphenyl]-5,6-dimethoxy-1-methylindole was heated under reflux for 17 hours. The reaction mixture was azeotropically distilled under reduced pressure with ethanol and benzene, and the residue was recrystallized from ethanol to yield 48 g of the title compound.
Reaction SMILES: CC(OC([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([B:19]([OH:21])[OH:20])[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)C.[ClH:22]>O1CCOCC1.C(OCC)C>[ClH:22].[O:11]1[C:12]2[CH:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][C:13]=2[CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: OB(O)c1ccc2c(c1)CNCCO2
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 95 %

Procedure:
(4-{[(1,1-dimethylethyl)oxycarbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (Example 1, step 2) (1.07 g, 3.64 mmol) was dissolved into 4M hydrogen chloride in dioxane and the resulting solution was allowed to stir at room temperature for 1.3 h. The heterogeneous mixture was then diluted with ethyl ether (100 mL) and the solid collected by filtration to give 2,3,4,5-tetrahydro-1,4-benzoxazepin-7-ylboronic acid hydrochloride salt (791 mg, 95%). 1H NMR (400 MHz, D2O): 7.79 (dd, 1H), 7.74 (d, 1H), 7.21 (d, 1H), 4.47 (s, 2H), 4.36 (m, 2H), 3.69 (m, 2H).
Reaction SMILES: [H-].[Na+].[CH:3]([Si:6]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2)([CH3:5])[CH3:4].Cl[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=1>CN(C=O)C>[CH3:31][S:30][C:26]1[N:27]=[C:28]([N:12]2[C:13]3[C:9](=[C:8]([O:7][Si:6]([CH:3]([CH3:5])[CH3:4])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)[CH:29]=[CH:24][N:25]=1
Reactant: CC(C)[Si](Oc1cccc2[nH]ccc12)(C(C)C)C(C)C
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ccc3c(O[Si](C(C)C)(C(C)C)C(C)C)cccc32)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (1.826 g) was added to DMF (400 mL) and cooled to 0° C. 4-(Triisopropyl-silyloxy)-1H-indole (12 g) was added portionwise at 0° C., and allowed to stir at 0° C. for 1 h. 4-Chloro-2-methylsulfanyl-pyrimidine (5.28 mL) was added dropwise, and the reaction mixture stirred at 0° C. for 4 h and then quenched with water. The aqueous layer was acidified with 1N HCl. The organic layer was extracted into DCM, and dried over sodium sulfate, filtered and the filtrate was concentrated and purified on a column with 100% hexane to 25% EtOAc/hexane to yield 1-(2-methylsulfanyl-pyrimidin-4-yl)-4-triisopropylsilanyloxy-1H-indole (11 g).
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10][C:9]=3[C:8]=2[C:27]#[N:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1C[O:34]CC1>>[O:34]=[C:10]1[C:9]2[C:8]([C:27]#[N:28])=[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2cc(N3CCCCC3)c(C#N)c3c2-c2ccccc2C3=O)cc1
Temperature: 2.5 °C

Procedure:
A solution of 2-(piperidin-1-yl)-4-p-tolyl-9H-fluorene-1-carbonitrile (364 mg) in THF was added sodium hydride (40 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCl. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Red solid; mp 230-232° C.; ESMS 379 (M++1); IR (KBr) 1703 cm−1 (CO), 2219 (CN); 1H NMR (300 MHz, CDCl3) δ 1.60-1.64 (m, 2H, CH2), 1.79-1.84 (m, 4H, 2CH2), 2.48 (s, 3H, CH3), 3.19-3.24 (m, 4H, 2CH2), 6.65-6.70 (m, 1H, ArH), 6.87 (s, 1H, ArH), 7.14-7.19 (m, 2H, ArH), 7.28-7.33 (m, 4H, ArH), 7.63-7.67 (m, 1H, ArH). HRMS calcd. for C26H22N2O 378.1732 found 378.1728.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[F:22])[C:17]([OH:19])=O)[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]([F:23])[F:22])[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:37][CH:38]=3)=[O:19])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Reaction time: 0.58 h

Procedure:
97.0 mg (253 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-difluorobutanoic acid (racemate), 42.0 mg (253 μmol) of ethyl 4-aminobenzoate, 36.0 mg (253 μmol) of Oxima and 39.0 μl (253 μmol) of DIC in 2.5 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 81.7 mg (60% of theory)
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10](=[O:11])[N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:8]([C:16]2[S:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[N:7]1)C.[OH-].[K+]>CO>[Cl:21][C:18]1[S:17][C:16]([C:8]2[N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:10](=[O:11])[N:6]([CH2:5][C:4]([OH:22])=[O:3])[N:7]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)Cn1nc(-c2ccc(Cl)s2)n(CCOC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COCCn1c(-c2ccc(Cl)s2)nn(CC(=O)O)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 g (9.25 mmol) of the compound of Example 14A were dissolved in 28 ml of methanol. 2.82 ml of 20% strength aqueous potassium hydroxide solution were then added. The mixture was stirred at RT for 2 h. On a rotary evaporator, the proportion of methanol was reduced by half. The mixture was then diluted with water and extracted once with 15 ml of ethyl acetate. The aqueous phase was acidified with 920 μl of concentrated hydrochloric acid and extracted twice with in each case 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated on a rotary evaporator. Drying under high vacuum gave 2.34 g (80% of theory) of the title compound.