Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]3[CH2:12][CH2:13][CH:14]([C:15]([O:17]C)=[O:16])[C:9]3=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+].Cl>C1COCC1.O>[N:1]1([C:6]2[N:11]=[C:10]3[CH2:12][CH2:13][CH:14]([C:15]([OH:17])=[O:16])[C:9]3=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)C1CCc2nc(-n3cnnn3)ccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CCc2nc(-n3cnnn3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-5-carboxylate (460 mg, 1.9 mmol) in THF (6 mL) was added lithium hydroxide (1.0 N aq. 3.8 mL, 3.8 mmol). The mixture was allowed to stir at 0° C. for 2 hours. The reaction was diluted with water (10 mL). The pH was carefully adjusted to about 5 with 1N HCl. The solution was then extracted with EtOAc (30 mL×3). The extractions were combined, dried over sodium sulfate, and concentrated to furnish the title compound: LC-MS (IE, m/z): 231 [M+1]+; 1H-NMR (500 MHz, CD3OD) δ ppm 9.87 (s, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 4.20 (t, J=8.0 Hz, 1H), 3.15 (m, 1H), 3.08 (m, 1H), 2.51 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]1C=C(C(F)(F)F)C=C(Cl)[N:4]=1.[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[CH3:36][C:37]([CH3:40])([O-])[CH3:38].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:36]=[C:37]([CH2:40][O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:38]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: FC(F)(F)c1cc(Cl)nc(CBr)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cncc(Br)c2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-butyl 4-(((6-chloro-4-(trifluoromethyl)pyridine-2-yl)methoxy)methyl)-4-(4-fluorophenyllpiperidine-1-carboxylate. 2-(bromomethyl)-6-chloro-4-(trifluoromethyl)pyridine (301 mg, 1.1 mmol) and tert-butyl 4-(hydroxymethyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (309 mg, 1.0 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. The reaction was treated with potassium tert-butoxide (244 mg, 2.0 mmol) portion wise. The reaction was stirred at 0° C. for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over magnesium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 215 mg (43%). 1H-NMR (CDCl3, 400 MHz) δ 7.38 (s, 1H), 7.29-7.36 (m, 2H), 7.14 (s, 1H), 7.01-7.10 (m, 2H), 4.48 (s, 2H), 3.74-3.79 (m, 2H), 3.47 (s, 2H), 2.99-3.06 (m, 2H), 2.21-2.25 (m, 2H), 1.83-1.86 (m, 2H), 1.42 (s, 9H). Mass spec.: 403.08 (MH)+.
Reaction SMILES: [C:1]([NH2:7])([C:3]([F:6])([F:5])[F:4])=[O:2].N[C@@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:48]([NH2:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1COCC1>[C:49]1([CH2:48][NH:55][C:20](=[O:22])[C@H:9]([NH:7][C:1](=[O:2])[C:3]([F:6])([F:5])[F:4])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: NC(=O)C(F)(F)F
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
An ice-cold solution of 15 g (50 mmol) of the N-trifluoroacetamide of D-tryptophan, synthesized by methods previously outlined (J. Org. Chem. 1979;44:2805-2807) in 50 mL of THF under N2 was treated sequentially with 7.1 g (52.5 mmol) of 1-hydroxybenzo-triazole then 10.83 g (52.5 mmol) of 1,3-dicyclohexylcarbodiimide. After 15 minutes, the solution was treated with 5.74 mL (52.6 mmol) of benzylamine. The solution was maintained at 0°-5° C. for 1 hour, then let warm to 25° C. overnight. The mixture was filtered and the collected solids were washed with ethyl acetate. The filtrate was concentrated to an oil that was dissolved in 250 mL of ethyl acetate. The solution was washed sequentially with 250 mL portions of 10% aqueous acetic acid, water, 5% aqueous sodium hydrogen carbonate, water and brine, then dried (NaSO4 ), and concentrated to a solid. Crystallization from 170 mL of 65:35 2-propanol:petroleum ether afforded 12.81 g (66% ) of (R)-N-(phenylmethyl)-α-[(trifluoroacetyl)amino]-1H-indole-3-propanamide [II: R1 =H, R2 =CH2CH(NHCOCF3)CONHCH2Ph, R3 =H] as an off-white solid which was used directly in the next reaction; mp 186°-188° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:8])([CH3:7])[N:6]=1.[CH3:9][C:10]([CH3:14])=[CH:11][CH2:12]Br.[CH3:15][O-:16].[Na+]>C(Cl)Cl>[CH3:15][O:16][C:2]1([CH3:1])[N:6]([CH2:12][CH:11]=[C:10]([CH3:14])[CH3:9])[C:5]([CH3:8])([CH3:7])[CH2:4][O:3]1
Reactant: C[O-]
Reactant: CC1=NC(C)(C)CO1
Reactant: CC(C)=CCBr
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C)OCC(C)(C)N1CC=C(C)C
Temperature: 20 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
226 g (2 mols) of 2,4,4-trimethyloxazoline were dropped at room temperature to 298 g (2 mols) 3-methyl-2-butenyl bromide in 400 ml absolute methylenchloride and were stirred for 12 hours at 20° C. After cooling to 0° C. 400 ml (2 mols) of a 30% solution of sodium methylate were added and the mixture was stirred for a further hour at room temperature. The solution was filtered and after removing off the solvent the residue was distilled. 368 g (1.72 mols, 86%) of 2-methoxy-3-(3-methyl-2-butenyl)-2,4,4-trimethyloxazolidine of boiling point 70°-76° C./0.05 mm Hg were obtained. NMR (CDCL3): α1.1 (s, 3H); 1.2 (s,3H); 1.4 (s,3H); 1.6-1.7 (bs, 6H); 3.2 (s, 3H); 3.25 (d,J=6.5 Hz, 2H); 3.65 (s, 2H); 5.25 (t, J=6.5 Hz, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1.Cl.[CH3:20][CH2:21]O>>[CH2:20]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([NH2:6])=[CH:12][CH:11]=1)[CH3:21]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Catalytic sulfuric acid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). 1H NMR (400 MHz, CDCl3) δ 6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H).
Reaction SMILES: CC1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=3)NCC[C:5]2=1.CC[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26].[Br:29][CH2:30][C:31](Br)=[O:32]>C1COCC1>[Br:29][CH2:30][C:31]([N:24]1[CH2:25][CH2:26][C:3]2[C:4]3[C:12](=[CH:13][CH:14]=[C:10]([CH2:9][C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=4)[CH:5]=3)[NH:11][C:28]=2[CH2:27]1)=[O:32]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCNC3c1cccc(O)c1
Reactant: O=C(Br)CBr
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)N1CCc2c([nH]c3ccc(Cc4cccc(O)c4)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-methyl-1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-beta-carboline (1 equiv) in THF was added Et3N (2.2 equiv) and alpha-bromoacetyl bromide (1.2 equiv). The solution was stirred at room temperature for 30 min to give crude 2-bromo-1-[1-(3-hydroxyphenyl)-6-methyl-(1,2,3,4-tetrahydro-beta-carbolin-2-yl)]ethan-1-one. To the solution was added morpholine (2 equiv). The solution was stirred overnight and purified to give 3-[6-methyl-2-(morpholin-4-ylacetyl)-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl]phenol 16.
Reaction SMILES: [CH3:1][O-:2].[Na+].[O:4]1C2C=CC=CC=2N[C:6](=O)[CH2:5]1.[CH3:15][N:16](C)[C:17]1C=C[C:20]([CH:21]=[O:22])=CC=1>CN(C=O)C>[CH2:5]([OH:4])[CH3:6].[CH3:15][N:16]([CH:1]=[O:2])[CH3:17].[CH2:21]([OH:22])[CH3:20]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C[O-]
Reactant: O=C1COc2ccccc2N1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
HSB-9 and HSB-10: Sodium methoxide was added in one portion to a mixture of 2H-1,4-benzoxazin-3(4H)-one (10 mmol) and 4-dimethylamino benzaldehyde (16 mmol) in dry DMF (10 ml). The reaction mixture was refluxed overnight, then cooled to room temperature and poured into crushed ice and left overnight in the refrigerator. The precipitated solid was collected by filtration, washed with water and dried. The crude product was purified by recrystallisation from ethanol (30% yield) and DMF-ethanol (40% yield) respectively (40% yield).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:28])[C:26]#[CH:27])[CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[C:20]3[C:19]([CH3:21])([CH3:22])[CH2:18][CH2:17][C:16]([CH3:23])([CH3:24])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:28])[C:26]#[C:27][C:32]3[CH:40]=[CH:39][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1cc(OCc2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC(C)(C)c1ccc(COc2cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 71 %

Procedure:
In a manner similar to that of Example 1g, by reacting 760 mg (1.9 mmol) of 1-[4-(4-tert-butylbenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]prop-2-yn-1-ol with 390 mg (1.6 mmol) of 4-iodobenzoic acid in the presence of 15 mg of copper iodide and 28 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of white crystals (m=600 mg; yield=71%; m.p.=254° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C1COCC1>[C:17]([C:16]1[CH:15]=[CH:14][C:13]([NH:12][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=2[Cl:1])=[CH:26][CH:25]=1)(=[O:18])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1ccc(NC(=O)c2cc(Cl)ccc2Cl)cc1
Yield: 84.3 %

Procedure:
Reaction of 2,5-dichlorobenzoic acid (300 mg, 1.50 mmol) in thionyl chloride (3.5 mL) then with 4-aminobenzophenone (100 mg, 0.51 mmol) in presence of triethylamine (90 μL) in THF (6 mL) according to method B gave N-(4-benzoyl-phenyl)-2,5-dichloro-benzamide (160 mg, 0.43 mmol, 84% yield) as a off-white powder after purification by chromatography on silica gel (eluent:EtOAc/exane 1/9 to 3/7).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])=[C:6]([Cl:16])[CH:5]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:16][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1ccc(OCCCC#N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCCOc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 3-Chloro-4-(4-nitrilo-butoxy)-benzoic acid methyl ester (6.24 g, 24.6 mmol in THF (100 ml) and methanol (100 ml) was treated with 5 N sodium hydroxide solution (35 ml) with stirring at room temperature for 1 h. The reaction mixture was concentrated in vacuo, diluted with water, and acidified to pH 1 with 5 N hydrochloric acid. The resulting suspension was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resulting off white solid was triturated with hot petroleum ether, cooled and filtered to give 5.58 g (95%) of the title compound as a white solid mp 150° C.; 1H NMR (CDCl3) δ2.22-2.28 (m, 2H), 2.69 (t, J=7.0 Hz, 2H), 3.90 (s, 3H), 4.23 (t, J=5.5 Hz, 2H), 6.97 (d, J=8.6 Hz, 1H), 8.01 (dd, J=8.6, 2.2 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H). IR (KBr) 3400, 2200, 1700, 1600, 1450, 1275 and 1050 cm−1, mass spectrum (EI), m/z 239/241. Anal. Calcd. for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.85. Found: C, 54.84; H, 4.01; N, 5.69.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:10])[CH3:9].[Br:11]Br.C(OC)(C)(C)C.[OH-].[Na+]>C(O)(=O)C>[Br:11][C:5]1[S:4][C:3]([CH2:7][CH:8]([NH2:10])[CH3:9])=[C:2]([Cl:1])[CH:6]=1
Reactant: CC(N)Cc1sccc1Cl
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: CC(N)Cc1sc(Br)cc1Cl
Temperature: 15 °C

Procedure:
In a sulfonation flask 5 g (0.028 mol) 2-(3-chlorothiphen-2-yl)-1-methylethylamine is dissolved in 70 ml of acetic acid. The mixture is then cooled to 15° C. and 4.8 g (0.30 m) of bromine is added under stirring (internal temperature 15-17° C.). After warming up to rt, the mixture is stirred for 16 hours. Then the mixture is poured to a mixture of tert. butylmethylether (ca. 250 ml) and 2N sodiumhydroxide. The final pH is 11. After washing with brine, drying with sodium sulphate and evaporation of the solvent the crude material is obtained. Purification is achieved by column chromatography over silicagel (eluent: tert. butylmethylether/EtOH 10:1). Yield: 5.4 g (75% of theory) of a colourless oil (1H-NMR: 1.18/d/3H, 2.68-2.87/m (diasterotopic protons)/2H, 3.2/m/1H, 6.87/s/1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.[NH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[NH:66][C:52]3[N:53]=[CH:54][N:55]=[C:56]([NH:57][C@@H:58]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH3:59])[C:51]=3[CH:50]=2)=[CH:45][CH:44]=1>CN(C=O)C>[C:60]1([C@H:58]([NH:57][C:56]2[C:51]3[CH:50]=[C:49]([C:46]4[CH:45]=[CH:44][C:43]([CH2:42][NH:41][C:9](=[O:11])[CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:48][CH:47]=4)[NH:66][C:52]=3[N:53]=[CH:54][N:55]=2)[CH3:59])[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCN4CCCCC4)cc3)cc12)c1ccccc1
Reaction time: 0.08 h

Procedure:
Under an atmosphere of nitrogen a mixture of 0.0865 g (0.55 mmol) 3-piperidin-1-yl-propionic acid and 0.117 ml (0.68 mmol) N,N-diisopropylethylamine in DMF (5 ml) is treated at RT and over a period of 5 min with a solution of 0.163 g (0.56 mmol) O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium-tetrafluroborate (TPTU, Fluka, Buchs, Switzerland) in 2 ml DMF. After stirring for 5 min the resulting solution is added slowly (1.5. h) at RT to 0.172 g (0.5 mmol) [6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine (step 40.5) in 3 ml DMF. The reaction mixture is allowed to stand over night after which the DMF is evaporated under reduced pressure. The residue is purified by flash chromatography using gradients of first dichloromethane/methanol 100:2.5 to 10:1 and then mixtures of dichloromethane/methanol/conc. ammonia 90:10:0.5 to 40:10:1. The title compound is obtained as yellowish solid; m.p. 140° C.; MS-ES+: (M+H)+=483. As a second product of this reaction N-{4-[4-((R)-1-phenyt-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acrylamide is obtained; m.p. 249-250° C.; MS-ES+: (M+H)+=398.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30](Cl)=[O:31].[CH2:33]([N:35](CC)CC)C>O1CCCC1>[C:33]([CH:22]1[CH2:21][O:20][CH:19]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[O:31])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)[CH2:24][CH2:23]1)#[N:35]
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: O=C(Cl)c1ccco1
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC1CCC(n2nc(-c3cccc(NC(=O)c4ccco4)c3)c3ccccc32)OC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.300 g, 0.94 mmol) in tetrahydrofuran (10 mL), was added 2-furoyl chloride (0.139 mL, 1.41 mmol) and triethyl amine (0.655 mL, 4.7 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was dried under vacuum and the title product was purified by column chromatography (SiO2, 20–30% ethyl acetate in hexanes) (0.370 g, 95%): ES-MS (m/z) 413 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O)(=O)C.C(O[C:27]1(O[Si](C)(C)C)[CH2:29][CH2:28]1)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[CH:27]2[CH2:29][CH2:28]2)=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)c1nnc(NC(=O)[C@@H]2CCCCN2)s1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nnc(NC(=O)[C@@H]2CCCCN2C2CC2)s1

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-1,3,4-thiadiazol-2-yl)-amide; hydrochloride (125 mg; 0.41 mmol) in methanol (3 mL) is added acetic acid (0.235 mL; 4.1 mmol), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.48 mL; 2.4 mmol) and sodium cyanoborohydride (116.25 mg; 1.85 mmol). The reaction mixture is heated at reflux for 5 hours. After cooling, the mixture is diluted with ethyl acetate and washed with saturated NaHCO3 aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by preparative HPLC affords the title compound, m/z 309 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([OH:9])=O)[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[C:7]([N:19]([O:20][CH3:21])[CH3:18])=[O:9])[CH3:2]
Reactant: CNOC
Reactant: CCOc1cc(C(=O)O)ccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N(C)OC)ccc1C(F)(F)F
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-ethoxy-4-trifluoromethyl-benzoic acid from step 6 (13.76 g, 59 mmol), N,O-dimethylhydroxylamine hydrochloride (9.17 g, 94 mmol), N-methylmorpholine (9.51 mL, 94 mmol) and 4-DMAP (718 mg, 6 mmol) in DCM (185 mL) and DMF (38 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (13.52 g, 70 mmol), and the mixture was stirred at 23° C. for 18 h. Poured onto ice cold 1 N HCl, extracted with TBME, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a light brown oil (16.15 g, 100%, which was used without further purification. MS (ISP) 278.4 [M+H].
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:7][N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:5]1)#[N:2].[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([CH2:3][C:4]1([N:19]2[CH:23]=[C:22]([C:24]3[C:25]4[CH:32]=[CH:31][N:30]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])[C:26]=4[N:27]=[CH:28][N:29]=3)[CH:21]=[N:20]2)[CH2:5][N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:18])[CH:9]=2)[CH2:7]1)#[N:2]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ncnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5ccc(C(=O)O)c(F)c5)C4)c3)ncnc21
Temperature: 35 °C
Reaction time: 24 h
Yield: 77.2 %

Procedure:
To a solution of methyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2-fluorobenzoate (1.22 g, 2.17 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide (0.21 g, 8.8 mmol) in water (9.8 mL). The reaction mixture was then stirred at 35° C. for 24 hours. The reaction mixture was diluted with water (5 mL) and pH was adjusted to ˜4 with 1 N HCl, extracted with ethyl acetate. The organic fraction was washed with water (1×), brine (1×), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solid was then triturated with methylene chloride-methanol (95:5), filtrated to afford the desired product (0.917 g, 77.1%). LCMS (M+H)+: m/z=562.2.