Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH2:5].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[C:29](O)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:9])[C:4]([NH2:5])([C:29]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:36])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(N)(C(=O)c1cccnc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 369.7 %

Procedure:
To a solution of L-valine methylester (3.0 g, 2.29 mmol), in DCM (30 mL) were added N-methyl morpholine (11.5 mL, 11.45 mmol), EDCI.HCl (8.7 g, 45.8 mmol) and nicotinic acid (3.3 g, 27.4 mmol). The mixture was allowed to stir at room temperature (25° C.) over 3 h under nitrogen atmosphere. The resulting mixture was diluted with ethyl acetate (200 mL), washed with water (3×100mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain required product as sticky solid (2.0 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:43][CH:42]([C:44](O)=[O:45])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:14]1[CH:13]=[C:12]([NH:16][C:17]([C:19]2([C:22](=[O:23])[NH:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[C:11]([F:32])=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:44]([CH:42]2[CH2:43][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41]2)=[O:45])[CH:7]=1
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (440 mg, 1 mmol) (as prepared in Example 9) and 1-(tert-butoxycarbonyl) azetidine-3-carboxylic acid (402 mg, 2 mmol) in DMF (5 mL) was added HATU (1.1 g, 3 mmol), followed by DIEA (516 mg, 4 mmol). The mixture was sparged with nitrogen and then stirred 50° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column on a silica gel chromatography to give tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate (250 mg, 40% yield). 1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 10.72 (s, 1H), 9.79 (s, 1H), 8.19 (d, J=5.6 Hz, 1H), 8.10-8.05 (m, 1H), 7.66 (s, 1H), 7.58-7.53 (m, 3H), 7.14 (t, J=8.8 Hz, 2H), 6.77-6.75 (m, 1H), 3.90-3.84 (m, 4H), 3.55-5.53 (m, 1H), 1.63-1.53 (m, 4H), 1.33 (s, 9H).
Reaction SMILES: [C:1]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:9](C(O)=O)[CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:32]([O:34]CC)=[O:33].[N:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[C:39]([C:47]([NH2:49])=[O:48])[CH:38]=1.[C:50](N[C@@H](C(O)=O)CCC1C=CC=CC=1)(OC(C)(C)C)=[O:51].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[C:39]([C:47]([NH2:49])=[O:48])[CH:38]=1.[C:1]([N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[C@H:9]([C:50]([NH:49][C@@H:47]([C:32]([OH:34])=[O:33])[CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:51])[CH2:10][CH2:11][CH2:12][NH2:13])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)O
Agent: NC(=O)c1cnc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](CCc1ccccc1)C(=O)O
Temperature: -10 °C
Reaction time: 2 h
Yield: 136.8 %

Procedure:
A solution of NaNd-bis-Boc-L-Ornithine (2.79 g, 8.4 mmol), triethylamine (1.29 mL, 9.2 mmol) and methylene chloride (90 mL) was stirred at 25° C. for 10 min, cooled to −10° C. and treated with ethyl chloroformate (0.80 mL, 8.4 mmol). The mixture was stirred at −10° C. for 2 hrs. During this time N-Boc-D-Homophenylalanine Quinoline-3-amide (2.27 g, 5.6 mmol) was treated with trifluoroacetic acid (15 mL) at 25° C. for 1 hr. The solution was concentrated to dryness and treated with diethyl ether (10 mL). The solid was filtered and dried. It was suspended in methylene chloride (40 mL) and neutralized with triethylamine (1.6 mL, 11.2 mmol). The resultant solution was added dropwise to the mixed anhydride and the mixture was allowed to warm up to 25° C. and stirred for an additional 1 hr. Saturated sodium bicarbonate (30 mL) was added, the organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness to afford crude product. It was purified by column chromatography on silica gel (ethyl acetate:hexane=2:1) to give the title compound (2.55 g) as white solid.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>C1C=CC=CC=1.CCCCC>[CH3:16][S:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26])=[CH:22][CH:23]=1
Reactant: CSc1ccc(N=C=S)cc1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCC
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCCCC(=N)NC(=S)Nc1ccc(SC)cc1

Procedure:
Following a procedure similar to that described in Example 42 but using 3.4 g. sodium in 500 ml. dry acetone, 24.7 g. heptanamidine hydrochloride, and 27.2 g. 4-(methylthio)phenyl isothiocyanate (m.p. 60°-61°C.; prepared from 4-methylthioaniline) in 120 ml. dry acetone there was obtained 1-[4-(methylthio)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 100°-101°C. (from benzene-n-pentane); hydrochloride (43.5 g.), m.p. 181°-182°C.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.O.[OH:25][N:26]1C2C=CC=CC=2N=N1.Cl.NO.C(N(CC)CC)C>CN(C=O)C>[CH:1]1([CH:7]=[CH:8][C:9]([NH:26][OH:25])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C=CC1CCCCC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C=CC1CCCCC1)NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
to a solution of 3-Cyclohexylacrylic acid (5.30 g, 31.3 mmol) in DMF (100 mL) was added EDC (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (7.80 g, 40.7 mmol) and HOBt (1-hydroxybenzotriazole hydrate) (5.07 g, 37.6 mmol). After stirring for 30 min at room temperature hydroxylamine hydrochloride (3.26 g, 47.0 mmol) and triethylamine (6.94 mL, 50.1 mmol) were added. After additional 18 hours stirring at room temperature the precipitate was filtered and washed with DMF. The DMF phases were combined. The solvent was concentrated in vacuo. 1 N HCl (50 mL) was added. After extraction with ethyl acetate (3×100 mL) and dichloromethane (2×100 mL) the organic layers were combined, washed with 1 N HCl (10 mL) and sodium chloride saturated solution (10 mL) and dried with magnesium sulfate. The solvent was removed in vacuo. The product was crystallized from ethyl acetate by addition of petroleum ether. This step removed large amounts of HOBt, the substance was then further purified by preparative HPLC using an acetonitrile/water gradient. This yielded (1.54 g, 9.08 mmol) of 3-Cyclohexyl-N-hydroxy-acrylamide. 1H NMR (300 MHz, [D6-DMSO]: δ=0.99-1.35 (m, 5H) and 1.56-1.73 (m, 5H) (cyclohexyl-CH2), 2.00-2.13 (m, 1H, cyclohexyl CH), 5.67 (d, J=15.7 Hz, 1H, C═C—H), 6.58 (dd, J=15.7 and J=6.3 Hz, 1H, C═C—H), 8.77 (s, 1H) and 10.49 (s, 1H) (NH and OH). 13C NMR (75 MHz, [D6-DMSO]: δ=25.2, 25.5, 31.5 (cyclohexyl-CH2), 41.1Acyclohexyl-CH), 118.8 and 147.1 (C═C), 162.8 (C(═O)NHOH). MS: m/z calcd for (C9H15NO2) [M+H]+ 170; found 170.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)CC1
Yield: 48 %

Procedure:
The title compound was synthesized in analogy to example 18 from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate, to give the desired product as a yellow oil (48%).
Reaction SMILES: [I-].C[S+](C)(C)=O.[C:7](O[K])(C)(C)[CH3:8].[CH3:13][C@@H:14]1[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][N:15]1[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22].O>CC(O)(C)C>[CH3:13][C@H:14]1[N:15]([C@@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH2:16][CH2:17][C@:18]2([O:20][CH2:8][CH2:7]2)[CH2:19]1
Reactant: CC(C)(C)O[K]
Reactant: C[C@@H]1CC(=O)CCN1[C@H](C)c1ccccc1
Agent: C[S+](C)(C)=O
Agent: [I-]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H]1C[C@]2(CCO2)CCN1[C@H](C)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (10.1 g, 46.0 mmol) in t-BuOH (anhydrous, 10 mL) was added tBuOK (1M in t-BuOH, 36.8 mL, 36.8 mmol) and the resulting mixture was stirred at 60° C. for 1 h. Then a solution of (R)-2-methyl-1-((R)-1-phenylethyl)piperidin-4-one (2 g, 9.20 mmol) in t-BuOH (6 mL) was added slowly. The reaction mixture was heated at 60° C. for 72 h, then cooled to room temperature and poured into water. The aqueous phase was extracted with EtOAc (2×). The organic phases were combined, washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (0-30% EtOAc/heptanes) to provide the desired isomer (4S,6R)-6-methyl-7-((R)-1-phenylethyl)-1-oxa-7-azaspiro[3.5]nonane as a colorless oil (0.67 g, 30%). 1H NMR (400 MHz, CD2Cl2) δ ppm 7.48 (d, J=7.83 Hz, 2H), 7.34 (t, J=7.58 Hz, 2H), 7.24 (t, J=6.82 Hz, 1H), 4.39-4.51 (m, 2H), 4.25 (q, J=6.74 Hz, 1H), 2.78-3.01 (m, 1H), 2.30-2.45 (m, 3H), 2.21-2.30 (m, 1H), 2.13 (td, J=2.56, 13.07 Hz, 1H), 1.85-1.95 (m, 1H), 1.44-1.62 (m, 2H), 1.28 (d, J=6.82 Hz, 3H), 1.20 (d, J=6.32 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH2:46])=[O:45])=[CH:42][CH:41]=1>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][C:40]1[CH:48]=[CH:47][C:43]([C:44](=[O:45])[NH2:46])=[CH:42][CH:41]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: NC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(C(N)=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To the solution of 1 (acetylsalicylic acid, 500 mg, 2.77 mmol) in 15 mL of dimethylformamide, hydroxybenzotriazole (412 mg, 3.05 mmol) and DCC (628 mg, 3.05 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 418 mg, 3.05 mmol) was added and stirred for 1 h at 0° C. and 3 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl 2-acetoxybenzoate (5) was obtained (410 mg, 47% yield).
Reaction SMILES: C(OC([N:8]1[CH2:39][CH2:38][C:11]2([CH2:15][N:14]([C:16](=[O:37])[C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:24][C:25]5[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=5[N:27]=4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:15]1[C:11]2([CH2:38][CH2:39][NH:8][CH2:9][CH2:10]2)[CH2:12][CH2:13][N:14]1[C:16]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[O:24][C:25]3[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][C:29]([C:35]#[N:36])=[CH:28][C:26]=3[N:27]=2)=[CH:21][CH:22]=1)=[O:37]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(C(=O)OC(C)(C)C)CC5)C4)cc3)oc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a solution of tert-butyl-2-[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoyl]-2,8-diazaspiro[4.5]decane-8-carboxylate (92 mg, 0.174 mmol) in dichloromethane (4 ml) was added trifluoroacetic acid (2 ml, 26.0 mmol). The mixture was stirred for 1 h at 25° C., at which point LC/MS analysis showed the desired amine. The mixture was concentrated and then co-concentrated with toluene to provide the title compound (94 mg, 0.173 mmol, 100% yield). Mass spectrum (ESI) 429.2 (M+).
Reaction SMILES: [C:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH2:6]3)[CH2:4]1)[CH2:10]2)#[CH:2].Cl[C:22]1[CH:27]=[N:26][CH:25]=[CH:24][N:23]=1>C(#N)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:23]1[CH:24]=[CH:25][N:26]=[CH:27][C:22]=1[C:2]#[C:1][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: C#CC12CC3CC(C1)CC(NC(=O)OC(C)(C)C)(C3)C2
Reactant: Clc1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC12CC3CC(CC(C#Cc4cnccn4)(C3)C1)C2
Temperature: 70 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a stirred solution of tert-butyl 3-ethynyl-1-adamantylcarbamate (120 mg, 0.44 mmol) and 2-chloropyrazine (120 mg, 1.05 mmol) in TEA (3 mL) and acetonitrile (15 mL) was added Pd(PPh3)4 (5 mg, 0.04 mmol), followed by an addition of Cut (5 mg, 0.026 mmol) under N2 atmosphere. After stirring at 70° C. for three hours, the reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5/1) to give 108 mg (70%) of the title compound, tert-butyl 3-(pyrazin-2-ylethynyl)-1-adamantylcarbamate as a white solid. ESI-MS m/z: 298 (M-55)+.
Reaction SMILES: [C:1]([C:3]([CH3:16])([CH3:15])[CH:4]([NH:8]S(C(C)(C)C)=O)[CH:5]1[CH2:7][CH2:6]1)#[N:2].[ClH:17].O1CCOCC1>CO>[ClH:17].[NH2:8][CH:4]([CH:5]1[CH2:7][CH2:6]1)[C:3]([CH3:16])([CH3:15])[C:1]#[N:2]
Reactant: CC(C)(C#N)C(NS(=O)C(C)(C)C)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C#N)C(N)C1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
To a solution of 2-methylpropane-2-sulfinic acid (2-cyano-1-cyclopropyl-2,2-dimethyl-ethyl)-amide (0.70 g, 2.90 mmol) in MeOH (5 mL) at room temperature was added 4.0 M HCl in dioxane (1.5 mL, 6.0 mmol). The reaction mixture was stirred at room temperature for 15 min then concentrated to afford 0.45 g (89%, 2 steps) of 3-amino-3-cyclopropyl-2,2-dimethyl-propionitrile hydrochloride as a white solid.
Reaction SMILES: Cl.C([N:5]1[C@H:10]([CH3:11])[CH2:9][N:8]([C@H:12]([C:20]2[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=2)[C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[C@@H:7]([CH3:33])[CH2:6]1)C=C.O>[Pd].CO>[CH3:33][C@H:7]1[CH2:6][NH:5][C@H:10]([CH3:11])[CH2:9][N:8]1[C@H:12]([C:20]1[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=1)[C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N(CC)CC)c2)C[C@H]1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)c1cccc([C@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)c1
Yield: 74.7 %

Procedure:
A mixture of (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide monohydrochloride (8.22 g, 17.1 mmol. Example 1) and 5.45 g (2.5 mmol) of 5% palladium on charcoal in 160 ml of methanol:water/3:1 was heated at reflux for 20 hours. The reaction mixture was filtered through Celite under nitrogen and the filtrate was evaporated. The residue was diluted with water and the pH was adjusted to 8 with aqueous 1M sodium hydroxide. The mixture was extracted with ethyl acetate, dried over sodium sulfate, and evaporated to give 5.05 g (75%) of (+)-3-((αR)-α-((2S,5R)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide as a light yellow solid. NMR (DMSO-d6, 200 MHz): δ1.1 (m, 12H); 2.0 (m, 1H); 2.6-2.9 (m, 3H); 3.0-3.5 (m, 7H); 5.25 (s, 1H); 6.7 (m, 3H); 7.2 (m, 3H); 7.4 (m, 2H); 9.5 (s, 1H). [α]D20 =+11.9° (abs ethanol, c=2.3). Titration of 0.20 g of product with ethanolic hydrogen chloride in ethanol solution to pH 3.5 and precipitation from dichloromethane with diethyl ether gave 0.103 g (47% recovery) of the monohydrochloride salt as an off-white solid. Calc. for C24H33N3O2HCl 0.75 H2O: C, 64.70; H, 8.03; N, 9.43; Cl, 7.96. Found: C, 64.97; H, 7.97; N, 9.38; Cl, 8.04. Mass spectrum (CI--CH4) m/e 396 (M+1, 38%); 282 (39%); 115 (100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1ccncc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCCc1ccncc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-propylpyridine (Intermediate 49), the title compound was obtained as a dark orange sticky solid after purification by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][CH2:5][C:6]([OH:8])=O)[CH3:2].CN(P(N(C)C)(N(C)C)=O)C.S(Cl)(Cl)=O.[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:32]([S:35]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])=[CH:31][C:29]=1[NH2:30]>C(OCC)C>[CH2:9]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]([NH:30][C:29]1[CH:31]=[C:32]([S:35]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)(=[O:36])=[O:37])[CH:33]=[CH:34][C:28]=1[O:27][CH3:26])=[O:8])[CH3:10]
Reactant: COc1ccc(S(=O)(=O)N2CCOCC2)cc1N
Reactant: CCN(CC)CCC(=O)O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCN(CC)CCC(=O)Nc1cc(S(=O)(=O)N2CCOCC2)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a three-neck flask they are introduced 7.2g 3-diethylaminopropionic acid (hydrochloride) and 180 ml hexamethylphosphorotriamide. The suspension is cooled with an ice-bath and then 2,90 ml thionylchloride are added while maintaining the inner temperature between +5° - +10° C. The reaction mixture progressively gives a yellow solution. After 2 hours stirring 10.9 g of 2-methoxy 5-morpholinylsulphonyl aniline are added portionwise and the whole mixture is kept under stirring for 4 hours at room temperature and then let to stand for a night. The dark solution is thereafter diluted with 1 l ethyl ether and it appears a precipitate. After 1 hour standing the precipitate is collected, suction-filtered and washed with acetone. After thoroughly drying the raw product weighing 11.3g is recovered and further recrystallised from acetone.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCOC(C)=O>C(O)C>[N:17]1[CH:18]=[CH:19][C:14]([NH:13][C:4]2[C:5](=[O:12])[C:6](=[O:11])[C:7]=2[O:8][CH2:9][CH3:10])=[CH:15][CH:16]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1c(Nc2ccncc2)c(=O)c1=O
Yield: 9.9 %

Procedure:
To a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (5.00 g, 29.4 mmol) in absolute ethanol (100 mL) was added a suspension of 4-aminopyridine (2.77 g, 29.4 mmol) in ethanol (50 mL). The reaction mixture was refluxed for 4 hours then concentrated to give crude product. Chromatography (EtOAc) afforded 0.632 g (10%) of a white solid: mp 120°-125° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][C:33]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNC(=O)Cc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 14 μL (0.11 mmol) phenylacetyl chloride. NMR was consistent with the proposed compound. Electrospray Mass Spectrum: M+1=479.