Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1N=CN(C(N2C=NC=C2)=O)C=1.[OH:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1>O>[OH:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:1](=[O:22])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:38][CH:37]=1
Reactant: CCCCCCCCC#CCC#CCC#CCCCC(=O)O
Reactant: Nc1ccc(O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: CCCCCCCCC#CCC#CCC#CCCCC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.2 %

Procedure:
In the same manner as in the above example, the intermediate formed from 1 g of 5,8,11-eicosatriynoic acid and 0.7 g of CDI is treated with 0.727 g of para-hydroxyaniline. The medium is then stirred for 24 hours at room temperature. Water is then added gradually to the mixture until all the product formed precipitates. It is drained and dried and then recrystallized in isopropyl ether. 0.85 g of N-(para-hydroxyphenyl)-5,8,11-eicosatriynamide is obtained in the form of beige-white crystals of melting point 121° C.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O.CCOC(C)=O.[Cl-].[Na+].O.O>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(C)CCCBr
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCCC(C)C)o1
Reaction time: 12 h
Yield: 62.2 %

Procedure:
To a vigorously stirred suspension of 5-(tetradecyloxy)furan-2-carboxylic acid (0.162 g, 0.5 mmol) in 10 mL of N,N-dimethylformamide was added 1-bromo-4-methylpentane (0.247 g, 1.5 mmol), cesium carbonate (0.243 g, 0.75 mmol) and sodium iodide (˜20 mg). The suspension appeared to go into solution briefly, and then a very finely dispersed white precipitate was observed. The reaction was allowed to stir for 12 hrs at which time HPLC analysis of the reaction solution indicated complete conversion of TOFA to a less polar product. The suspension was diluted with EtOAc (40 mL), brine (20 mL) and water (20 mL). The phases were separated and the organic phase was washed with water (20 mL) and brine (20 mL) and then dried and concentrated. The resulting crude material was purified by flash chromatography eluting with 0-20% EtOAc in hexanes to yield 0.127 g (62%) of the title compound. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.22 (t, 2H), 4.10 (t, 2H), 1.18-1.80 (m, 29H), 0.89 (t, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10](OCC)=[O:11])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[NH2:19][NH2:20]>CO>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9]([C:10]([NH:19][NH2:20])=[O:11])=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Reactant: NN
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NN)CC(C)(C)N1

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-aminooxamide was prepared by the hydrazinolysis of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate with 64% aqueous hydrazine in methanol.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]3[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=3)[C:38]2=[O:57])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][C:47]3[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=3)[C:38]2=[O:57])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: COC(=O)c1ccc(CN2C(=O)C(c3cc4c(cc3O)OCO4)c3ccccc32)cc1
Product: COC(=O)c1ccc(CN2C(=O)C(CO)(c3cc4c(cc3O)OCO4)c3ccccc32)cc1

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with methyl 4-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate, the title compound was obtained (81%): MS (ES+) m/z 448.1 (M+1).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.CN(C)CCN(C)C.[C:28](=[O:30])=[O:29].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[CH3:19][O:18][C:14]1[C:15]([C:28]([OH:30])=[O:29])=[CH:16][C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[O:7][CH3:6]
Reactant: COc1ccc2c(OC)cccc2c1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2cccc(OC)c2cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.9 %

Procedure:
n-Butyllithium (2.5M in hexanes; 220 ml) was added dropwise at 700° C. under nitrogen to a stirred solution of 1,6-dimethoxynaphthalene (95 g) in tetrahydrofuran (1000 ml). N, N, N', N'-Tetra-methylethylenediamine (150 ml) was added and the mixture was stirred at ambient temperature for 20 hours, then cooled to -20° C. and poured onto crushed solid carbon dioxide (500 g). When effervescence had ceased, the mixture was diluted with water (1000 ml), basified by the addition of sodium carbonate (100 g), washed with ether (2×100 ml) and acidified by the addition of concentrated hydrochloric acid. The product was extracted into ethyl acetate and the extracts were washed with brine, dried over magnesium sulphate, and the solvents removed in vacuo. The residue crystallised from ethyl acetate to give a solid which was collected by filtration, dried in vacuo, and ground to give 3,8-dimethoxy-2-naphthoic acid as a cream powder (45.6 g), m.p. 151°-153° C. Concentration of the liquor yielded a second crop of 3,8-dimethoxy-2-naphthoic acid (5.4 g).
Reaction SMILES: [C:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=3)[C:22]#[N:23])=[CH:12][CH:11]=2)=[C:6]([CH2:28][CH2:29][CH3:30])[C:5]=1[OH:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>>[OH:31][C:5]1[C:6]([CH2:28][CH2:29][CH3:30])=[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:25])[C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:22]4[N:32]=[N:33][NH:34][N:23]=4)[CH:24]=3)=[CH:14][CH:15]=2)[CH:26]=[CH:27][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2ccc(C(O)c3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2ccc(C(O)c3cncc(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O
Yield: 32.5 %

Procedure:
Using the general procedure of Example 1 using 5-{[4-(4-Acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-nicotinonitrile (473 mg, 1.14 mmol), sodium azide (738 mg, 11.4 mmol), and triethylamine hydrochloride (1.56 g, 11.4 mmol) to yield the title product as a white solid (170 mg, 33%): 1H NMR (DMSO-d6) δ 0.85 (t, 3H), 1.35 (s, 1H), 1.47 (sextet, 2H), 2.56 (m, 5H), 5.22 (bs, 2H), 5.93 (d, 1H), 6.29 (d, 1H), 6.71 (d, 1H), 7.45 (q, 4H), 7.78 (d, 1H), 8.39 (t, 1H), 8.77 (d, 1H), 9.07 (d, 1H), 12.83 (s, 1H); MS (esi negative) m/z (rel intensity) 458 (100).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[ClH:18]>CO>[ClH:18].[CH:1]1([N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC2)CC1
Agent: Cl
Solvent: CO
Product: C1CC(N2CCNCC2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82 %

Procedure:
To the mixture of tert-butyl 4-cyclobutylpiperazine-1-carboxylate (48 g, 200 mmol) in MeOH (100 mL) was added 2.0 M HCl in MeOH (400 mL) carefully at 0° C. The mixture was stirred at rt for 5 h, concentrated under reduced pressure to afford the desired compound 1-cyclobutylpiperazine hydrochloride (35 g, 82%) [LCMS: Rt=0.94 min, m/z 141.3 (M+H)+].
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][Si](C(C)(C)C)(C)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O>CO.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@@H:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][C@H:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO[Si](C)(C)C(C)(C)C)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOCC
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@H](CCCCCO)CC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]12C
Yield: 100.8 %

Procedure:
A solution of 48 g of 17β-acetoxy-7α-(5-tert-butyldimethylsilyloxypentyl)-estr-4-en-3-one in 350 ml of methanol is allowed to stand with 35 ml of 8 vol % sulfuric acid for 30 minutes at room temperature. The solution is diluted with diethyl ether, washed neutral with water, and dried. After the concentration by evaporation, 37.7 g of 17β-acetoxy-7α-(5-hydroxypentyl)-estr-4-en-3-one is obtained as oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)([OH:42])=[O:41]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:47]3[CH:46]=[CH:45][CH:44]=[C:43]([C:40]([OH:42])=[O:41])[CH:48]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3cccc(C(=O)O)c3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 3-carboxyphenylboronic acid replacing phenylboronic acid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([N:7]=[N+:8]=[N-:9])[CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[CH:17]#[CH:18]>CC(C)=O>[OH:1][C@H:2]1[C@H:6]([N:7]2[CH:18]=[CH:17][N:9]=[N:8]2)[CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1
Reactant: C#C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](n2ccnn2)C1

Procedure:
A solution of trans 3-hydroxy-4-azido-1-N-(tert.-butoxy carbonyl)pyrrolidine (3.8 g, 17 mmol) in dry acetone (50 ml) was heated at 75°-80° C. for 40 hrs. After releasing the excess of acetylene, the reaction mixture was concentrated and the residue was purified on silica gel using ethyl acetate as eluant. Yield 3.66 g (87%) m.p. 91-93° C.; 1H NMR (CDCl3) δ: 1.46 (S, 9H), 3.25-4.25 (m, 5H), 4.83 (m, 1H), 7.63 (S, 1H), 7.70 (S, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:5]([N+:14]([O-])=O)=[CH:4][CH:3]=1>[Pt]=O.C(O)C>[NH2:14][C:5]1[C:6]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)COc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: COC(=O)COc1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-chloro-2-(methoxycarbonyl)methoxy-3-nitropyridine, platinum oxide and ethanol is stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system is purged with nitrogen, then, the reaction solution is filtrated through Celite, and the filtrate is concentrated. The residue is subjected to silica gel column chromatography to obtain 3-amino-6-chloro-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([Zn]CC)[CH3:10]>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.O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][CH3:10])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CC[Zn]CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL 3-necked round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2,5-dibromopyridine (20 g, 84.43 mmol, 1.00 equiv), Pd(PPh3)4 (9.7 g, 8.39 mmol, 0.10 equiv) and tetrahydrofuran (500 mL). To the resulting mixture was then added diethylzinc (46.2 mL) dropwise with stirring at −78° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water (10 mL). The resulting mixture was then concentrated under vacuum. The resulting solution was diluted with ethyl acetate (200 mL). The resulting solution was extracted with 4N HCl (2×200 mL) and the aqueous layers combined. The pH value of the solution was adjusted to pH 14 with aqueous LiOH. The resulting solution was extracted with ethyl acetate (2×200 mL) and the organic layers combined. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (4.6/95.4) to yield 5-bromo-2-ethylpyridine as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:20]1[O:21][C:22]2[C:23](=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][CH:28]=2)[N:24]=1>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[O:21][C:22]3[C:23](=[C:25]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:27][CH:28]=3)[N:24]=2)[CH2:10][C@@H:9]1[CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)[C@@H](C(C)C)C3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-(S)-2-isopropylpiperazine (384 mg, 1.7 mmol) in DME (10 mL) was added NaH (70 mg of 60% suspension in mineral oil, 1.6 mmol) and the mixture was stirred for 1 h at room temperature. Methyl 2-chlorobenzoxazole-4-carboxylate (368 mg, 1.6 mmol) was added to the reaction mixture and suspension formed was stirred at room temperature for 17 h. The reaction mixture was quenched with CH3OH (10 mL), silica gel (15 mL) was added, and solvent removed under reduced pressure. The mixture was purified by column chromatography (silica gel, 0 to 80% EtOAc in CH2Cl2) to afford methyl 2-(4-(tert-butoxycarbonyl)-(S)-3-isopropylpiperazin-1-yl)benzoxazole-4-carboxylate (255 mg, 39%) as a white foam. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:26])[CH2:9][NH:10][C:11]([CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:12])#[N:2].O.CC1C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:26])[CH2:9][NH:10][C:11]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)N2CCC[C@H]2C#N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: N#C[C@@H]1CCCN1C(=O)CNC(=O)C1CCNCC1
Reaction time: 24 h

Procedure:
To a solution of (S)-tert-butyl 4-(2-(2-cyanopyrrolidine-1-yl)-2-oxoethylcarbamoyl)piperidine-1-carboxylate (0.100 g, 0.274 mmol) in 2 ml Acetonitrile was 4-methylbenzenesulfonic acid hydrate (0.073 g, 0.384 mmol) added and the mixture was stirred for 24 h. After evaporation of the volatiles, the sample was purified by preparative HPLC to yield an reddish oil.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]3([CH3:40])[CH2:29][CH2:28][N:27]([C:30](=[O:39])[C:31]4[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:38])[CH2:26][CH2:25]3)[CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl.C([O-])(O)=O.[Na+]>O.CO>[CH3:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([CH3:37])[C:31]=1[C:30]([N:27]1[CH2:28][CH2:29][C:24]([CH3:40])([N:21]2[CH2:20][CH2:19][CH:18]([N:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:23][CH2:22]2)[CH2:25][CH2:26]1)=[O:39]
Reactant: COC(=O)c1ccc(CN(c2ccccc2)C2CCN(C3(C)CCN(C(=O)c4c(C)cccc4C)CC3)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CO
Solvent: O
Product: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(N(Cc3ccc(C(=O)O)cc3)c3ccccc3)CC2)CC1

Procedure:
A mixture of 4-({[1′-(2,6-Dimethyl-benzoyl)-4′-methyl-[1,4′]bipiperidinyl-4-yl]-phenyl-amino}-methyl)-benzoic acid methyl ester (180 mg, 0.325 mmol), methanol (10 ml), water (3 ml) and 33 mmol) was heated under reflux for 2 h. The pH was adjusted LiOH (200 mg to 1 with 2 N HCl and then to pH 7 with NaHCO3. The mixture was extracted with ethyl acetate and dried with Na2SO4. The solvent was evaporated and the residue crystallized from methanol/water to give 4-({[1′-(2,6-Dimethyl-benzoyl)-4′-methyl-[1,4′]bipiperidinyl-4-yl]-phenyl-amino}-methyl)-benzoic acid. MS/ESI 540 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:33][C:12]3[C:13](=[O:32])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]5)[N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[CH2:34]=O>CO.C(Cl)Cl.CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:33][C:12]3[C:13](=[O:32])[N:14]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C@@H:26]5[CH2:31][CH2:30][CH2:29][CH2:28][N:27]5[CH3:34])[N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=2)=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5)n4)c(=O)c3s2)cc1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cnn(Cc4cccc(OC[C@@H]5CCCCN5C)n4)c(=O)c3s2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-methoxyphenyl)-6-({6-[(2S)-piperidin-2-ylmethoxy]pyridin-2-yl}methyl)thieno[2,3-d]pyridazin-7(6H)-one (290 mg, 0.627 mmol) in MeOH/DCM 1:1(15 ml), were added (polystyrylmethyl)trimethylammonium cyanoborohydride (460 mg, 1.881 mmol, 4.1 mmol/g) and formaldehyde (100 μl, 1.25 mmol) followed by AcOH (one drop). After stirring at rt. for 3 h the resin was filtered off and washed with MeOH. The filtrate was collected and evaporated in vacuo. Purification by silica gel flash chromatography using a 25+M Biotage column with EtOAc/MeOH/TEA 100:10:1 gave the title compound as a light yellow solid. Yield: 201 mg (67%). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.61 (m, 2H), 7.47 (t, 1H, J=7.8 Hz), 7.34 (s, 1H), 6.96 (m, 2H), 6.71 (d, 1H, J=7.3 Hz), 6.63 (d, 1H, J=8.3 Hz), 5.47 (s, 2H), 4.26 (m, 2H), 3.84 (s, 3H), 2.81 (dt, 1H, J=11.5 Hz, J=3.1 Hz), 2.27 (s, 3H), 2.11 (m, 1H), 2.02 (m, 1H), 1.66 (m, 2H), 1.54 (m, 2H), 1.42 (m, 1H), 1.20 (m, 1H). 13C NMR (400 MHz, CDCl3) δ 163.7, 161.1, 157.4, 153.94, 153.88, 140.5, 139.2, 135.4, 133.3, 128.3, 125.5, 117.2, 114.9, 114.2, 110.1, 67.8, 63.1, 57.5, 55.8, 55.6, 43.6, 29.5, 26.0, 24.3. MS (ESI+) 477.25 (M+1H+)
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)#[CH:16].C(N(CC)CC)C.O>O1CCCC1>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH:16]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
To a solution (15 ml) of methyl 4-[chloro(hydroxyimino)methyl]benzoate (0.425 g) and 1-ethynyl-4-trifluoromethylbenzene (0.534 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (0.697 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-ethyl acetate to give methyl 4-[5-(4-trifluoromethylphenyl)-3-isoxazolyl]benzoate (0.563 g, yield 65%) as colorless needle crystals. melting point: 183–184° C.
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:17]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[N:20][N:19]4[CH2:28][CH2:29][CH2:30][C:18]=34)=[CH:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>O1CCCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:17]([C:11]2[C:10]3[C:15](=[CH:16][C:7]([N:6]4[CH2:2][CH2:3][O:4][C:5]4=[O:31])=[CH:8][CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[C:18]2[CH2:30][CH2:29][CH2:28][N:19]2[N:20]=1
Reactant: O=C(Nc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1)OCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1OCCN1c1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reaction time: 18 h

Procedure:
To a solution of [4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-yl]-carbamic acid 2-hydroxy-ethyl ester (40.2 mg, 0.097 mmol) and triphenylphosphine (35.0 mg, 0.14 mmol) in tetrahydrofuran (1 mL) at room temperature is added diethyl 40% azodicarboxylate in toluene (50 μL, 0.11 mmol). The mixture is stirred 18 h, filtered, and the filtrate concentrated in vacuo. The residue is chromatographed on SiO2 (2% to 15% methanol in dichloromethane) to yield the desired product, 15.2 mg (40%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[N:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[C:8]([OH:10])=O.C[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH2:26][CH2:25][CH2:24]2.N1C2C(=CC=CC=2)CCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[O:5][C:6]1[C:7]([C:8]([N:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:30][CH:29]=3)[CH2:24][CH2:25][CH2:26]2)=[O:10])=[CH:11][C:12]([F:15])=[CH:13][N:14]=1
Reactant: Cc1ccc2c(c1)CCCN2
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc(F)c(Cl)c1
Agent: c1ccc2c(c1)CCCN2
Product: O=C(c1cc(F)cnc1Oc1ccc(F)c(Cl)c1)N1CCCc2ccccc21

Procedure:
The title compound was prepared in analogy to Example 31, Step 2, replacing 2-(2,5-dichloro-phenoxy)-nicotinic acid with 2-(3-chloro-4-fluoro-phenoxy)-5-fluoro-nicotinic acid and 6-methyl-1,2,3,4-tetrahydro-quinoline with 1,2,3,4-tetrahydro-quinoline ([CAS RN 635-46-1]). MS (ISP): 401.0 [M+H]+.