Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19]C1C=CC(C(C)(C)C)=CC=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[C@H](CO[C:49]1[CH:54]=[CH:53][C:52]([C:55](C)([CH3:57])[CH3:56])=[CH:51][CH:50]=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC([Cl:84])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:84].[OH:2][CH:3]([CH2:18][O:19][C:50]1[CH:49]=[CH:54][CH:53]=[C:52]([CH:55]([CH3:57])[CH3:56])[CH:51]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C(C)C)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M-15,.1), 251 (18), 250 (100), 163 (6), 121 (21), 117 (5), 114 (10), 91 (9).
Reaction SMILES: C(N(CC)CC)C.S(=O)(=O)(O)O.[C:13](#[N:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>C1(C)C=CC=CC=1>[C:14]1([C:13]2[NH:23][N:22]=[N:21][N:20]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: c1ccc(-c2nnn[nH]2)cc1
Temperature: 97.5 °C
Yield: 98 %

Procedure:
Into the same device as used in Example 1 were placed 6.58 g (0.065 mole) of triethylamine and 52 ml of toluene. To the mixture were added 3.19 g (0.033 mole) of concentrated sulfuric acid with stirring. Further added were 5.16 g (0.050 mole) of benzonitrile and 4.23 g (0.065 mole) of sodium azide. The mixture was heated to a temperature from 95 to 100° C. to undergo a reaction for 7 hours. The same subsequent treatment as in Example 1 was conducted, giving 7.11 g (0.049 mole) of 5-phenyl-1H-tetrazole (yield 97.3% based on benzonitrile).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](I)[C:7]([NH2:11])=[N:6][CH:5]=1.O=[C:14]([CH3:18])[C:15]([OH:17])=[O:16].CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[CH:18]=[C:14]([C:15]([OH:17])=[O:16])[NH:11][C:7]2=[N:6][CH:5]=1)=[O:12]
Reactant: COC(=O)c1cnc(N)c(I)c1
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2[nH]c(C(=O)O)cc2c1
Reaction time: 1 h

Procedure:
A solution of 5.6 g 6-Amino-5-iodo-nicotinic acid methyl ester, 5.3 g 2-Oxo-propionic acid, 11.1 g NEt3, 4.2 g Triphenylphosphine and 1.1 g Pd(OAc)2 in 100 mL DMF was heated under argon to 100° C. After 10 h the reaction mixture was concentrated under reduced pressure and the residue was strirred with 250 mL water for 1 h. The precipitated product was collected by filtration and washed with water. The crude product was subjected to the next reaction step without further purification.
Reaction SMILES: O[C@H:2]1[CH2:7][C@H:6]2[CH2:8][C@H:4]([C:5]2([CH3:10])[CH3:9])[C@@H:3]1CCOC1CCCCO1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CCOCC>[CH3:9][C:5]1([CH3:10])[CH:6]2[CH2:8][CH:4]1[CH2:3][CH2:2][CH2:7]2
Reactant: CC1(C)[C@H]2C[C@H](O)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CCCC1C2
Reaction time: 0.25 h
Yield: 265.9 %

Procedure:
To a solution of 13 g of (1S,2S,3S,5R)-3-hydroxy-6,6-dimethyl-2-[2-(tetrahydropyran-2-yloxy)-ethyl]bicyclo[3.1.1]heptane 14 [Jap. Unexamined Pat. Pub. No. 13551/1983] in 130 ml of dichloromethane is added 9.9 ml of triethylamine in a stream of nitrogen and then 6.16 g of methanesulfonyl chloride is dropwise added at -20° C., and the resulting mixture is stirred at the same temperature for 15 minutes. The reaction mixture is diluted with ether, washed with water, a saturated aqueous solution; of ammonium chloride and a saturated sodium chloride aqueous solution successively, dried over sodium sulfate, and evaporated under reduced pressure to give 16 g of the titled compound 14a, of which the physical constant is as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Cl[CH2:9][CH:10]=O>CCO>[N:7]1[CH:9]=[CH:10][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: O=CCCl
Reactant: Nc1cnccn1
Solvent: CCO
Product: c1cn2ccnc2cn1

Procedure:
A round bottom set up with reflux condenser was charged with pyrazin-2-amine (1000 mg, 10.52 mmol), 2-chloroacetaldehyde (˜50% wt) (2.03 ml, 31.55 mmol), and EtOH (23 mL) and heated under reflux overnight. Next day LC/MS showed completion. The mixture was concentrated and passed through a plug of silica (solvent used: 1% MeOH/DCM) to afford imidazo[1,2-a]pyrazine as off-white solid. MS [M+H]=120.1; Calc'd for C6H5N3: 119.1
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)=O.Cl.[F:14][C:15]([F:26])([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>CCO>[F:14][C:15]([F:25])([F:26])[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23]/[N:24]=[CH:1]/[C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(/C=N/Nc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a magnetically stirred solution of methyl 4-formylbenzoate (1.71 g, 10.41 mmoL) dissolved in EtOH (mL) was added (4-(trifluoromethoxy)phenyl)-hydrazine hydrochloride (2 g, 10.41 mmoL) and the reaction was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and dried under high vacuum to give (E)-methyl 4-((2-(4-(trifluoromethoxy)phenyl)-hydrazono)methyl)benzoate (3.08 g, 87%): mp 142-145° C.; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.72-7.65 (m, 3H), 7.13 (q, J=8.9 Hz, 4H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −58.36; ESIMS m/z 338 ([M+H])+.
Reaction SMILES: C[O-].[Na+].CO[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8].[S:12]1[C:16]2[S:17][CH2:18][CH2:19][C:20](=[O:21])[C:15]=2[CH:14]=[CH:13]1>C1C=CC=CC=1>[OH:21][C:20]1[C:15]2[CH:14]=[CH:13][S:12][C:16]=2[S:17][CH2:18][C:19]=1[C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCSc2sccc21
Reactant: COC(=O)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)C(=O)C1=C(O)c2ccsc2SC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
A mixture of sodium methoxide (21.6 g, 0.4 mole) and dimethyloxalate (47.2 g, 0.4 mole) in benzene (300 ml) is refluxed for 5 min. in order to dissolve most of the solid. To the cooled solution is added a solution of 5,6-dihydro-4H-thieno[2,3-b]-thiopyran-4-one (34 g, 0.2 mole) in benzene (300 ml) and the mixture is stirred for 3 hrs. to give a yellow suspension. The mixture is poured into ice-water mixture (1750 ml). After separating the aqueous layer from the benzene layer, the benzene layer is extracted with 1(N) NaOH solution (250 ml), and the combined aqueous solution is washed once with ether (100 ml) and acidified with (N) HCl. The yellow crystalline glyoxalate is filtered off and dried over P2O5 to give 45.8 g (91%) of the desired product; m.p. 53°-56° C. IR (CHCl 3) 3120-3040 (b, OH), 1735 (C=O), 1605 (C=C-C=O) cm-1. NMR (CDCl3) δ 10.6 (s, 1, OH, exchangeable); 7.35 (d, 1, C2); 7.05 (d, 1, C3); 4.4 (s, 2, C6); 3.9 (s, 3, OCH3). λmaxEtOH 320 (5,600), 238 (10,800) mμ. Anal. Calcd. for C10H8O4S2 : C, 46.86; H, 3.15; S, 25.02. Found: C, 46.92; H, 3.23; S, 24.58, 24.64.
Reaction SMILES: O1CCOCC1.[CH2:7]([C:9]1[CH:10]=[CH:11][C:12]([CH:15]=[CH2:16])=[N:13][CH:14]=1)[CH3:8].[Br:17]N1C(=O)CCC1=O.[OH2:25]>>[Br:17][CH2:16][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:7][CH3:8])=[CH:14][N:13]=1)[OH:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=Cc1ccc(CC)cn1
Reactant: O
Solvent: C1COCCO1
Product: CCc1ccc(C(O)CBr)nc1
Temperature: 27.5 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a stirred mixture of 225 mL 1,4-dioxane and 225 mL water, 75 g (0.5639 mol) of 5-ethyl-2-vinyl-pyridine was added, followed by 149 g (0.8371 mol) N-bromosuccinimide was added in to it. Reaction mixture was stirred at 25-30° C. for 4 hr. and subsequently quenched with excess water. Product was extracted with dichloromethane. Organic layer was separated and dried over calcium chloride. On concentrating the organic layer and purifying the residue, it gave 110.24 g (85%) of desired product.
Reaction SMILES: C([CH:8]([NH2:24])[CH2:9][CH2:10][NH:11][C:12]([P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:13])(OC(C)(C)C)=O.CCN(CC)CC.[O:32]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:32]([C:39]1[CH:44]=[CH:43][C:42]([S:45]([NH:24][CH2:8][CH2:9][CH2:10][NH:11][C:12]([P:14]([O:16][CH:17]([CH3:18])[CH3:19])([O:20][CH:21]([CH3:22])[CH3:23])=[O:15])=[O:13])(=[O:47])=[O:46])=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)OP(=O)(OC(C)C)C(=O)NCCC(N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OP(=O)(OC(C)C)C(=O)NCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
1-Boc-amino-3-[diisopropylphosphonoformamido]propane (0.7 g, 4 mmol) was dissolved in 5 ml TFA. The reaction was stirred for 30 min. The excess of TFA was removed by evaporation in vacuo with toluene. To the residue in 15 ml DCM were added Et3N (5 eq, 2.8 ml, 20 mmol) and 4-phenoxybenzenesulfonyl chloride (1 g, 45 mmol). The reaction was stirred overnight at room temperature. The mixture was washed with 1N HCl; the organic layer was dried over Na2SO4 and the solvent was evaporated. The product was purified by silica gel chromatography [eluent: CHCl3/1-2% MeOH] to yield 1 g (50%) yellow oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:10]=[C:11](Cl)[C:12]2[S:17][C:16]([NH2:18])=[N:15][C:13]=2[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:29][C@H:30]([CH2:33][CH2:34][CH3:35])[CH2:31][OH:32].O>CN1C(=O)CCC1>[NH2:18][C:16]1[S:17][C:12]2[C:11]([NH:29][C@H:30]([CH2:33][CH2:34][CH3:35])[CH2:31][OH:32])=[N:10][C:9]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:14][C:13]=2[N:15]=1
Reactant: CCC[C@@H](N)CO
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 110 °C
Yield: 97 %

Procedure:
5-(Benzylthio)-7-chloro[1,3]thiazolo[4,5-d]pyrimidin-2-amine (6.0 g, 19.4 mmol) was dissolved in NMP (30 mL). DIPEA (8.4 mL, 48.5 mmol) and 2-amino-(2R)-1-pentanol (3.5 g, 33.9 mmol) were added and the mixture was heated to 110° C. for 4 days. After cooling to ambient temperature, the mixture was poured into water (200 mL). The precipitated product was collected by filtration, washed with water and used in the next step without further purification (7.0 g, 97% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:32])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C@H:9]([C:11]1[N:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13](=[O:25])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[CH3:10].[CH:33](OCC)(OCC)OCC>>[C:26]1([N:12]2[C:11]([C@@H:9]([NH:8][C:7]3[CH:6]=[CH:5][N:4]=[C:3]4[S:32][CH:33]=[N:1][C:2]=34)[CH3:10])=[CH:20][C:19]3[C:14](=[C:15]([C:21]([F:23])([F:22])[F:24])[CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(OCC)OCC
Reactant: C[C@H](Nc1ccnc(S)c1N)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Product: C[C@H](Nc1ccnc2scnc12)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of (S)-3-(1-(3-amino-2-mercaptopyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoro methyl)isoquinolin-1(2H)-one III-35 (80 mg, 0.175 mmol, 1.0 eq) in triethyl orthoformate (180 mL) was stirred at reflux for 2 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-2% MeOH-DCM) to afford the product, (S)-2-phenyl-3-(1-(thiazolo[5,4-b]pyridin-7-ylamino)ethyl)-8-(trifluoromethyl)isoquinolin-1(2H)-one III-36. ESI-MS m/z: 467.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:28][C@H:29]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:30][C:31](O)=[O:32])(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:31](=[O:32])[CH2:30][C@H:29]([O:28][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: ClCCCl
Solvent: CI
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 89.4 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-dodecanoyloxytetradecanoic acid (935 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.08 g (90%) of N-[(R)-3-dodecanoyloxytetradecanoyl]-L-serine benzyl ester: mp 53-54° C. 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.5 Hz), 1.1-1.6 (m, 46H), 2.30 (t, 2H, J=7.7 Hz), 2.50 (d, 2H, 5.6 Hz), 2.62 (t, 1H, J=6.2 Hz), 3.97 (m, 2H), 4.65 (m, 1H), 5.19 (m, 3H), 6.63 (d, 1H, J=6.8 Hz), 7.35 (br s, 5H).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][OH:23])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(C)=O>ClCCl>[C:1]([O:5][C:6]([C@@:8]1([CH:22]=[O:23])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO)(C(=O)OC(C)(C)C)CC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@H](c1ccccc1)N1C[C@@](C=O)(C(=O)OC(C)(C)C)CC1=O
Reaction time: 17 h
Yield: 71.7 %

Procedure:
(3S)-3-Hydroxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (4.0 g, 12.52 mmol) was dissolved in dichloromethane. Triethylamine (6.34 g, 62.62 mmol), dimethyl sulfoxide (3.91 g, 50.09 mmol), and a SO3-pyridine complex (3.99 g, 25.05 mmol) were sequentially added at 0° C., and the mixture was stirred for 17 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (60% ethyl acetate/hexane) to give 2.85 g of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][C:9](=[O:11])[CH3:10])=S)=[CH:4][CH:3]=1.Cl.Cl.[NH2:16][CH:17]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:18]([NH:20][C:21]1([C:28]#[N:29])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[O:19]>>[C:9]([N:8]=[C:6]([NH:16][CH:17]([CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:18]([NH:20][C:21]1([C:28]#[N:29])[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1)=[O:19])[C:5]1[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: CC(=O)NC(=S)c1ccc(F)cc1
Agent: Cl
Product: CC(=O)N=C(NC(CC1CCCCC1)C(=O)NC1(C#N)CCN(C)CC1)c1ccc(F)cc1

Procedure:
The title compound was prepared starting from N-(4-fluoro-thiobenzoyl) acetamide and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide bis hydrochloride salt according to the procedure from Example 72, step b. MS, m/z 456=M+1.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([OH:5])=O.C(Cl)Cl.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31]>N1C=CC=CC=1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH2:32])=[O:31])=[O:5]
Reactant: O=C(O)C(Br)c1ccc(F)cn1
Reactant: NC(=O)c1ccccc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1ccccc1NC(=O)C(Br)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0.5 M solution of 2-bromo-2-(5-fluoropyridin-2-yl)acetic acid in 99:1 DCM/DMF is added oxalyl chloride (1.2 equiv) and the mixture is allowed to stir at rt for 30 min or until the reaction is substantially complete. The mixture is then cooled to 0° C. and 2-aminobenzamide (1 equiv) in pyridine (2 mL) is added slowly, and the mixture is allowed to warm to rt over ca. 1 h. The mixture is concentrated under reduced pressure and the residue is purified by chromatography to afford 2-(2-bromo-2-(5-fluoropyridin-2-yl)acetamido)benzamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][C:4](=O)[C@@H:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])(=O)C.[NH4+:17]>CO>[NH2:17][C:4]1[CH2:5][CH2:6][C@@H:2]([CH3:1])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)[C@H]1C(=O)CCC1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)C1=C(N)CC[C@H]1C
Reaction time: 20 h
Yield: 96.9 %

Procedure:
To a solution of (R)-ethyl 2-methyl-5-oxocyclopentanecarboxylate (106 g, 622 mmol) in 1.2 L MeOH was added ammonium acetate (240 g, 3.1 mol). The reaction was stirred for 20 hours and concentrated to remove MeOH. The resulting residue was dissolved in CH2Cl2, washed with H2O, brine, dried (Na2SO4), filtered and concentrated to give the title compound (102 g, 97% yield) as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([OH:16])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]2[CH:57]=[CH:56][C:55]3[C:54]4[C:49](=[CH:50][C:51]([C:58](=[O:61])[CH2:59]Br)=[CH:52][CH:53]=4)[CH2:48][CH2:47][C:46]=3[CH:45]=2)=[CH:42][N:43]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]([O:16][CH2:59][C:58]([C:51]2[CH:52]=[CH:53][C:54]3[C:55]4[C:46](=[CH:45][C:44]([C:41]5[NH:40][C:39]([CH:35]6[CH2:36][CH2:37][CH2:38][N:34]6[C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[N:43][CH:42]=5)=[CH:57][CH:56]=4)[CH2:47][CH2:48][C:49]=3[CH:50]=2)=[O:61])=[O:15])[CH:12]2[CH2:17][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(C(=O)CBr)ccc2-3)[nH]1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(C(=O)COC(=O)C4C5CCC(C5)N4C(=O)OC(C)(C)C)ccc2-3)[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (167 mg, 0.69 mmol) and DIPEA (0.11 mL, 0.67 mmol) was added to a solution of 2-{5-[7-(2-bromo-acetyl)-9,10-dihydro-phenanthren-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.37 mmol, crude) in acetonitrile (5 mL). The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO3 solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-9,10-dihydro-phenanthren-2-yl}-2-oxo-ethyl)ester 2-tert-butyl ester as a brown solid (132 mg, 51% over two steps). m/z 697.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.P([Cl:31])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:31])[C:2]([F:14])([F:13])[F:1])=[CH:7][CH:8]=1
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1ccc(NC(=O)C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(N=C(Cl)C(F)(F)F)cc1
Temperature: 82 °C
Yield: 88.5 %

Procedure:
Seven grams (34.5 mmol) of 2,2,2-trifluoro-N-(4-methylphenyl)acetamide, 18.49 g (68.9 mmol) of diphenyl chlorophosphate, 6.97 g (68.9 mmol) of triethylamine, and 35 ml of acetonitrile were introduced into a 100 ml flask and reacted for 18 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 25 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 6.77 g of N-(4-methylphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 88.6%).
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[O:4]1.[CH3:19]I.Cl>CN(C)C=O>[O:11]1[C:10]2[CH:9]=[CH:8][C:7]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[O:4][CH2:3][CH2:12]1
Reactant: CCOC(=O)Cc1ccc2c(c1)OCCO2
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc2c(c1)OCCO2

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (1.13 g) was added to a solution in N,N-dimethylformamide (65 ml) of ethyl 3,4-ethylenedioxyphenylacetate [M. Sasamoto, Chem. Pharm. Bull., 8, 324 (1969)] (6.00 g) in an ice bath. Thereafter, methyl iodide (1.76 ml) was added dropwise and the resulting mixture was stirred under ice-cooling for 4 hours. To the reaction mixture was added 1 N hydrochloric acid and the resulting mixture was subjected to extraction with diethyl ether, after which the extraction solution was washed with water and then dried. The solvent was removed by distillation under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (5.57 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][B-](F)(F)F.F[N+]1C(C(Cl)(Cl)Cl)=CC=CC=1Cl>ClC(Cl)CCl>[F:9][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:8]
Reactant: F[B-](F)(F)F
Reactant: Oc1ccc(Br)cc1
Agent: F[n+]1c(Cl)cccc1C(Cl)(Cl)Cl
Solvent: ClCC(Cl)Cl
Product: Oc1ccc(Br)cc1F
Temperature: 45 °C

Procedure:
A mixture of 0.86 g of 4-bromophenol, 1.67 g of N-fluoro-2-chloro-6-(trichloromethyl)pyridinium fluoroborate, and 40 ml of 1,1,2-trichloroethane was placed in a 100 ml 3-necked round bottomed flask equipped with a magnetic stirring bar, a thermometer, and a reflux condenser. The mixture was heated to 45° C. and allowed to react at that temperature for 23 hours under nitrogen. The mixture was then allowed to cool. Analysis by standardized gas-liquid chromatography using a mass spectrometer detector indicated that the title product was present in 74 percent conversion. The product identity was confirmed by its known 19F and 1H NMR spectra.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=1>O1CCCC1>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][O:12][C:18]2[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(=O)Nc1ccc(OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(OCCOc2ncc(Cl)cn2)cc1

Procedure:
A mixture of 2-(4-acetamidophenoxy)ethanol (25 g), granular sodium hydride (3.1 g) and dry tetrahydrofuran (250 ml) was heated under reflux for a period of 2 hours. 2,5-Dichloropyrimidine* (19 g) was added and the mixture was heated under reflux for a further 8 hours. The solvent was removed by distillation under reduced pressure, water was added and the crystalline product was collected and dried to give 2-[2-(4-acetamidophenoxy)ethoxy]-5-chloropyrimidine (35 g), m.p. 160° C.