Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[CH:26]=[CH:27][C:28]2[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]3[C@@H:31]([CH3:35])[CH2:32][O:33][C:34]=1[C:29]=23>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[CH:26]=[CH:27][C:28]4[C:38](=[O:39])[C:37]([C:40]([OH:42])=[O:41])=[CH:36][N:30]5[C@@H:31]([CH3:35])[CH2:32][O:33][C:34]=3[C:29]=45)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N3CC[C@@H](C4(N)CC4)C3)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 100 °C
Yield: 36.5 %

Procedure:
After adding 3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]pyrrolidine (252 mg, 1.12 mmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (3 ml), 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (244 mg, 928 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 18 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduce pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml) and saturated saline solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (6 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 4 ml of water to the reaction solution and washing this acidic aqueous solution with chloroform (10 ml×3), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by recrystallization from ethanol and then dried under a reduced pressure. 125 mg (36.5%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [CH2:1]([C@@H:8]1[N:11]([Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:10](=[O:19])[C@H:9]1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:23])=[N-]>CCOCC>[CH2:1]([C@@H:8]1[N:11]([Si:12]([C:15]([CH3:17])([CH3:16])[CH3:18])([CH3:13])[CH3:14])[C:10](=[O:19])[C@H:9]1[O:20][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](O)[C@@H]1Cc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CO[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of 4(S)-benzyl-1-(tert-butyldimethyl-silyl)-3(S)-hydroxyazetidin-2-one (150 mg, 0.51 mmol) in Et2O (70 mL) at 0° was added silica gel (40-60 μm, 9 g). The vigorously stirred mixture was treated with diazomethane in Et2O (50 mL, 0.3-0.5 M solution). Once the yellow color had almost disappeared after about 15 min, additional diazomethane solution (20 mL) was added. This procedure was repeated several times until no more starting material could be detected on TLC (about 1.5 h). The reaction mixture was stirred for an additional hour at room temperature then filtered and concentrated to give 4(S)-benzyl-1-(tert-butyl-dimethylsilyl)-3(S)-methoxyazetidin-2-one (157 mg, 99% yield) as a white solid which was pure enough for further manipulation. 1H-NMR (400 MHz, CDCl3) δ7.27-7.20 (m, 5H), 4.16 (d, J=1.9 HZ, 1H), 3.67 (ddd, J=11.1, 3.8, 1.9 Hz, 1H), 3.23 (dd, J=13.5, 3.8 Hz, 1H), 2.94 (s, 3H), 2.57 (dd, J=13.4, 11.1 Hz, 1H), 1.01 (s, 9H), 0.32 (d, J=6 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([CH2:18][CH:19]=[CH2:20])[CH:8]=1)[CH3:2].[CH3:25][C:26]1[O:30][C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH2:37][CH2:38]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH2:38][CH2:37][C:27]2[N:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:30][C:26]=2[CH3:25])=[C:9]([CH2:18][CH:19]=[CH2:20])[CH:8]=1)[CH3:2]
Reactant: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1O
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCc1cc(CC(OCC)C(=O)OCC)c2ccccc2c1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedure described in example 17 a], [rac]-3-(3-allyl-4-hydroxy-naphthalen-1-yl)-2-ethoxy-propionic acid ethyl ester was reacted with 2-(5-methyl-2-phenyl-oxazole-4yl)-ethanol in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-3-{3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-ethoxy-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-3-{3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-naphthalen-1-yl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=O)[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:39]([F:42])([F:41])[F:40])(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:52])=CC=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[S:52])[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:39]([F:42])([F:41])[F:40])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CS(=O)(=O)c1ccc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1C(F)(F)F

Procedure:
1-[4-(4-Methanesulfonyl-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-4-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-butan-1-one (7 mg; 0.011 mmol, prepared in accordance with Example 30) is reacted with Lawesson's reagent (2 mg; 0.006 mmol) according to the general conditions described in Example 109. The desired product is obtained following purification by preparative HPLC (2 mg; 0.004 mmol). The structure was confirmed using Protocol I-B. Calculated mass=637; observed mass=637; HPLC retention time=4.48 min.
Reaction SMILES: [O:1]=[C:2]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:3][CH2:4][NH:5]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:5][CH2:4][CH2:3][C:2]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:1]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(=O)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
Tert-butyl 3-oxo-3-(phenylsulfonamido)propylcarbamate (3.6 g, 15.1 mmol) was dissolved in dichloromethane (60 mL). Then CF3COOH (1.1 mL, 0.3 mmol, 20 equiv) was added to the mixture at 0° C. and stirred for 2 h at 0° C. The reaction mixture was concentrated and purified by flash chromatograph to give 3-amino-N-(phenylsulfonyl)propanamide as a white solid (1.4 g, 40%). EDI-MS: 229.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 7.79˜7.71 (m, 2H), 7.70˜7.43 (brs, 3H), 7.42˜7.34 (m, 3H), 2.83 (t, 2H), 2.24 (t, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[C:18]([OH:23])(=[O:22])[C:19]([CH3:21])=O.C([BH3-])#N.[Na+]>>[C:18]([CH:19]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH3:21])([OH:23])=[O:22]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: CC(=O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(N[C@@H](C)C(=O)N1C2CCCCC2C[C@H]1C(=O)O)C(=O)O

Procedure:
As described in Example 5, react 1 -[(S)-alanyl ]octahydroindole-2(S)-carboxylic acid (prepared as described in Example 1) and pyruvic acid with sodium cyanoborohydride to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11](=[O:16])[N:10]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21](C(OC(C)(C)C)=O)[CH:22]=[N:23][C:19]=2[CH:18]=1.Br[CH2:34][CH3:35]>>[NH:21]1[C:20]2[CH:31]=[CH:32][C:17]([N:10]3[CH:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])[C:13]([CH3:14])=[C:12]([O:15][CH2:34][CH3:35])[C:11]3=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: CCBr
Reactant: CC1=C(O)C(=O)N(c2ccc3c(c2)ncn3C(=O)OC(C)(C)C)C1c1cccc(F)c1F
Product: CCOC1=C(C)C(c2cccc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from tert-butyl 5-(2-(2,3-difluorophenyl)-4-hydroxy-3-methyl-5-oxo-2H-pyrrol-1(5H)-yl)-1H-benzo[d]imidazole-1-carboxylate (0.22 g, 0.5 mmol), bromoethane (0.056 ml, 0.75 mmol) and PrtBu (0.191 ml, 0.75 mmol) according to the method described above.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11]O>OS(O)(=O)=O>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)nc1
Temperature: 60 °C

Procedure:
To a solution of 10 g 6-Amino-nicotinic acid in 100 mL MeOH, 0.8 mL concentrated H2SO4 were added and the mixture was heated to 60° C. for 12 h. Then the reaction mixture was concentrated under reduced pressure. After addition of 50 mL ice water the mixture was brought to pH 8 by addition of K2CO3. The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined organic layers were dried over MgSO4. Removal of the solvent yielded 5.5 g of the desired product which was subjected to the following reaction without further purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:34][C:35]1[CH:36]=[C:37]([CH2:41][NH2:42])[CH:38]=[CH:39][CH:40]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[C:37]([CH2:41][NH:42][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:38]=[CH:39][CH:40]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Reactant: NCc1cccc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2)n1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A mixture of 6-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (600 mg, 1.326 mmol), 1-(3-bromophenyl)methanamine (247 mg, 1.326 mmol), HBTU (o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (603 mg, 1.591 mmol) and Et3N (0.924 mL, 6.63 mmol) in DCM was stirred at room temperature over the weekend. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was then purified with flash chromatography eluting with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (632 mg, 49.9%). LC-MS m/z 620 (M+H)+, 0.89 min (ret time).
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[NH:6]([C:13]1[N:18]=[C:17]([CH2:19][NH:20][CH2:21][CH2:22][OH:23])[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[Br-].[Na+]>C(Cl)Cl>[NH:6]([C:13]1[N:18]=[C:17]([CH2:19][N:20]2[CH2:21][CH2:22][O:23][CH2:2][C:3]2=[O:4])[CH:16]=[CH:15][N:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)CCl
Reactant: OCCNCc1ccnc(Nc2ccccc2)n1
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1COCCN1Cc1ccnc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.7 %

Procedure:
A solution of chloroacetyl chloride (268 mg, 2.38 mmol) in dry DCM (5 ml) was added dropwise over 10 minutes to a stirred solution of 2-anilino-4-(2-hydroxyethylaminomethyl)pyrimidine (Method 19; 582 mg, 2.38 mmol) and triethylamine (332 μl, 2.38 mmol) in dry DCM (20 ml) under nitrogen. The reaction mixture was then stirred for 20 hours at ambient temperature. The mixture was diluted with DCM and washed with water (×2), saturated brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was dissolved in dry THF (20 ml), sodium bromide (227 mg, 2.2 mmol) added and the mixture stirred at 0° C. under nitrogen sodium hydride (88 mg of a 60% dispersion in oil) was added in one portion and the reaction stirred at 0° C. for 10 minutes and then at ambient temperature for 72 hours. The volatiles were removed by evaporation and the residue partition between EtOAc and water. The layers were separated and the organic layer washed with water, saturated brine, dried (Na2SO4) and the solvent removed by evaporation. The residue was purified by chromatography eluting with EtOAc. The purified product was triturated with diethyl ether, collected by filtration, washed with diethyl ether and dried to give the title compound (438 mg, 70%) as a white solid. NMR: 3.43 (t, 2H), 3.87 (t, 2H), 4.13 (s, 2H),4.52 (s, 2H), 6.72 (d, 1H), 6.93 (t, 1H), 7.25 (t 2H), 7.75 (d, 2H), 8.42 (d, 1H), 9.55 (s, 1H); m/z 285.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH:7]=[C:8]([C:19]([CH3:21])=O)[C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])=[O:10])([O-:3])=[O:2].C(O)(=O)C.[C:29]([CH2:32][C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34])(=[NH:31])[NH2:30].C[O-].[Na+]>C(O)(C)C>[NH2:30][C:29]1[NH:31][C:19]([CH3:21])=[C:8]([C:9]([O:11][CH2:12][CH2:13][CH2:14][O:15][N+:16]([O-:18])=[O:17])=[O:10])[CH:7]([C:6]2[CH:22]=[CH:23][CH:24]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:32]=1[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][N+:40]([O-:42])=[O:41])=[O:34]
Reactant: N=C(N)CC(=O)OCCCO[N+](=O)[O-]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OCCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC1=C(C(=O)OCCCO[N+](=O)[O-])C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCCCO[N+](=O)[O-])=C(N)N1
Yield: 65.9 %

Procedure:
500 ml of an isopropanol solution containing 18.8 g (55.7 mmoles) of 3-nitrooxypropyl 2-(3-nitrobenzylidene)acetoacetate, 14.76 g (55.7 mmoles) of 3-nitrooxypropyl amidinoacetate acetate and 3.00 g (55.7 mmoles) of sodium methoxide were heated under reflux for 90 minutes. The solution was then cooled and insolubles were filtered off. The isopropanol was then evaporated off under reduced pressure. The resulting residue was dissolved in methylene chloride, and the solution was washed with water and dried over anhydrous sodium sulfate. The methylene chloride was evaporated off under reduced pressure, to give a residue, which was purified by silica gel column chromatography, eluted with a 3:1 by volume mixture of toluene and ethyl acetate, and the product was recrystallized from toluene, to afford 19.3 g (yield 65.9%) of the title compound as yellow powdery crystals, melting at 145°-146° C.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].O.[CH3:14][N:15](C=O)C>>[CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:14]#[N:15])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4]
Reactant: CC(C)(CO)c1ccc(Br)cc1
Reactant: CN(C)C=O
Solvent: O
Product: CC(C)(CO)c1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
p-(1,1-Dimethyl-2-hydroxyethyl)bromobenzene, 148 g, 0.646 mole, was added to a 1 L flask fitted with a reflux condenser, magnetic stirrer and oil bath. Dimethylformamide, 350 mL, and cuprous cyanide, 69.4 g, 0.775 mole were then added to the flask. The heterogeneous mixture was heated to gentle reflux whereupon it became somewhat more homogeneous and would then easily stir. The mixture was heated at reflux for five hours. While still hot the mixture was cast into 1 L of water using 100 mL of hot DMF for washing out the flask. The precipitated residue was stirred by hand as well as possible, allowed to settle and the greater portion of the water decanted and discarded. A freshly prepared solution of ferric chloride, 340 g; conc. HCl, 85 mL; water, 510 mL was added to the residue to destroy copper complexes. The mixture was heated with good stirring at 60° to 70° C. for 20 to 30 minutes. The crude nitrile was then extracted with three 200 mL portions of benzene. The benzene extracts were combined and dried over anhydrous K2CO3 for 1/2 hour. Benzene was removed in a rotoevaporator to give a yellowish oil which crystallized easily when cooled to room temperature and scratched. The yield was about 102 g (90%), mp=70°-82° C.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH:25]([CH3:27])[CH3:26])[C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Cl)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]([CH:25]([CH3:26])[CH3:27])[C:19](=[O:24])[CH2:20][CH2:21][CH2:22][O:3][CH2:2][CH2:1][OH:4])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)N(C(=O)CCCCl)C1CCN(Cc2ccccc2)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)N(C(=O)CCCOCCO)C1CCN(Cc2ccccc2)CC1
Yield: 50.4 %

Procedure:
A mixture of ethylene glycol (15 mL, 268 mmol) and N-(1-benzylpiperdin-4-yl)-N-isopropyl 4-chlorobutyramide (5.0 g, 14.9 mmol) was heated at 140° C. for 2 h in the presence of a catalytic amount p-toluenesulfonic acid. The reaction mixture was then dissolved in dichloromethane and the solution washed with 1 N sodium hydroxide, aqueous sodium bicarbonate solution and brine; and dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (dichloromethane/methanol/ammonium hydroxide: 90/9/1) to give 2.72 g of the title intermediate as viscous oil (51% yield).
Reaction SMILES: [CH2:1]([CH:4]([C:8]([CH3:10])=[CH2:9])[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[CH2:1]([CH:4]([C:8]1([CH3:10])[O:19][CH2:9]1)[C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3]
Reactant: C=CCC(C(=C)C)C(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: C=CCC(C(C)=O)C1(C)CO1
Reaction time: 3 h
Yield: 23.3 %

Procedure:
To a solution of 3-allyl-4-methyl-pent-4-en-2-one (20.0 g) in methylene chloride (100 ml) was added dropwise a solution of m-chloroperbenzoic acid (29 g) in methylene chloride (300 ml) at 0° to 5° C. The reaction mixture was stirred at 0° to 5° C. for 3 hours and then at 20° C. overnight. The reaction solution was progressively washed with an aqueous sodium hydrogen carbonate solution, aqueous sodium sulfite solution, aqueous sodium hydrogen carbonate solution and then with an aqueous sodium chloride solution. After removing the solvent by evaporation, the residue was distilled to obtain 7.2 g of the unreacted material and 5.2 g of the objective 3-allyl-4-methyl-4,5-epoxy-pentan-2-one.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.[C:44](O)([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl>[CH3:41][C:37]1[CH:36]=[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:42])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:45][CH2:44][C:46]([F:49])([F:48])[F:47])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)[CH:40]=[CH:39][N:38]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from [2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M105) (0.41 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (260 mg, 79%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:19])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:20][C:21]1[N:22]=[C:23]([CH3:29])[NH:24][C:25]=1[C:26](O)=[O:27]>>[Cl:20][C:21]1[N:22]=[C:23]([CH3:29])[NH:24][C:25]=1[C:26]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:19])=[O:27]
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cccc(Oc2c(Cl)ccc(CN)c2F)c1
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cccc(C#N)c3)c2F)[nH]1
Yield: 40.1 %

Procedure:
A solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.20 g, 0.56 mmol), sodium formate (0.057 g, 0.84 mmol) and Pd(Ph3P)4 (0.032 g, 0.028 mmol) in DMF (1.13 ml) was heated at 100° C. for 6 h. Water was added and the mixture was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and dried to afford 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}benzonitrile, which was used without further purification. The above amine (0.28 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.040 g, 0.25 mmol) were employed in a similar process described herein to prepare the title compound (0.042 g, 40%) as a white solid after purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) followed by neutralization. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.89 (br. s., 1H), 7.32-7.45 (m, 2H), 7.12-7.31 (m, 4 H), 7.08 (s, 1H), 4.70 (d, J=5.91 Hz, 2H), 2.37 (s, 3H). ES-LCMS: m/z 419.0, 421.0 (M+1).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[CH:7]([C:9]1[CH:10]=[CH:11][C:12]2[S:16][CH:15]=[C:14]([CH2:17][CH2:18][NH:19][C:20]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:13]=2[CH:28]=1)=[O:8]>CC(C)=O.O.CC(C)=O>[CH:22]1([C:20]([NH:19][CH2:18][CH2:17][C:14]2[C:13]3[CH:28]=[C:9]([C:7]([OH:2])=[O:8])[CH:10]=[CH:11][C:12]=3[S:16][CH:15]=2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=Cc1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc2scc(CCNC(=O)C3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.7 g of potassium permanganate in 50 ml of an acetone/water mixture (50/50) are added at room temperature to a solution of 6.88 mmol of the product obtained in Step E in 30 ml of acetone. The solution is stirred for 2 hours at room temperature and then filtered. The filtrate is concentrated under reduced pressure and chromatographed over silica gel to yield the title product.