Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C[O-].[Na+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:24][C:25]2[N:30]=[C:29]([C:31](=O)[CH3:32])[CH:28]=[C:27]([CH2:34][O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:26]=2)[CH:15]=[CH:16][C:17]=1[N:18]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+].O.CO>[F:2][CH:3]1[CH2:6][N:5]([CH:31]([C:29]2[CH:28]=[C:27]([CH2:34][O:35][CH2:36][C:37]([F:40])([F:39])[F:38])[N:26]=[C:25]([NH:24][C:14]3[CH:15]=[CH:16][C:17]([N:18]4[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19]4)=[C:12]([O:11][CH3:10])[CH:13]=3)[N:30]=2)[CH3:32])[CH2:4]1
Reactant: FC1CNC1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-n1cnc(C)c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)N3CC(F)C3)n2)ccc1-n1cnc(C)c1
Reaction time: 0.03 h

Procedure:
3-Fluoroazetidine hydrochloride (28 mg, 0.25 mmol) was mixed with methanol (5 mL). Sodium methoxide (0.046 mL, 0.25 mmol) was added followed by 1-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-yl)ethanone (90 mg, 0.21 mmol). The mixture was stirred for 2 min. Acetic acid (0.044 mL, 0.76 mmol) was added. The mixture was stirred for 5 min. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred at rt under nitrogen atmosphere for 16 hours. Water was added and the mixture was stirred for 5 min then diluted with DCM and sodium bicarbonate (sat, aq). The phases were separated and the aqueous layer was extracted with DCM. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica eluting with a gradient of MeOH and DCM. The residue was purified by preparative HPLC to give the title compound as a dry film, 33 mg (32%).
Reaction SMILES: [Br:1][C:2]1[C:7]2=[N:8]S[N:10]=[C:6]2[C:5]([Br:11])=[CH:4][CH:3]=1.N1SN=C2C=CC=CC=12>[Zn].C(O)(=O)C.O>[Br:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:10])[C:5]([Br:11])=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)c2nsnc12
Agent: [Zn]
Agent: c1ccc2nsnc2c1
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(Br)ccc(Br)c1N
Temperature: 70 °C
Yield: 70 %

Procedure:
4,7-dibromobenzo[1,2,5]thiadiazole (6.0 g, 20.3 mmol), prepared according to WO 00/55927 PCT/GB00/00911 by bromination of benzo[1,2,5]thiadiazole, was placed in a 200-mL flask under a nitrogen atmosphere. Zinc dust (13.2 g, 203 mmol) and a mixture of acetic acid/water (35 mL/35 mL) were added. The flask was loosely capped with an inverted 1-neck flask. The reaction mixture was heated to 70° C. for 1 hr at which time reaction was complete as determined by TLC. The mixture was then cooled to room temperature and filtered. The solid was extracted with diethylether (3×100 mL). The extract was washed with saturated aqueous sodium bicarbonate and dried over MgSO4. The solution was filtered and evaporated to dryness using a rotary evaporator. The solid was purified by chromatography on a silica gel column, using dichloromethane as eluent. The appropriate fractions were combined and the solvent was removed under reducing pressure. A light yellow product was obtained. Yield: 70%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[CH:8][CH:9]=[C:10]([C:16]([O:18]C)=[O:17])[C:11]([C:12]([O:14]C)=[O:13])=[C:6]2[N:5]=[C:4]1[CH3:20])[CH3:2].[OH-].[Na+].Cl>CO>[CH2:1]([N:3]1[C:7]2=[CH:8][CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]([C:12]([OH:14])=[O:13])=[C:6]2[N:5]=[C:4]1[CH3:20])[CH3:2]
Reactant: CCn1c(C)nc2c(C(=O)OC)c(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c(C)nc2c(C(=O)O)c(C(=O)O)ccc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A mixture of dimethyl 1-ethyl-2-methyl-4,5-benzimidazoledicarboxylate (5.30 g, 19.2 mmol), methanol and 5N sodium hydroxide (30 mL, 150 mmol) is stirred for 4 hours at 100° C., cooled, acidified with hydrochloric acid and filtered to give the title product as a lemon yellow powder (4.07 g, 85.5%), identified by 1HNMR spectral analysis.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([C:40]([N:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CNCCN1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(=O)N2CCNCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, 1-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidine-4-carboxylic acid was reacted with piperazine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H49Cl2N6O3 [(M+H)+] 719.3238, observed 719.3243.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.Br[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:34])=[C:23]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:34][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:8]([C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)[N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)=[CH:24][C:23]=1[O:25][C:26](=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Oc1cc(CBr)ccc1Cl)c1ccccc1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(Cl)c(OC(=O)c3ccccc3)c2)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 200 mg, 5.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMF (20 mL) at r.t. The mixture was stirred for 1 hour at this temperature and benzoic acid 5-bromomethyl-2-chloro-phenyl ester (CAB02138, 1.63 g, 5.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (75 mL) was added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc, Rf: 0.31) to give a white solid. Yield: 1.773 g (82%). 1H-NMR (400 MHz, CDCl3) δ=4.93 (s, 2H), 6.66 (d, 9.0 Hz, 2H), 7.06 (dd, J=8.2, 2.0 Hz, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.45 (d, J=8.2 Hz, 1H), 7.47-7.58 (m, 4H), 7.60-7.69 (m, 1H), 8.16-8.21 (m, 2H), 8.24 (s, 2H). LRMS (FAB+): 430.1 (100, [M+H]+).
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[N+:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=1[CH3:25])([O-:17])=[O:16]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:11][CH:10]([O:12][C:21]2[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[C:19]([CH3:25])[CH:20]=2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
In a dry flask, N-Boc-3-hydroxy-azetidine (9.8 g, 57 mmol) was dissolved in 200 mL of dry THF. The solution was cooled with an ice-water bath and sodium hydride (2.0 g, 83.mmol) was added in several portions. The suspension was stirred for an additional 0.5 hours, then 7.9 g of 2-nitro-5-fluorotoluene (7.9 g, 51 mmol) in 100 mL of dry THF was added dropwise. The solution was stirred overnight at room temperature. The THF was removed under vacuum and the residue was partitioned between ethyl acetate and water (100 mL each). The organic layer was collected and the aqueous layer was subsequently extracted twice with ethyl acetate. The combined organic layers were washed with 1 N HCl, water, saturated sodium bicarbonate and brine (50 mL each). The organic layer was dried over anhydrous sodium sulfate, concentrated. The residue was purified by silica gel column (EtOAc/Hexanes 1:19→1:4 gradient) to give 12.0 g (43 mmol, 84% yield) of the title compound, which was used directly in the next step. MS: 309 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.O.[C:12]([O:19][CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][O:19][C:12](=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)CCC(=O)OCC(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(NN=C(COC(=O)CCC(C)=O)OCc2ccccc2)cc1
Yield: 104.4 %

Procedure:
5.2 g of p-methoxyphenylhydrazine were suspended in 25 ml of glacial acetic acid and 90 ml of water and 10 g of benzyl levulinoyloxyacetate were slowly added at room temperature while stirring. After stirring for 1 hour, the mixture was extracted by shaking with toluene, the toluene solution was washed neutral with water, dried and concentrated. 15.1 g of benzyl levulinoyloxyacetate (p-methoxyphenyl)-hydrazone were obtained as a brownish oil, which was not purified but was dissolved in 25 ml of absolute pyridine, and then 100 ml of ether were added and mixed with a solution of 8.7 g of p-chlorobenzoyl chloride in 50 ml of ether at 0°C with the introduction of nitrogen. After boiling for 2 hours under nitrogen, the solution was cooled, washed neutral with water, dried and concentrated by evaporation. 19 g (crude yield) of N(2) -(p-chlorobenzoyl)-N(2) -(p-methoxyphenyl)-hydrazone of benzyl levulinoyloxyacetate were obtained. This product was further treated without purification, by taking it up in 75 ml of glacial acetic acid and heating for 5 hours at 80°C. After evaporating off the glacial acetic acid under vacuum, the further treatment was carried out as described in Example 1. The yield of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate amounted to 11% of the theoretical, based on the total amount of hydrazine.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:32])[CH2:8][CH2:9][CH2:10][C:11]([CH3:31])(O)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:29])(O)[CH2:17][CH2:18][CH2:19][CH:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:3].CCCCCCC>[Pd].C(O)(=O)C>[CH3:26][CH:24]([CH2:23][CH2:22][CH2:21][CH:20]([CH2:19][CH2:18][CH2:17][CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][CH2:8][CH:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:3])[CH3:1])[CH3:32])[CH3:31])[CH3:29])[CH3:27])[CH3:25]
Reactant: CC(C)CCCC(C)CCCC(C)(O)CCCCC(C)(O)CCCC(C)CCCC(C)C
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C

Procedure:
In a 300 ml autoclave were placed 20 g of 2,6,10,15,19,23-hexamethyltetracosane-10,15-diol, 40 ml of n-heptane, 0.4 ml of acetic acid and 0.4 g of 5 % palladium on active carbon and the mixture was hydrogenated at 200° C under a hydrogen pressure of 100 kg/cm2 for 15 hours to give squalane quantitatively.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(=O)(O)[O-].[Na+].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](Cl)=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1>O1CCCC1.O>[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25](=[O:26])[NH:4][CH2:3][CH2:1][OH:2])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: NCCO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
To a stirred mixture of ethanolamine (0.49 g, 8 mmol), tetrahydrofuran, water and sodium bicarbonate (1.5 g, 18 mmol) at 6° C., was added a solution 9-fluorenylmethylchloroformate (2.27 g, 8.8 mmol) in tetrahydrofuran in one portion, stirring was continued for 1 h allowing the mixture to warm to room temperature. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate filtered and evaporated to a crude product. The crude product was re-crystallised from dichloromethane to give (2-hydroxy-ethyl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a white solid (1.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:33][O:34][C:35]1[CH:45]=[CH:44][C:43](/[CH:46]=[CH:47]/[C:48](=[O:61])[C:49]2[CH:54]=[C:53]([O:55][CH3:56])[C:52]([O:57][CH3:58])=[C:51]([O:59][CH3:60])[CH:50]=2)=[CH:42][C:36]=1[O:37][CH2:38][C:39](O)=[O:40]>ClCCl.O>[CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:39](=[O:40])[CH2:38][O:37][C:36]3[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](=[O:61])[C:49]4[CH:50]=[C:51]([O:59][CH3:60])[C:52]([O:57][CH3:58])=[C:53]([O:55][CH3:56])[CH:54]=4)[CH:44]=[CH:45][C:35]=3[O:34][CH3:33])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2sc(N)nc12
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2c(C)cccc2s1
Yield: 802 %

Procedure:
To a solution of 4-methyl-2-aminobenzothiazole (164 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9k) (440 mg, 80% yield)
Reaction SMILES: C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:44][N:43]2[C:45]([CH2:48][C:49]([F:52])([F:51])[F:50])=[N:46][N:47]=[C:42]2[CH:41]([CH2:53][C:54](O)=[O:55])[CH2:40][CH2:39]1.[Cl-].[Cl-].[O:59]=[C:60]1[NH:68][C:63]2=[NH+:64][CH:65]=[CH:66][CH:67]=[C:62]2[N:61]1[CH:69]1[CH2:74][CH2:73][NH2+:72][CH2:71][CH2:70]1>C(#N)C.CN(C)C=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[F:30][C:31]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH:38]1[CH2:44][N:43]2[C:45]([CH2:48][C:49]([F:50])([F:52])[F:51])=[N:46][N:47]=[C:42]2[CH:41]([CH2:53][C:54]([N:72]2[CH2:71][CH2:70][CH:69]([N:61]3[C:62]4[C:63](=[N:64][CH:65]=[CH:66][CH:67]=4)[NH:68][C:60]3=[O:59])[CH2:74][CH2:73]2)=[O:55])[CH2:40][CH2:39]1
Reactant: O=c1[nH]c2[nH+]cccc2n1C1CC[NH2+]CC1
Reactant: O=C(O)CC1CCC(c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(CC1CCC(c2cccc(F)c2F)Cn2c(CC(F)(F)F)nnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reaction time: 4 h

Procedure:
Triethylamine (146 μL, 1.044 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69 mg, 0.358 mmol), and 1-hydroxy-7-azabenzotriazole (41 mg, 0.298 mmol) were added to a solution of the hydrochloride salt of [6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetic acid (127 mg, 0.298 mmol) and 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (87 mg, 0.298 mmol) in acetonitrile (3 mL) and N,N-dimethylformamide (1 mL). After 4 h, the reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine, dried with sodium sulfate, filtered and concentrated to give the title compound. Purification by reverse phase HPLC (100% water→100% acetonitrile with 0.1% trifluoroacetic acid) gave racemic cis compounds 1-(1-{[(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one and 1-(1-{[(6R,9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; MS 590.2299 (M+1), and racemic trans compounds 1-(1-{[(6S,9S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one and 1-(1-{[(6R,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl]acetyl}piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one; MS 590.2293 (M+1). The trans enantiomers were separated by Chiralpak OD column (2×35 cm), 60% hexanes (0.1% diethylamine)/ethanol at 6 mL/min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[CH:34]1([N:37]([CH3:44])[CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][NH:40]2)[CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH:34]1([N:37]([CH2:38][C@@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH3:44])[CH2:35][CH2:36]1
Reactant: CN(C[C@@H]1CCCN1)C1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (165 mg, 0.33 mmol), cyclopropyl-methyl-(S)-1-pyrrolidin-2-ylmethyl-amine (65 mg, 0.46 mmol), HOBt (687 mg, 0.5 mmol), EDAC (101 mg, 0.53 mmol) and TEA (0.1 mL) in DMF (4 mL) was stirred at rt for 48 hours. The reaction was concentrated, diluted with sodium bicarbonate, extracted with DCM. The combined DCM was dried, concentrated and purified on a silica gel column to give the titled compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].[NH2:16][C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH2:18][C@H:17]([NH:16][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)[CH2:26][CH2:25]3)[CH2:28][CH2:29]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(Trifluoroacetyl)benzoic acid (0.50 g, 2.4 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 20 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (97 mg, 0.43 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (85 μL, 0.61 mmol) in methylene chloride (35 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 98 mg (54%) of the title compound as slightly yellow crystals: mp 91-93° C.; [α]21D -47° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 453 (27, M+).
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>CCOCC>[O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][C:13]([CH3:21])([C:17]([F:18])([F:19])[F:20])[C:14]([O:16][CH3:26])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Oc1ccc(Oc2ccccc2)cc1)(C(=O)O)C(F)(F)F
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(C)(Oc1ccc(Oc2ccccc2)cc1)C(F)(F)F

Procedure:
A solution of (±)-2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionic acid (6.4 g.) in ether is treated with an excess of ethereal diazomethane at 0° C. The solution is evaporated and the residue distilled to give (±)-methyl 2-(4-phenoxyphenoxy)-3,3,3-trifluoro-2-methylpropionate (3.3 g.), b.p. 187° C. at 0.1 mm. pressure.