Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:36])[C@@H:18]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[C:27]([Cl:35])[CH:26]=3)[CH2:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:12]2)=[CH:6][CH:5]=1.Cl>O1CCOCC1.O>[Cl:35][C:27]1[CH:26]=[C:25]([C@@H:18]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:17]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)[N:12]=2)=[O:36])[CH:30]=[CH:29][C:28]=1[S:31]([CH3:34])(=[O:32])=[O:33]
Reactant: COC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
The 4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid methyl ester (prepared in example 44, 840 mg, 1.54 mmol) was dissolved in dioxane (20 mL) and 6.0 M aqueous hydrochloric acid (20 mL) was added. The reaction was heated to 80° C. in a sealed vial while stirring for 8 h. Upon cooling, the reaction was diluted with water (25 mL) and the product extracted into ethyl acetate (3×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the desired product, 4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (328 mg, 40%) as a white powder: ESI-LRMS m/e calcd for C26H28ClN3O5S [M+] 529.1, found 530.2 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.13 (m, 2H, CH2), 1.33-1.80 (m, 8H, 4×CH2), 1.94-2.19 (m, 1H, CH), 3.32 (s, 3 H, SO2CH3), 3.83-3.93 (m, 1H, CH), 5.26 (s, 2H, NCH2), 6.47 (d, J=2.2 Hz, 1H, Ar), 7.26 (d, Jo=8.4 Hz, 2H, Ar), 7.55 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.65 (d, Jm=1.7 Hz, 1H, Ar), 7.74 (d, J=2.2 Hz, 1H, Ar), 7.87 (d, Jo=8.4 Hz, 2H, Ar), 7.97 (d, Jo=8.2 Hz, 1H, Ar), 10.78 (s, 1H, NH), 12.88 (br.s., 1H, CO2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[S:14][C:15]([F:18])([F:17])[F:16].Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.[OH-].[Na+]>>[F:17][C:15]([F:18])([F:16])[S:14][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: CCOC(=O)Cc1ccc(O)c(SC(F)(F)F)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(SC(F)(F)F)c1

Procedure:
In analogy to the procedure of Example XIV, the title compound is prepared from 10 g (0.036 mol) of ethyl 4-hydroxy-3-trifluoromethylthiophenylacetate, 7.7 g (0.036 mol) of 2-chloromethylquinoline and 2.88 g (0.072 mol) of sodium hydroxide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]=O)[CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[BH4-].[Na+]>CO.ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][NH:22][CH:19]2[CH2:21][CH2:20]2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2cccnc12
Reactant: NC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: c1cnc2c(CNC3CC3)cccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a dichloromethane (0.13 M) solution of 8-quinolinecarbaldehyde (1 eq.) was added magnesium sulphate (1 eq.) and cyclopropyl amine (2 eq.). The resulting suspension was stirred at RT for 16 h. The insolubles were removed via filtration and rinsed with dichloromethane before the combined filtrate was concentrated in vacuo. The crude imine thus obtained was taken up in methanol (0.13 M) and then added sodium borohydride (1.5 eq.) portionwise. The reaction mixture was stirred at RT for 2 h before it was quenched with 1 N aq. HCl. The pH of the solution was then adjusted to ˜10 with 1 N aq. NaOH before it was extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford the crude title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](I)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8].[CH2:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)[CH3:33]>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([C:37]3[CH:38]=[CH:39][C:34]([CH2:32][CH3:33])=[CH:35][CH:36]=3)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=1)=[O:8]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(I)c(C)c2)s1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2c(C)cc(OC(CCC(F)(F)F)c3ccc(C(=O)NCCC(=O)OC)s3)cc2C)cc1

Procedure:
This compound is made by the general method as exemplified in Preparation 77 using 3-({5-[4,4,4-trifluoro-1-(4-iodo-3,5-dimethyl-phenoxy)-butyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester - chiral Isomer 1 and 4-ethyl-phenyl boronic acid as the starting materials. MS(ES): 548.3 [M+H]+.
Reaction SMILES: Br.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9].CCOCC.[CH3:31][C:32]1[CH:41]=[CH:40][C:35]([CH2:36][C:37](Cl)=[S:38])=[CH:34][CH:33]=1.C(N(CC)CC)C>O>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:9][C:37]([CH2:36][C:35]1[CH:40]=[CH:41][C:32]([CH3:31])=[CH:33][CH:34]=1)=[S:38]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(CC(=S)Cl)cc1
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=S)Cc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
4.0 G (0.01 mol) of L-phenylalanyl-L-phenylalanine methylester hydrobromide was dissolved in 50 ml of water. To the solution was added 10 ml of an ether solution containing 2.21 g (0.011 mol) of 4-methylbenzylthiocarbonylchloride and was further dropwise added an aqueous solution containing 2.28 g (0.022 mol) of triethylamine for 15 minutes. After this, the mixture was stirred for 30 minutes while cooling with ice and was further stirred at room temperature for 4 hours. After completion of reaction, the reaction mixture was extracted with about 50 ml of ethylacetate. The ethylacetate layer was washed with 2N hydrochloric acid and then with water and was dried over anhydrous sodium sulfate. After drying, the drying agent was filtered. After removing the solvent of filtrate by evaporation in vacuo, the resultant solid material was recrystallized from 25 ml of ethylacetate and about 40 ml of n-hexane to obtain 3.7 g of white crystals.
Reaction SMILES: [ClH:1].Cl.N1(C2CCCCC2(CCC2C=CC(OCC3C=CC=CC=3C(F)(F)F)=CC=2)O)CCNCC1.[OH:36][C:37]1([CH:43]([C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[C:73]([F:76])([F:75])[F:74])=[CH:61][CH:60]=2)[C:44]([N:46]2[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]2)=O)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[ClH:1].[ClH:1].[N:46]1([CH2:44][CH:43]([C:37]2([OH:36])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:59]2[CH:64]=[CH:63][C:62]([O:65][CH2:66][C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[C:73]([F:76])([F:75])[F:74])=[CH:61][CH:60]=2)[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(OCc3ccccc3C(F)(F)F)cc2)C2(O)CCCCC2)CC1
Agent: Cl
Agent: OC1(CCc2ccc(OCc3ccccc3C(F)(F)F)cc2)CCCCC1N1CCNCC1
Product: OC1(C(CN2CCNCC2)c2ccc(OCc3ccccc3C(F)(F)F)cc2)CCCCC1

Procedure:
In an analogous manner to Example 1, step 2, 1-[2-piperazin-1-yl-1-(4-{[2-(trifluoromethyl)benzyl]oxy}phenylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[(1-hydroxycyclohexyl)(4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)acetyl]piperazine-1-carboxylate. MS (ES) m/z 463.3; HRMS: calcd for C26H33F3N2O2+H+, 463.25669; found (ESI-FT/MS, [M+H]1+), 463.2574.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[O:4].N[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.ClC1C=CC(Cl)=CC=1Cl.CNC>>[C:8]1([NH:5][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)C(N)=O
Reactant: Nc1ccccc1
Agent: CNC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CN(C)C(=O)Nc1ccccc1
Temperature: 205 °C
Reaction time: 5.5 h

Procedure:
3.35 g (0.038 mol) of N,N-dimethylurea and 2.33 g (0.025 mol) of aniline were added with stirring into 28 ml of 1,2,4-trichlorobenzene. The reaction mixture was slowly heated to 205° C., dimethylamine being passed in from 60° C. After 5.5 hours, 11.8 g (0.27 mol) of dimethylamine had been passed in and the reaction was complete. The reaction mixture was cooled to room temperature, whereupon a precipitate deposited. The precipitate was filtered off, washed with 1,2,4-trichlorobenzene, dried and then boiled in water. The aqueous mixture was cooled, and the precipitate was filtered off with suction and dried. 3.3 g of N-phenyl-N',N'-dimethylurea, i.e. 81% of theory, having a melting point of 130° to 133° C. were obtained in this way.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN([C:20]([O:24][N:25]1N=NC2C=CC=N[C:26]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>C(Cl)Cl.O>[CH3:20][O:24][N:25]([CH3:26])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (10 g, 43 mmol) in DCM (60 mL) was added HATU (19 g, 50 mmol) in portions, The mixture was stirred at room temperature for 0.5 h. Then DIPEA (12.9 g, 100 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.0 g, 51.5 mmol) were added in the mixture. The mixture was stirred at room temperature overnight. Water (40 mL) was added and the mixture was extracted by DCM (100 mL*3). The organic layer was washed with brine (5 mL) and dried over sodium sulfate. Concentration and purification by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-10/1) to give tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (10 g, 84%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:30]=[CH:31][CH:32]=3)[CH:16]=[C:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:20]1[CH2:21][CH2:22][C:17](=[CH:16][C:15]2[CH:14]=[C:13]([CH:32]=[CH:31][CH:30]=2)[O:12][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(N4CCCC4)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C(=C1CCNCC1)c1cccc(Oc2ccc(N3CCCC3)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of tert-butyl 4-(3-(5-(pyrrolidin-1-yl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.335 g, 0.769 mmol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.88 mL, 11.49 mmol). The resulting mixture was stirred for 1 h at RT. The solution was concentrated and then quenched with saturated NaHCO3 solution. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.224 g, 86.8%). 1H NMR (500 MHz, DMSO-d6): δ 7.59 (s, 1H), 7.23 (m, 1H), 6.95 (m, 1H), 6.89 (d, J=7.5 Hz, 1H), 6.82 (m, 3H), 6.25 (s, 1H), 3.27 (m, 4H), 2.98 (m, 2H), 2.86 (m, 2H), 2.49 (m, 2H), 2.34 (m, 2H), 2.02 (m, 4H); m/z (336.2, MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:8]([C:6]2[N:5]=[C:4]([NH2:23])[N:3]=[C:2]([NH:29][C:28]3[CH:30]=[CH:31][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH:7]=2)[CH:13]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCC2CCCCC2)n1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Cl)ccc2OCC2CCCCC2)n1
Yield: 98 %

Procedure:
Following the method described in Example 72, 4-chloro-6-(5-chloro-2-cyclohexylmethoxy-phenyl)-pyrimidin-2-yl-amine and 4-chloro-aniline provided the title compound (98% yield). 1H NMR (DMSO-d6) δ 1.15-1.19 (m, 4H, CH2) δ 1.65-1.73 (m, 6H, CH2), 3.89 (d, 2H, J=5.7 Hz, Ar), 6.49 (s, 1H, Ar), 7.27 (d, 1H, J=8.4 Hz, Ar), 7.46 (d, 2H, J=8.7 Hz, Ar), 7.61 (d, 2H, J=8.5 Hz, Ar), 7.82-7.85 (m, 2H, Ar).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:35]=[CH:34][C:24]([O:25][C:26]2[CH:27]=[C:28]([CH2:29][N:4]3[CH2:3][CH2:2][N:1]([C:7]4[CH:8]=[CH:9][C:10]5[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=5)[N:12]=4)[CH2:6][CH2:5]3)[CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(Oc2cccc(C=O)c2)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cc1ccc(Oc2cccc(CN3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)c2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-(4-methylphenoxy)benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[3-(4-methylphenoxy)phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[O:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CO>[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[O:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]=1
Reactant: O=Cc1cc(Br)c(-c2nc(-c3ccc(Cl)cc3)no2)o1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Clc1ccc(-c2noc(-c3oc(CN4CCOCC4)cc3Br)n2)cc1
Reaction time: 24 h
Yield: 16.6 %

Procedure:
To a stirring solution of 5-(3-bromo-5-formyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole (60 mg, 0.170 mmol), sodium cyanoborohydride (10.5 mg, 0.167 mmol), acetic acid (10.0 μL, 0.173 mmol), and methanol (2.0 mL) under argon was added morpholine (50 μL, 0.57 mmol). The solution was stirred for 24 h and concentrated to dryness. The product was purified by column chromatography (2:1, hexane:ethyl acetate) to yield 12 mg (17%) of 5-(3-bromo-5-morpholinomethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole as a white solid. 1H NMR (CDCl3): 8.12 (d, J=8.51 Hz, 2H), 7.49 (d, J=8.52 Hz, 2H), 6.60 (s, 1H), 3.74 (t, J=4.67 Hz, 4H), 3.67 (s, 2H), 2.56 (t, J=4.67 Hz, 4H); and to also yield 12 mg (20%) of 5-(3-bromo-5-hydroxymethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole as a white solid. 1H NMR (CDCl3): 8.11 (dd, J=8.79, 2.20 Hz, 2H), 7.49 (dd, J=8.79, 2.20 Hz, 2H), 6.67 (s, 1H), 4.77 (d, J=6.32 Hz, 2H), 2.09 (t, J=6.46 Hz, 4H).
Reaction SMILES: S(=O)(=O)(O)[O-].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22](O)([CH2:23][CH3:24])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:15]2=[O:26])=[C:10]([F:27])[CH:9]=1>C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:22](=[CH:23][CH3:24])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[C:15]2=[O:26])=[C:10]([F:27])[CH:9]=1
Reactant: CCC1(O)C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)cc1F
Reaction time: 0.25 h

Procedure:
One part of potassium bisulfate and 25.3 parts of 2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-3-hydroxy-3-ethyl-1H-isoindol-1-one were heated with occasional stirring in an oil bath at 160°-170° for 15 minutes. The melt was poured into 200 parts of chloroform and washed successively with 100 parts of water, 50 parts of 10% aqueous sodium chloride solution and 100 parts of saturated aqueous sodium chloride solution. After drying the organic phase with anhydrous sodium sulfate, the solvent was evaporated at 300 mm. Hg at 50° to 22.3 parts of brown, glassy 2-(4-chloro-2-fluorophenyl) -2,3,4,5,6,7-hexahydro-3-ethylidene-1H-isoindol-1-one. The mixture of geometric isomers present was indicated by the absorption in the nuclear magnetic resonance spectrum of 5.1δ (1H, singlet vinyl proton) and 0.95δ (3H, singlet vinyl proton) and 1.3δ (1H, singlet vinyl proton) and 1.3δ (3H, singlet allylic methyl) for the isomer present in 40% of the total mixture.
Reaction SMILES: [Cl:1][C:2]([O:5]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][C@H:22]([CH2:26][CH3:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].N1C=CC=CC=1>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]([Cl:1])=[O:5])[C@H:22]([CH2:26][CH3:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 262.3 %

Procedure:
Bis-(trichloromethyl)-carbonate (13.9 g, 47 mM) was dissolved in dichloromethane (500 mL) and cooled to 0° C. A mixture of (R)-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester (26.5 g; 0.124 M) and pyridine (10.9 mL, 0.136 M) in dichloromethane (150 mL) was added dropwise with stirring (0–3° C.). Stirring was continued for another ½ h at room temperature. The mixture was washed with water and brine, the water phases were extracted with dichloromethane, organic phases were pooled, dried with Na2SO4 and evaporated to yield a brown oil (34 g, 99%) which crystallized upon standing; MS (EI): 276.2 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[NH:7][C:6]([C:13]([OH:15])=O)=[CH:5]2.[CH3:16][CH:17]([NH:19][C:20]1[C:21]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1)[CH3:18].N=C=N>>[CH3:18][CH:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:13]([C:6]2[NH:7][C:8]3[C:4](=[CH:3][C:2]([F:1])=[C:10]([O:11][CH3:12])[CH:9]=3)[CH:5]=2)=[O:15])[CH2:30][CH2:31]1)[CH3:16]
Reactant: CC(C)Nc1cccnc1N1CCNCC1
Reactant: COc1cc2[nH]c(C(=O)O)cc2cc1F
Agent: N=C=N
Product: COc1cc2[nH]c(C(=O)N3CCN(c4ncccc4NC(C)C)CC3)cc2cc1F

Procedure:
Following the general procedure of EXAMPLE 16A and making non-critical variations but starting with 5-fluoro-6-methoxyindole-2-carboxylic acid (PREPARATION 92, 0.30 g), 1-[3-(1-methylethylamino)-2-pyridinyl]piperazine (0.32 g) and 1-(ethyl)-3-dimethylaminopropyl) carbodiimide (0.33 g), the title compound is obtained, mp 193°-194°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)CC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)C(CC)Oc1ccc(OCc2ccccc2)cc1

Procedure:
In analogy to the procedure described in Example 1b), the alkylation of 4-benzyloxy-phenol [Example 2a)] with ethyl (RS)-2-bromobutyrate in acetone using cesium carbonate as the base yielded the (RS)-2-(4-benzyloxy-phenoxy)-butyric acid ethyl ester as a brown oil; MS: m/e=314 (M)+.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[N:17]1CCOCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>C1COCC1>[C:1]([NH:8][C@@H:9]([C:13]([NH2:17])=[O:15])[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To a stirred solution of Boc-D-Valine (25 g, 115 mMol) in THF (300 mL) at 0° C. was added N-Methylmorpholine (15 mL, 136 mMol) followed by the dropwise addition of isoButyl chloroformate (18 mL, 139 mMol) over 5 minutes. The reaction was stirred at 0° C. for 30 minutes after which a solution of 30 wt. % NH4OH (50 mL, 385 mMol) was quickly poured into the reaction. (Vigorous gas evolution was seen which subsided after a few minutes.) The reaction was allowed to warm to RT and stirred for 4 h. The reaction was concentrated under vacuum on the rotoevaporator to a volume which precipitated most of the product. The thick white slurry was diluted with an equal volume of water, filtered, rinsed with water, pressed dry then dried under vacuum to give the title compound (22.56 g, 91%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 6.17 (br s, 1H), 5.75 (br s, 1H), 5.12 (d, 1H), 4.00 (app. t, 1H), 2.13 (m, 1H), 1.44 (s, 9H), 0.99 (d, 3H), 0.94 (d, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][C:11](=[N:13]O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:12][C:11]1[N:13]=[C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[O:8][CH:10]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)=NO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1coc(-c2cccnc2)n1
Temperature: 130 °C
Yield: 31.3 %

Procedure:
30 g of nicotinoyl chloride is added to 5.1 g of cooled acetoxime, then the mixture is heated to 130° C. The exothermic reaction mixture is maintained under agitation for 6 hours at 140° C. After cooling, iced water is added, followed by alkalizing with sodium carbonate and extracting with methylene chloride. The solvent is evaporated, the residue is taken up with ether and filtered; the solvent is evaporated and the residue is distilled at 150° C. under 0.08 mbar. 3.5 g of expected product is obtained which is purified by chromatography on silica (eluant: cyclohexane-ethyl acetate 7-3), with further distillation. After cooling, a solid product is obtained.
Reaction SMILES: ClC1N=CC=CN=1.NCCSCC1OC(CN2CCC([NH:25][C:26]3[N:30](CC4C=CC(F)=CC=4)[C:29]4[CH:39]=[CH:40][CH:41]=[CH:42][C:28]=4[N:27]=3)CC2)=CC=1.C(=O)([O-])O.[Na+]>C(O)C>[NH:27]1[C:28]2[CH:42]=[CH:41][CH:40]=[CH:39][C:29]=2[N:30]=[C:26]1[NH2:25]
Reactant: NCCSCc1ccc(CN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)o1
Agent: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2ccccc2[nH]1

Procedure:
A mixture of 1.14 parts of 2-chloropyrimidine, 5 parts of N-[1-[[5-[(2-aminoethyl)thiomethyl]-2-furanyl]methyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 8 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The main fraction was collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane, yielding 1.2 parts (21%) of 1-[(4-fluorophenyl)methyl]-N-[1-[[5-]]2-(2-pyrimidinylamino)ethyl]thiomethyl]-2-furanyl]methyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 128.9° C. (compound 50).