Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18]1([CH3:34])[CH:23]=[CH:22][C:21]([C:24]2[O:28][C:27]([CH2:29][CH2:30][C:31](O)=[O:32])=[N:26][CH:25]=2)=[CH:20][CH:19]=1>>[CH3:34][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:28][C:27]([CH2:29][CH2:30][C:31]([NH:17][C:14]3[CH:15]=[C:16]4[C:11]([CH:10]=[N:9][N:8]4[CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)=[O:32])=[N:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: Cc1ccc(-c2cnc(CCC(=O)O)o2)cc1
Product: Cc1ccc(-c2cnc(CCC(=O)Nc3ccc4cnn(CCN5CCCC5)c4c3)o2)cc1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(5-p-tolyl-oxazol-2-yl)-propionic acid were processed to provide the title compound. MS (DCI/NH3) MS m/z 444 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.82 (m, 2 H), 1.98 (m, 2 H), 2.32 (s, 3 H), 2.93 (t, J=7.02 Hz, 2 H), 3.03 (m, 2 H), 3.15 (t, J=7.02 Hz, 2 H), 3.52 (m, 2 H), 3.69 (q, J=5.93 Hz, 2 H), 4.67 (t, J=6.24 Hz, 2 H), 7.10 (m, 1 H), 7.25 (m, 2 H), 7.47 (s, 1 H), 7.55 (m, 2 H), 7.71 (m, 1 H), 8.08 (s, 1 H), 8.31 (s, 1 H), 9.60 (br s, N H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH2:24]>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH2:23][NH:24][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: COc1ccccc1CCN
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Product: COc1ccccc1CCNC(=O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2-(2-methoxyphenyl)ethylamine. The product was purified by chromatography on silica gel eluting with methanol/dichloromethane (3:97) to give the title compound as a yellow solid. δH (CD3OD): 2.94 (2H, t), 3.59 (2H, t), 3.78 (3H, s), 6.84 (1H, t), 6.89 (1H, d), 6.97 (1H, s), 7.12-7.18 (2H, m), 7.60 (1H, s), 8.55 (1H, s); m/z (ES+)=330 [M+H]+.
Reaction SMILES: C[C:2]([CH3:4])=[O:3].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH:29]1[C:34]([OH:35])=[CH:33][C:32]2[O:36][C:37]([CH:39]=[CH:40][C:31]=2[CH:30]=1)=[O:38].C1C[O:44]CC1>>[CH:29]1[C:34]([OH:35])=[CH:33][C:32]2[O:36][C:37]([CH:39]=[C:40]([CH2:4][C:2]([OH:44])=[O:3])[C:31]=2[CH:30]=1)=[O:38]
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: CC(C)=O
Reactant: C1CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Product: O=C(O)Cc1cc(=O)oc2cc(O)ccc12
Yield: 69 %

Procedure:
20.0 g of poly(HEMA4.0 -MMA1) was dissolved in 500 cc THF plus acetone (3:2) at boiling (60° C.). 0.271 g CMU was added and stirred until dissolved. 0.245 g dicyclohexylcarbodiimide and 25 mg dimethylaminopyridine, each dissolved in THF, were added and the solution stirred for 3 hours at boiling (60° C.). The reaction solution was then work-up as described for i., giving a limegreen powder, weight 13.81 g (69% yield) of poly(HEMA4.0 -MMA1) with a theoretical molar substitution of 0.96% umbelliferone on HEMA monomer. Actual substitution was 0.53%.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19](C(O)(C)C)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2.Cl[CH2:28][C:29](=[O:31])[CH3:30].C([O-])([O-])=[O:33].[K+].[K+]>CC(C)=O>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19]([O:33][CH2:28][C:29](=[O:31])[CH3:30])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(C(C)(C)O)c(C)c34)ccc2[nH]1
Reactant: CC(=O)CCl
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1cn2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2c1C
Yield: 90.7 %

Procedure:
A mixture of Example 1 (3.1 g, 10 mmol), chloroacetone (1.02 g, 11 mmol), and K2CO3 (4.1 g, 30 mmol) in acetone (100 mL) was heated at 50° C. for 6 h. The mixture was cooled and concentrated to give a beige solid which was washed with ethyl acetate/dichloromethane (1:1). The filtrate was purified by passing through a short pad of silica gel to afford the desired product (3.34 g, 91% yield) as a light beige solid. MS: (M+H)+=369.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10]([NH2:11])=[C:9]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:8]=[C:7]([S:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=2)[N:6]=1)=[O:4].CN.[CH3:34][N:35]([CH2:37]CN)[CH3:36]>>[CH3:34][N:35]([CH2:37][CH2:1][NH:2][C:3]([C:5]1[C:10]([NH2:11])=[C:9]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:8]=[C:7]([S:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])=[CH:22][CH:21]=2)[N:6]=1)=[O:4])[CH3:36]
Reactant: CN(C)CCN
Reactant: CNC(=O)c1nc(Sc2ccc(NC(=O)C3CC3)cc2)nc(Nc2cc(C)[nH]n2)c1N
Agent: CN
Product: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)nc(C(=O)NCCN(C)C)c2N)n[nH]1

Procedure:
The title compound was prepared in the manner described above for compound 9 with the exception that the methylamine reagent was replaced with 2-(N,N-dimethylamino)ethylamine. The title compound was recovered as a yellow-off white solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61]C(=O)C4C=CC(I)=CC=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:71]([O-:73])=[O:72])[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][CH:42]([CH2:43]3)[CH2:41]1)[CH2:47]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)(C)C.ClCCCl>[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:6]5[CH:5]=[CH:4][S:3][C:2]=5[Cl:1])=[CH:15][CH:14]=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:71]([O-:73])=[O:72])[CH2:49][CH:44]3[CH2:43][CH:42]([CH2:48][CH:46]([CH2:45]3)[CH2:47]1)[CH2:41]2
Reactant: O=C(O)c1ccc(-c2ccsc2Cl)cc1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(I)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: O=C(NS(=O)(=O)c1ccc(NCC23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(-c2ccsc2Cl)cc1
Reaction time: 8 h

Procedure:
A room temperature mixture of Example 29A (39.4 mg, 0.17 mmol), resin-bound dicyclohexylcarbodiimide (225.0 mg, 1.83 mmol/g), and dimethylaminopyridine (60.0 mg, 4.95 mmol) was treated with a solution of Example 28A (40 mg, 0.11 mmol) in a 1:1 mixture of 1,2-dichloroethane and 2-methyl-2-propanol (3 mL), and agitated overnight on an Argonaut Technologies Quest 210. The mixture was treated with resin bound p-TsOH (990 mg, 1.44 mmol/g), agitated for 1 hour, decanted, and washed with dichloromethane. The combined extracts were concentrated and purified by HPLC using 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 586 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ12.50 (s, 1H), 8.66 (d, 1H), 8.57 (t, 1H), 7.96 (d, 2H), 7.95 (dd, 1H), 7.71 (d, 2H), 7.59 (d, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.29 (d, 1H), 3.17 (d, 2H), 1.97 (s, 3H), 1.58 (m, 12H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH3:32][C:33]1[C:37](B(O)O)=[C:36]([CH3:41])[O:35][N:34]=1>>[NH2:23][C@H:18]1[C@@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:37]3[C:33]([CH3:32])=[N:34][O:35][C:36]=3[CH3:41])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cc1noc(C)c1-c1nc(C(=O)Nc2cnn(C)c2[C@@H]2CC[C@@H](N)[C@@H](F)CO2)cs1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3R,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 100), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (3,5-dimethylisoxazol-4-yl)boronic acid gave 244. 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.47 (s, 1H), 7.83 (s, 1H), 5.01 (d, J=50.4 Hz, 1H), 4.84 (d, J=10.2 Hz, 1H), 4.24-4.06 (m, 1H), 4.06-3.88 (m, 1H), 3.78 (s, 3H), 3.45-3.31 (m, 1H), 2.77 (s, 3H), 2.56 (s, 3H), 2.09-1.84 (m, 3H), 1.76-1.68 (m, 1H). LCMS (ES+) m/z 435 (M+1).
Reaction SMILES: C(S[N:4]=[CH:5][C:6]1[C:7]([CH:17]([CH3:19])[CH3:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])C.[CH3:20][O:21][CH2:22][CH2:23][C:24]([NH:26][NH2:27])=O>C(O)(=O)C>[CH:17]([C:7]1[C:6]([C:5]2[NH:4][C:24]([CH2:23][CH2:22][O:21][CH3:20])=[N:26][N:27]=2)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:16])[CH:8]=1)([CH3:18])[CH3:19]
Reactant: CCSN=Cc1cc(C(=O)OC)c(C)cc1C(C)C
Reactant: COCCC(=O)NN
Solvent: CC(=O)O
Product: COCCc1nnc(-c2cc(C(=O)OC)c(C)cc2C(C)C)[nH]1
Temperature: 80 °C

Procedure:
Methyl 5-((ethylthio)(imino)methyl)-4-isopropyl-2-methylbenzoate (compound 198.4, 33 mg, 0.12 mmol, 1.0 equiv), 3-methoxypropanehydrazide (compound 143.1, 21 mg, 0.18 mmol, 1.5 equiv) and acetic acid (1.2 mL) were added to a 4-mL vial and heated at 80° C. with a loose cap for 4 hours. The solvent was removed in vacuo and the residue was dissolved in DCM (10 mL) and washed with saturated NaHCO3 (5 mL) then brine (5 mL), dried (Na2SO4), filtered and evaporated to a colorless oil (theoretical yield). m/z (ES+) 318 (M+H)+.
Reaction SMILES: C(=[N:14][C:15]1[CH:42]=[CH:41][C:18]2[N:19]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:20]([CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]([CH:32]([CH3:34])[CH3:33])[C:24]3=[O:35])=[N:21][C:17]=2[CH:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1>Cl.C1COCC1>[NH2:14][C:15]1[CH:42]=[CH:41][C:18]2[N:19]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:20]([CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]([CH:32]([CH3:34])[CH3:33])[C:24]3=[O:35])=[N:21][C:17]=2[CH:16]=1
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(N=C(c3ccccc3)c3ccccc3)ccc21
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(N)ccc21
Yield: 85.1 %

Procedure:
A solution of 1-[5-(benzhydrylidene-amino)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one (32 mg, 0.06 mmol) in 0.5 M HCl-THF was stirred at ambient temperature for 1 h. The solvent was evaporated and the residue purified by prep-HPLC (gradient 10%-100% B) to give 20 mg (85%) of 1-[5-amino-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-3-isopropyl-1,3-dihydro-benzoimidazol-2-one as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]=2[CH3:22])=[CH:5][C:4]=1[B:23]1[O:27]C(C)(C)C(C)(C)[O:24]1.Cl.I([O-])(=O)(=O)=O.[Na+].C(OCC)(=O)C>O>[C:16]([O:15][C:13]([C:12]1[CH:20]=[CH:21][C:9]([C:6]2[CH:5]=[C:4]([B:23]([OH:27])[OH:24])[C:3]([O:2][CH3:1])=[N:8][CH:7]=2)=[C:10]([CH3:22])[CH:11]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ncc(-c2ccc(C(=O)OC(C)(C)C)cc2C)cc1B(O)O

Procedure:
A solution of tert-butyl 4-[6-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]-3-methylbenzoate (INTERMEDIATE 31, 16.0 g, 37.6 mmol), HCl (150 mL, 150 mmol), sodium periodate (24.14 g, 113 mmol) and ethyl acetate (150 mL) was stirred rapidly at room temperature for 1 hour, at which time LCMS showed complete boronate ester hydrolysis. The reaction was diluted with some water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated. The crude was purified by silica gel chromatography to give the title compound. LCMS (M+H)+: 343.95. 1H NMR (500 MHz, CDCl3) δ 8.24 (d, 1H), 8.14 (d, 1H), 7.93 (s, 1H) 7.88 (d, 1H), 7.28 (d, 1H), 5.84 (br, 2H) 4.13 (s, 3H), 2.35 (s, 3H), 1.64 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OCC)=[O:19].[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:15])(=[O:16])[N:4]([CH3:17])[C:3]=1[C:18]([NH:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1)=[O:19]
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2cnccn2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 52 %

Procedure:
Prepared analogous to Example 1 from ethyl 4-hydroxy-2-methyl-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and aminopyrazine with a yield of 52% of theory.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17]([O-])(O)=O.[Na+]>CO>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:7]=1[Br:6]
Reactant: O=C([O-])O
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C)ccc1Br
Temperature: 25 °C

Procedure:
1 mL H2SO4 is added to 2-bromo-5-methyl-benzoic acid (7.5 g, 70 mmol) in 75 mL methanol. The reaction mixture is refluxed 16 hours and cooled to room temperature. 100 mL saturated NaHCO3 (aq) is added. Methanol is removed in vacuo. The resulting mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound.
Reaction SMILES: [OH:1][CH2:2][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4]1.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][CH2:2][N:3]1[CH:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:4]1)(=[O:28])[CH3:27]
Reactant: N#Cc1cn(CO)cc1-c1ccccc1Cl
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)OCn1cc(C#N)c(-c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
41.4 g of N-hydroxymethyl-3-(2-chlorophenyl)-4-cyanopyrrole are dissolved in 350 ml of pyridine and 1.8 g of dimethylaminopyridine are added. Then 21.4 ml of acetic anhydride are slowly added dropwise at 0° to 7° C. and the mixture is stirred for 12 hours. The reaction mixture is then poured into ice-water and extracted twice with ethyl acetate. The extracts are washed twice with dilute ice-cold hydrochloric acid and twice with a semi-saturated aqueous solution of sodium chloride, dried over sodium sulfate and filtered. The filtrate is concentrated and the residue is recrystallised from diethyl ether/hexane to give the title compound in the form of colourless crystals with a melting point of 91°-95° C.
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:13]([O:14][CH2:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]4[N:30]([CH3:31])[N:29]=[N:28][CH:27]=4)[CH:17]=3)[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32][CH2:33][C:34]#[C:35][CH2:36]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:32][CH2:33][C:34]#[C:35][CH2:36][N:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]3[N:30]([CH3:31])[N:29]=[N:28][CH:27]=3)[CH:17]=2)[C@@H:8]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1nncc1-c1cc(CO[C@H]2CCCN[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: ClCC#CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(CC#CCCl)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [2S,3S]-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine hydrochloride (270 mg) in N,N-dimethylformamide (3.0 ml) was slowly added to a solution of 1,4-dichlorobut-2-yne (189 ml) and potassium carbonate (269 mg) in N,N-dimethylformamide (5.0 ml). The solution was stirred for 18 hours at room temperature and the solvent removed under reduced pressure. To the residue was added water (40 ml) and the product was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with water, saturated brine, dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue was purified by MPLC (40% ethyl acetate/hexane) to give [2S,3S]-1-(4-chlorobut-2-yn-1-yl)-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow oil (142 mg). 1H NMR (360 MHz,CDCl3) δ 1.52 (2H, m), 2.16 (2H, m), 2.64 (1H, m), 3.00 (1H, m), 3.30 (2H, m), 3.48 (1H, br s), 3.57 (1H, s), 3.98 (3H, s), 4.11 (1H, d, J=11.0 Hz), 4.15 (1H, s) 4.52 (2H, d, J=11.0 Hz), 7.17-7.26 (4H, m), 7.40-7.47 (4H, m), 7.68 (1H, s).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1.[NH2:17][CH2:18][CH2:19][CH:20]([O:26]C1CCCCO1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].S([O-])([O-])(=O)=O.[Na+].[Na+].[SH:40][CH2:41][C:42](O)=[O:43].Cl>O.C(Cl)(Cl)Cl.CO>[OH:26][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18][N:17]1[C:42](=[O:43])[CH2:41][S:40][CH:2]1[CH2:3][CH2:4][CH2:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=1
Reactant: CCCCCC(CCN)OC1CCCCO1
Reactant: O=C(O)CS
Reactant: CCOC(=O)c1ccc(CCCC=O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCC(O)CCN1C(=O)CSC1CCCc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.6 %

Procedure:
Ethyl 4-(4-oxobutyl)benzoate (4.63 g., 21 mmol.) is added dropwise to 1-amino-3-(tetrahydro-2H-pyran-2-yloxy)octane (4.82 g., 21 mmol.) at ambient temperature. The resulting mixture is stirred for 15 minutes before adding anhydrous sodium sulfate (4 g.), and then stirred for 1 hour. The solid is subsequently removed by filtration and washed with a small quantity of benzene. The combined filtrate and washings are diluted with benzene (70 ml.) and then treated with mercaptoacetic acid (1.93 g., 21 mmol.). The resulting solution is refluxed in a Dean-Stark apparatus for 3 hours. The reaction mixture is allowed to cool to room temperature, washed successively with dilute hydrochloric acid, 5% sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated to give an oil residue. A methanol solution (50 ml.) of the oil residue is treated with concentrated hydrochloric acid (0.2 ml.) and then stirred at ambient temperature for 16 hours. The reaction mixture is diluted with cold water, followed by extraction with ether. The ethereal extract is washed with water, 5% sodium bicarbonate, dried over anhydrous magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo provides an oil residue which is then applied to a silica gel column (300 g.) with chloroform. Elution with chloroform-methanol (100:1; v:v; 1950 ml.) provides impure material; further elution with the same eluant (450 ml.) gives the title compound as a pale yellow oil (2.80 g., 6.64 mmol., 31%), pmr (CDCl3) δ0.90 (3H, t), 1.40 (3H, t), 3.53 (2H, s), 4.40 (2H, q), 4.70 (1H, m), 7.22 (2H, d), 8.0 (2H, d).
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:48][C@@H:49]([CH2:57][C:58]1[CH:63]=[CH:62][C:61]([O:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:60][CH:59]=1)[C:50]([NH:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C.C(OCC)C>[CH2:65]([O:64][C:61]1[CH:62]=[CH:63][C:58]([CH2:57][C@H:49]([NH:48][C:12]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:14])[C:50](=[O:51])[NH:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[CH:59][CH:60]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(C)(C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C1(c2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
1-Phenyl-1-cyclopentanecarboxylic acid (0.171 g, 0.899 mmol) was dissolved in dry DMF (3 mL) under a nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added in succession N,N-diisopropylethylamine (0.310 mL, 1.80 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.341 g, 0.899 mmol, Novabiochem, La Jolla, Calif.). The resulting reaction mixture was stirred at 0° C. for 30 minutes, (S)-2-Amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (0.293 g, 0.899 mmol) was then added. After an additional 60 minutes stirring at 0° C., the reaction mixture was mixed with 60 mL of diethyl ether. The resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution and brine, and was dried over Na2SO4. The solution was concentrated in vacuo, and an oil was obtained. The crude residue was purified by chromatography (silica gel, 60% ether in hexanes) to give the title compound as a white foam (0.20 g, 45%); mp 40-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:56][C:57]([F:67])([F:66])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64][NH2:65]>C1COCC1.CN(C=O)C>[Cl:26][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([NH:65][CH2:64][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=3[C:57]([F:56])([F:66])[F:67])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1(C)Cc2c(c(C(=O)NCc3ccccc3C(F)(F)F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 21.5 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.050 g, 0.127 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.082 g, 0.255 mmol), N-methyl morpholine (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and 1-[2-(trifluoromethyl)phenyl]methanamine (Intermediate-4, 0.027 g, 0.154 mmol) to afford 0.015 g of the desired product. 1HNMR (DMSO-d6): δ 1.21 (s, 3H), 1.48 (s, 3H), 3.01 (s, 2H), 4.68 (m, 2H), 7.19 (s, 1H), 7.46-7.51 (m, 2H), 7.62 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 8.27 (m, 1H), 8.41 (s, 2H), 10.89 (s, 1H), 11.42 (s, 1H); MS [M+H]+: 550.31.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([C:13]2[NH:17][N:16]=[N:15][N:14]=2)=[CH:5][CH:4]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:12][C:10]2[S:11][C:7]3[C:6]([C:13]4[NH:14][N:15]=[N:16][N:17]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2nnn[nH]2)c2sc(N)nc12
Solvent: c1ccncc1
Product: COc1ccc(-c2nnn[nH]2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
Using 4-methoxy-7-(1H-tetrazol-5-yl)-benzothiazol-2-ylamine and 4-fluoro-benzoyl chloride in pyridine the title compound was obtained as a tan solid (70% yield), MS: m/e=371.2 (M+H+).