Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][C:11]([OH:13])=O)=[CH:8][CH:7]=[CH:6][C:5]=12.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[O:43]=[S:44]1(=[O:66])[CH2:49][CH2:48][CH2:47][N:46]2[C:50](=[O:65])[N:51]([CH2:61][CH2:62][CH2:63][NH2:64])[C:52](=[O:60])[C:53]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:45]12>O.ClCCl>[O:66]=[S:44]1(=[O:43])[CH2:49][CH2:48][CH2:47][N:46]2[C:50](=[O:65])[N:51]([CH2:61][CH2:62][CH2:63][NH:64][C:11](=[O:13])[CH2:10][C:9]3[N:4]4[CH:3]=[CH:2][N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=3)[C:52](=[O:60])[C:53]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[C:45]12
Reactant: O=C(O)Cc1cccc2nccn12
Reactant: NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1cccc2nccn12)NCCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dichloromethane solution of 601 mg (2.5 mmol) of imidazo[1,2-a]pyridin-5-acetic acid and 383 mg (2.5 mmol) of HOBt, 479 mg (2.5 mmol) of WSC and 0.5 ml (3.6 mmol) of triethylamine were added. After the reaction mixture was stirred at 0° C. for 30 minutes, 1.158 g (3 mmol) of 3-(1,1,6,8-tetraoxo-9-phenyl-2,3,4,8-tetrahydropyrimido[6,1-b][1,3]thiazin-7-yl)propylamine hydrochloride and 0.84 ml (6 mmol) of triethylamine were added, followed by stirring at room temperature for 3 hours and then at 40° C. for 14 hours. After water was added, the mixture was extracted with dichloromethane and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=25/1) to yield 74.7 mg (5.9%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([CH2:9][CH2:10][CH3:11])[CH2:4][C:3]=1[NH:12][CH:13]([CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28](=[O:37])[C:29]1[C:34]([Cl:35])=[CH:33][N:32]=[CH:31][C:30]=1[Cl:36])[CH2:23][CH2:22]2)[C:14]([O:16]C)=[O:15].ClC1C=NC=C(Cl)C=1C(N1C2C(=CC(CC(NC3C4(CCCCC4)C(=O)C=3)C(O)=O)=CC=2)CC1)=O>>[Cl:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([CH2:9][CH2:10][CH3:11])[CH2:4][C:3]=1[NH:12][CH:13]([CH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28](=[O:37])[C:29]1[C:30]([Cl:36])=[CH:31][N:32]=[CH:33][C:34]=1[Cl:35])[CH2:23][CH2:22]2)[C:14]([OH:16])=[O:15]
Reactant: CCCC1CC(=O)C(Cl)=C(NC(Cc2ccc3c(c2)CCN3C(=O)c2c(Cl)cncc2Cl)C(=O)OC)C1
Agent: O=C(O)C(Cc1ccc2c(c1)CCN2C(=O)c1c(Cl)cncc1Cl)NC1=CC(=O)C12CCCCC2
Product: CCCC1CC(=O)C(Cl)=C(NC(Cc2ccc3c(c2)CCN3C(=O)c2c(Cl)cncc2Cl)C(=O)O)C1

Procedure:
The title compound was prepared from the compound of Example 34 in a similar manner to the compound of Example 2 as a white solid (114.7 mg, 74.5%). δH NMR (d6 DMSO) 8.82 (2H, s), 8.03 (0.86H, d) & 5.74 (0.14H, d), 8.97 (0.15H, d) & 7.20 (2H, m), 7.15 (0.86H, d) & 6.80 (0.14H, d), 4.62 (1H, dd), 3.76 (2H, t, J 7.3 Hz), 3.21 (1H, dd), 3.13 (2H, t), 3.02 (1H, dd), 1.23-0.76 (8H, m), 1.04 (3H, s). m/z (ES+, 70V) 550 (MH+).
Reaction SMILES: C([N:4]([C@@H:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C=C.C(N([C@@H](C)C1C=CC=CC=1)[C@@H](C=CC1C=CC=CC=1)CC(OC(C)(C)C)=O)C=C.C1(CC=CC(OC(C)(C)C)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:24][C@H:17]([NH:4][C@@H:5]([CH:14]([CH3:16])[CH3:15])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CCN([C@H](CC(=O)OC(C)(C)C)C(C)C)[C@@H](C)c1ccccc1
Agent: C=CCN([C@@H](C=Cc1ccccc1)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Agent: CC(C)(C)OC(=O)C=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H](CC(=O)OC(C)(C)C)N[C@@H](C)c1ccccc1

Procedure:
The title compound (34) was prepared from compound (16) of Example 6 using the above-described procedure. [α]D21 -52.7 (c 1.57, CHCl3); νmax (CHCl3)/cm-1 1724 s (C=O); δH (300 Hz; CDCl3) 7.38-7.21 (5H, m, Ph), 3.88 (1H, q, J=6.5, PhCHCH3), 2.60 (1H, m, NCHCH2), 2.38, 2.27 (2H, ABX system, JAB =14.4, JAX =5.4, JBX =6.2, CH2CO), 1.68 (1H, m, (CH3)2CH), 1.47 (9H, s, (CH3)3C), 1.33) (3H, d, J=6.5, PhCHCH3), 0.89 (3H, d, J=6.8, (CH3)2CH), 0.81 (3H, d, J=6.8, (CH3)2CH); δC (50 MHz; CDCl3) 172.67 (C=O), 146.58 (Ph:Cipso), 128.42, 127.12 (Ph:Cortho, Cmeta), 126.95 (Ph:Cpara), 80.19 (C(CH3)3), 57.82, 55.37 (CHN), 36.81 (CH2CO), 31.14 ((CH3)2CH), 28.03 (C(CH3)3), 24.76 (NCHCH3), 18.78, 18.32 ((CH3)2CH); m/z (CI) 292 (MH+, 100%), 236 (20), 192 (20), 176 (17), 105 (20); (Found: C, 74.07; H, 10.31; N, 4.58. C18H29NO2 requires C, 74.18; H, 10.03; N, 4.81%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[OH-].[K+].Cl[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26](=[O:30])[S:27][CH2:28][CH3:29])=[CH:24][CH:23]=1.O>CS(C)=O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26](=[O:30])[S:27][CH2:28][CH3:29])=[CH:24][CH:23]=2)[C:4]([CH3:17])=[N:3]1
Reactant: CCSC(=O)c1ccc(CCl)cc1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCSC(=O)c1ccc(CON=Cc2c(C)nn(C)c2Oc2ccccc2)cc1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethyl sulfoxide, and after adding 0.3 g (0.0053 mole) of powdery potassium hydroxide, the resulting solution was stirred. To this solution was added 0.92 g (0.0043 mole) of S-ethyl 4-cloromethylbenzothiate, and reaction was carried out at room temperature for 3 hours. After completion of the reaction, 200 ml of water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.4 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:17][C:11]=2[N:10]=1)[C:3]([O:5]CC)=[O:4].Cl[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:30])([CH2:8][C:9]1[N:13]([CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:17][C:11]=2[N:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2[nH]1
Reactant: ClCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc2ccccc2c1)C(=O)O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottomed flask were added a stirbar, ethyl 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)propanoate (300 mg, 0.75 mmol), 2-(chloromethyl)naphthalene (168 mg, 0.75 mmol), potassium carbonate (310 mg, 2.25 mmol), and DMF (20 mL). The mixture was heated to 70° C. After 18 h, the flask was cooled to RT and concentrated to dryness. The resulting residue was dissolved in MeOH (9 mL) and THF (9 mL). To the solution was added 5% aqueous NaOH (2 mL) and the mixture was stirred at 40° C. overnight. The mixture was cooled and acidified to ˜pH=4-5 with 6 N HCl, then extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness and purified by reverse phase HPLC to give the title compound. MS (ESI): mass calcd. for C33H29N3O3, 515.22; m/z found, 516.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.34 (d, J=8.5, 1H), 8.04 (d, J=8.4, 1H), 7.92 (d, J=8.2, 1H), 7.84-7.66 (m, 5H), 7.59 (t, J=7.5, 1H), 7.48-7.40 (m, 3H), 7.31-7.21 (m, 2H), 7.19 (dd, J=8.5, 1.7, 1H), 7.01 (dd, J=8.8, 2.4, 1H), 5.67 (s, 2H), 5.40 (s, 2H), 3.17 (s, 2H), 1.30 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[O:10])[O:8][C:4]=2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:26]=[CH:25][C:5]4[N:6]=[C:7]([C:9]([NH:11][CH:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]5)=[O:10])[O:8][C:4]=4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3o2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a stirred solution of tert-butyl 4-(6-hydroxybenzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate (0.15 g, 0.41 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.1 g, 0.49 mmol), 1-(4-(trifluoromethyl)phenyl) piperidin-4-ol (0.1 g, 0.41 mmol), and triphenylphosphine (0.13 g, 0.49 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=2/3) to afford tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate (compound 1) as a off-white solid (0.16 g, 66%). 1H-NMR (CDCl3, 300 MHz): δ 7.65 (m, 1H), 7.48 (m, 2H), 7.15 (m, 1H), 7.05 (m, 2H), 6.96 (m, 2H), 4.56 (m, 1H), 4.12 (m, 3H), 3.60 (m, 2H), 3.28 (m, 2H), 2.93 (m, 2H), 2.04 (m, 8H), 1.47 (s, 9H) ppm; MS (ESI): 589.6 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[C:18]([O:28][CH3:29])[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:15][C:16]1[N:21]=[C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:24][CH2:23]2)[CH:19]=[C:18]([O:28][CH3:29])[N:17]=1
Reactant: COc1cc(N2CCNCC2)nc(OC)n1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)nc(OC)n1
Yield: 111.1 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g), 1-(2,6-dimethoxypyrimidin-4-yl)piperazine (1.1 g) and potassium carbonate (1.0 g) in dimethylformamide (10 ml) was stirred at 80° C. for 2 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil (2.1 g). The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) and crystallized from ethyl acetate:diisopropyl ether (1:2, 30 ml) to give the title compound (1.0 g) as white crystals, m.p.=89-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([CH3:11])([OH:10])[CH3:9])[N:3]=1.N1C(C)=CC=CC=1C.[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C:27](Cl)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:25][C@H:26]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[C:27]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])([CH3:11])[CH3:9])[N:3]=2)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
In a round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 56 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 45% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (102 mg, 74%) as a white foam: [α]30589=−13.3° (c=0.12, methylene chloride); ES-HRMS m/e calcd for C21H27N3O2Cl2 (M+H)+ 424.1553, observed 454.1553; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 6H, 2×CH3), 1.09 (m, 2H, CH2), 1.34-1.79 (m, 8H, 4×CH2), 2.03 (m, 1H, CH), 3.80 (m, 1H, ArCHCO), 3.86 (s, 2H, NCH2), 4.65 (s, 1H, OH), 6.45 (s, 1H, Ar), 7.35 (brd, 1H, Ar), 7.51 (s, 1H, Ar), 7.58 (m, 2H, Ar), 10.73 (s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]([C:27]1[N:31](COCC[Si](C)(C)C)[C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)(O)[C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].FC(F)(F)C(C1N(COCC[Si](C)(C)C)C2C=C(C#N)C=CC=2N=1)(O)C1C(SC)=CC(C)=C2C=1C=[CH:54][N:55]2S(C1C=CC(C)=CC=1)(=O)=O.Cl.S(Cl)(Cl)=O.CN>CN(C=O)C>[F:47][C:2]([F:46])([F:1])[C:3]([C:27]1[NH:31][C:30]2[CH:40]=[CH:41][C:42]([C:44]#[N:45])=[CH:43][C:29]=2[N:28]=1)([C:4]1[C:12]([S:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[NH:55][CH3:54]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(O)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)(c1c(SC)cc(C)c2c1ccn2S(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Temperature: 60 °C

Procedure:
To a mixture of (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and (±)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile (Example 14-A) (0.37 g, 0.528 mmol) was added HCl (1.25M in MeOH, 4.22 mL, 5.28 mmol) and the mixture was stirred at 60° C. After 40 minutes the mixture was cooled to room temperature and concentrated. The residue was dissolved in CHCl3 (10.56 mL), and thionyl chloride (0.385 mL, 5.28 mmol) and a few drops of DMF were added and the mixture was heated at 70° C. After 2 hours the reaction was cooled to room temperature and concentrated. The residue was dissolved in methylamine (33% in EtOH, 6.57 mL, 52.8 mmol) and stirred at room temperature. After 5 minutes the reaction was concentrated and purified directly by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 584.2 (M+H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13]12[CH2:18][CH:17]1[C:16](=[O:19])[NH:15][C:14]2=[O:20].[CH2:21](O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:15]1[C:16](=[O:19])[CH:17]2[CH:13]([CH2:18]2)[C:14]1=[O:20]
Reactant: OCCCCCCCO
Reactant: O=C1NC(=O)C2CC12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1C2CC2C(=O)N1CCCCCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Diethyl azodicarboxylate (0.94 g) was added to a mixture of 3-azabicyclo[3.1.0]hexane-2,4-dione (0.5 g), 1,7-heptanediol (2.46 g), triphenylphosphine (1.42 g) and 4 angstrom sieves (1.5 g) in dry tetrahydrofuran (10 ml) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 days and was then filtered. The solids were washed with ethyl acetate (2×50 ml) and the combined filtrates were evaporated in vacuo. The residue was purified by chromatography on silica using 60-70% ethyl acetate/hexane as eluant, followed by kugelrohr distillation (b.p. 200-220° C. @ 1 mmHg) to give the subtitle compound as a viscous oil.
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[CH:8]=[N:9][N:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[C:11]=2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]1([C:11]2[N:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:20][CH:19]=3)[N:9]=[CH:8][C:7]=2[CH2:6][C:5]2[CH:4]=[CH:3][C:2]([C:31]#[N:32])=[CH:30][CH:29]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: FC(F)(F)Oc1ccc(-n2ncc(Cc3ccc(Br)cc3)c2C2CCCCC2)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(Cc2cnn(-c3ccc(OC(F)(F)F)cc3)c2C2CCCCC2)cc1
Temperature: 75 °C

Procedure:
A mixture of 782 mg 4-(4-bromobenzyl)-5-cyclohexyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazole from Step D above, 115 mg zinc cyanide, and 94 mg tetrakis(triphenylphosphine)palladium(0) in 5 mL DMF was heated under nitrogen in a 75° C. oil bath over night. Evaporate most of DMF. The residue was purified on silica gel using 10-40% EtOAc in hexanes to give the title compound as a yellowish solid. 1H NMR (CDCl3, 500 MHz) δ 7.61˜7.64 (m, 2H), 7.40˜7.44 (m, 2H), 7.33˜7.37 (m, 4), 7.31 (s, 1H), 4.06 (s, 2H), 2.70 (tt, J=3.1 & 12.5 Hz, 1H), 1.73˜1.79 (m, 4H), 1.66˜1.71 (m, 1H), 1.50˜1.58 (m, 2H), 1.09˜1.24 (m, 3H). LC-MS: 2.46 min. (M+H=426.2).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5](=[O:11])[N:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:8]([C:6]5[C:5](=[O:11])[N:4]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=6)[N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: CCn1cc(C(=O)O)c(=O)n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Yield: 32.8 %

Procedure:
Using 1-ethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (270 mg, 1.2 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (260 mg, 0.79 mmol), HATU (450 mg, 1.2 mmol), diisopropylethylamine (300 mg, 2.4 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (140 mg, 34%) was obtained as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:23]=2)[C:10]=1[CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])C.[OH-].[Na+]>>[C:40]([CH2:39][CH2:38][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24]([S:33]([CH2:36][CH3:37])(=[O:34])=[O:35])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:45])=[O:3])([OH:42])=[O:41]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccsc3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccsc2)c1
Yield: 51.7 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(3-ethanesulfonyl-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (111 mg, 0.17 mmol) and 1.0 N aqueous sodium hydroxide (1.7 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(3-ethanesulfonyl-5-thiophen-3-yl-phenoxy)-hexyl]-phenoxy]-butyric acid (53 mg, 52%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C31H38O8S2 (M+Na)+ 625.1900, found 625.1904.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].[C:13]1([CH2:23][CH2:24][NH2:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:25][CH2:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: NCCc1cccc2ccccc12
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CC[C@H](N)[C@H](O)C(=O)NCCc1cccc2ccccc12

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using 2-(naphthalen-1-yl)ethanamine in the seventh step (step B7).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:8]([N:10]2[CH2:17][CH2:16][C@:15]3([CH3:19])[CH2:18][C@@H:11]2[CH2:12][C:13]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:14]=23)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:25]N(C)C=O.CI>O1CCCC1.O>[CH:3]1([C:8]([N:10]2[CH2:17][CH2:16][C@:15]3([CH3:19])[CH2:18][C@@H:11]2[CH2:12][C:13]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:14]=23)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: C[C@]12CCN(C(=O)C3CCCC3)[C@@H](Cc3ccc(O)cc31)C2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)[C@]1(C)CCN(C(=O)C3CCCC3)[C@@H](C2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.01 g) is added to a solution of cyclopentyl-[(2R,6R)-8-hydroxy-6-methyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (0.10 g) in tetrahydrofuran (6 mL; alternatively N,N-dimethylformamide may be used). The mixture is stirred for 30 min at room temperature before methyl iodide (25 μL) is added. The resulting solution is stirred at room temperature overnight. Then, water is added and the resulting mixture is extracted with dichloromethane. The combined extracts are dried (Na2SO4) and the solvent is evaporated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate).