Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:16].CC[O-].[Na+]>CCO>[CH2:15]([O:17][C:18](=[O:24])[C:19](=[O:20])[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)[CH3:16]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
Sodium hydride (0.4163 g, 17.35 mmol) was added slowly to a NaCl ice bath containing EtOH (5.3 mL, 2.5 M) stirring under N2. 66 (2.4253 g, 13.28 mmol) and diethyloxalate (1.803 g, 13.28 mmol) were mixed together, and then added to the chilled NaOEt solution. After stirring for 5 minutes, the reaction was warmed to room temperature. After 10 minutes, the reaction solidified and an additional 10 mL EtOH was added. After stirring for ˜5 h, the reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 1:1 Hexanes:CH2Cl2): Only pure fractions were combined and concentrated to obtain 67 (1.7561 g, 46.8%): 1H (CDCl3, 400 MHz): δ 14.27 (1H, broad s), 7.22 (2H, d, J=8.3 Hz), 7.10 (2H, d, J=8.3 Hz), 6.32 (1H, s), 4.31 (2H, q, J=7.2 Hz), 2.92 (2H, t, J=7.8 Hz), 2.78 (2H, t, J=7.8 Hz), 1.34 (3H, t, J=7.2 Hz) ppm. 13C (CDCl3, 100 MHz): δ 201.59, 166.07, 161.79, 138.51, 132.00, 128.53, 128.54, 101.72, 62.38, 42.08, 29.60, 13.88 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 13.88; CH2 carbons: 62.38, 42.08, 29.60; CH carbons: 129.53, 128.54, 101.72 ppm. HPLC: 11.103 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([CH3:10])([CH2:7][CH2:8]O)[C:5](=[O:11])[N:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[C:3]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46]>ClCCl>[CH3:1][C:2]1([CH3:25])[C:6]([CH3:10])([CH2:7][CH2:8][Br:46])[C:5](=[O:11])[N:4]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=2)[C:3]1=[O:24]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(C)CCBr
Reaction time: 1 h
Yield: 37.1 %

Procedure:
To a solution of compound 20a (33 mg, 0.097 mmol) in anhydrous dichloromethane (2 mL) at 0° C. under argon were added triphenylphosphine (50 mg, 0.194 mmol) and carbontetrabromide (64 mg, 0.194 mmol). The solution was allowed to return to room temperature and stirred for 1 hr. The resulting solution was diluted with dichloromethane (25 mL) and filtered on a cotton plug. Purification of the resulting crude product by flash chromatography using a gradient of ethyl acetate/hexane (3:97 to 3:7) as an eluant gave the desired compound 21a (15 mg, 40% for 2 steps). 1H NMR (400 MHz, Acetone-d6) δ: 1.36 (s, 3H), 1.39 (s, 3H), 1.40 (s, 3H), 2.28 (m, 2H), 3.68 (m, 2H), 8.03 (dd, 1H, J1=6.57 Hz, J2=1.84 Hz), 8.14 (d, 1H, J=1.45 Hz), 8.24 (d, 1H, J=8.40 Hz).
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[C:8]([O:12][C:13](=[O:16])[NH:14][NH2:15])([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([O:12][C:13]([NH:14][N:15]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1)=[O:16])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=c1ccocc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)Nn1ccc(=O)cc1
Yield: 55.2 %

Procedure:
4-Pyranone (1 g, 10.4 mmol) and t-butylcarbazate (1.32 g, 10 mmol) were heated at reflux in ethanol for 48 h. The solvent was gradually allowed to distil from the mixture and the residue was chromatographed on silica gel 60, eluting with ethanol, dichloromethane (1:19) to give the title compound (1.16 g, 50%); υmax (KBr) 1723, 1630, and 1550 cm-1 ; δH 1.54 (9H, s), 6.47 (2H, d), and 7.60 (2H, d); M+ 210.
Reaction SMILES: C1COCC1.C([O:8][C:9](=[O:21])[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[NH:20])[N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)C.[OH-].[Li+]>O>[CH3:18][N:17]([CH3:19])[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:21])=[O:8])=[CH:11][CH:12]=1)=[NH:20]
Reactant: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=N)c1ccc(C(=O)O)cc1
Reaction time: 6 h

Procedure:
To a THF solution of ethyl-4(N,N-dimethylcarbamimidoyl)benzoate (G) was added an aqueous solution of lithium hydroxide (2 eq.) and the reaction mixture was stirred for 6 hr. The completion of the reaction was confirmed by HPLC. To the reaction mixture was added water, followed by extraction with ethyl acetate. The aqueous layer was acidified with 6N HCl to pH between 3-4 at which point the desired 4-(N,N-dimethylcarbamimidoyl)benzoic acid precipitated as the white solid. The white solid isolated was washed with hexane to afford 4-(N,N-dimethylcarbamimidoyl)benzoic acid as an hydrochloride salt (A).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][C:24]([F:23])([F:34])[F:35])[CH:27]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (495 mg) in DMF (5 mL) was added potassium carbonate powder (763 mg) and 3-(trifluoromethoxy) benzyl bromide (1.41 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH:14][NH2:15])=[O:13])=[N:7]1.[C:19]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:13][C:27]([C:26]3[CH:30]=[CH:31][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)=[N:15][N:14]=2)=[N:7]1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: Cc1nc(C(=O)NN)nn1Cc1cccc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2nnc(-c3ccc(C(C)(C)C)cc3)o2)nn1Cc1cccc(Br)c1
Temperature: 100 °C
Yield: 32.4 %

Procedure:
To a solution of 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carbohydrazide (2.22 g, 7.16 mmol) dissolved in POCl3 (6 mL) was added 4-(tert-butyl)benzoic acid (1.27 g, 7.16 mmol). The reaction was heated to 100° C. for 2.5 h. The solvent was removed under reduced pressure and the crude material was taken up in EtOAc. The organic layer was then washed with NaHCO3 (3×40 mL) and brine (1×40 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified on a Biotage pre-packed silica gel column with a gradient of 12% to 100% EtOAc:Hexanes to afford 2-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazole (1.05 g, 32%). MS (ES+) C22H22BrN5O requires: 451, 453 found: 452, 454 [M+H]+(1:1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S(=O)(=O)(O)O.[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccccc1-c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccccc1-c1ccccc1
Yield: 97 %

Procedure:
2-Acetoxybiphenyl [compound (41)] was obtained by dissolving 59 g of 2-hydroxybiphenyl in 40 ml of acetic anhydride, adding a small amount of concentrated sulfuric acid, heating them under reflux for 20 min, pouring the reaction mixture in water, filtering the formed crystals and recrystallizing the same from methanol to obtain the compound (41) in a yield of 97%. M.P. 63°-64° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C[O:41]CC1>>[CH3:1][C:2]1([CH3:27])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12](=[O:26])[CH:13]([OH:41])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH:8]=2)[O:3]1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COc1cc(C(O)C(=O)c2ccc3c(c2)C=CC(C)(C)O3)cc(OC)c1OC
Temperature: 25 °C

Procedure:
The 1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (184.1 mg, 0.5 mmol) dissolved in THF (3 mL) is added dropwise to a stirring cold (−78° C.) solution of NaHMDS (0.6 mL, 1.0M in THF) in THF (3 mL). The resulting reaction mixture is stirred for 30 minutes before (+/−)-camphoryl-sulfonyloxaziridine (187 mg, 0.75 mmol) in THF (3 mL) is added dropwise. After 15 minutes the reaction mixture is quenched with sat. NH4I (aqueous) solution (3 mL) and diluted with diethyl ether. The mixture is allowed to warm up to room temperature. The aqueous layer is extracted with diethyl ether. Combined organic layers are washed with water, brine, dried over sodium sulfate, filtered, and concentrated. Crude 1-(2,2-dimethyl-2H-chromen-6-yl)-2-hydroxy-2-(3,4,5-trimethoxy-phenyl)-ethanone is purified using silica gel chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1>>[F:22][C:5]1[CH:4]=[CH:3][C:2]([C:27]2[CH:28]=[N:23][CH:24]=[N:25][CH:26]=2)=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1F
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc(-c2cncnc2)ccc1F

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 57 using 5-bromo-2-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 59.1) and pyrimidin-5-ylboronic acid to afford the title compound as a white powder. UPLC-MS (Condition 2) tR=1.04 min, m/z=378.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.39 (d, J=8.99 Hz, 2H) 7.56 (t, J=9.19 Hz, 1H) 7.85 (d, J=8.99 Hz, 2H) 8.01-8.09 (m, 1H) 8.15 (dd, J=6.65, 2.35 Hz, 1H) 9.22 (s, 3H) 10.72 (s, 1H).
Reaction SMILES: CO[C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:12]=[CH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[N:17]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]=3[N:16]=2)=[N:6][CH:5]=1.[NH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1.C([Mg]Cl)(C)C>C(Cl)Cl>[CH3:23][N:21]([CH3:22])[C:20]([C:18]1[N:17]([CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:15]2[N:16]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([N:31]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]4)=[O:30])=[CH:5][N:6]=3)[N:12]=[CH:13][C:14]=2[CH:19]=1)=[O:24]
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccc(Nc2ncc3cc(C(=O)N(C)C)n(C4CCCC4)c3n2)nc1
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC(O)CC4)cn3)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.3 %

Procedure:
To a solution of 6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid methyl ester (200 mg, 0.49 mmol) and piperidin-4-ol (500 mg, 4.9 mmol) in 5 mL of CH2Cl2 is added dropwise a solution of iPrMgCl (2.45 mL, 4.9 mmol) at 0° C. and allow to warm up to room temperature overnight. After 18 h, added another 10 equivalents of i-PrMgCl and stirred for another 5 h. The reaction mixture is quenched with saturated NH4Cl and extracted with dichloromethane (3×100 mL). The combine organic ished with NaCl and dried over Na2SO4 and concentrated. Following SiO2 chromatography, eluting with 85/15% (CH2Cl2/MeOH) gave 7-cyclopentyl-2-{5-(4-hydroxy-piperidine-1-carbonyl)-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (120 mg, 51%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: [NH2:1][C:2](=[O:93])[CH2:3][NH:4][C:5](=[O:92])[C@@H:6]([NH:13][C:14](=[O:91])[C@@H:15]([N:17]([CH3:90])[C:18]([C@H:20]([CH2:86][C:87](O)=[O:88])[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[C:94]1([CH2:100][SH:101])[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1.CC(C)N=C=NC(C)C>ClCCl.CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:1][C:2](=[O:93])[CH2:3][NH:4][C:5](=[O:92])[C@@H:6]([NH:13][C:14](=[O:91])[C@@H:15]([N:17]([CH3:90])[C:18]([C@H:20]([CH2:86][C:87](=[O:88])[S:101][CH2:100][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:75])[CH3:76])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:69])[CH3:70])[N:33]([CH3:66])[C:34](=[O:65])[CH2:35][NH:36][C:37](=[O:64])[C@H:38]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[N:39]([CH3:56])[C:40](=[O:55])[C@H:41]([CH3:54])[NH:42][C:43](=[O:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:51])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: SCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C)N(C)C(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
(9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-Amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-12,27-dibenzyl-18-isobutyl-24-isopropyl-2,2,9,11,17,21-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontan-32-oic acid (Compound P-145, (Boc-Gly-Ala-MePhe-Gly-MeLeu-Ala-Val-Phe-Asp-MeAla-Ser(tBu)-Gly-NH2)) (50.0 mg, 0.038 mmol) was dissolved in dichloromethane (320 μL) and DMF (80 μL), phenylmethanethiol (9.49 mg, 0.076 mmol), DIC (9.64 mg, 0.076 mmol) and N,N-dimethylpyridin-4-amine (3.54 mg, 0.029 mmol) were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (10 mM aqueous ammonium acetate solution:methanol) to afford the title compound (11.8 mg, 21.8%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:11]1[O:21][C:15]2([CH2:20][CH2:19][N:18]([C:2]3[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=3[C:4]#[N:5])[CH2:17][CH2:16]2)[O:14][CH:12]1[CH3:13]
Reactant: CC1COC2(CCNCC2)O1
Reactant: N#Cc1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1COC2(CCN(c3ccc(F)cc3C#N)CC2)O1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
A mixture of 2,5-difluorobenzonitrile (2.272 g, 16.33 mmol) and 4-piperidone propylene ketal (2.570 g, 16.34 mmol) was stirred at room temperature (11 d). The resulting mixture was diluted with dichloromethane and sodium carbonate solution and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed in vacuo. PCTLC (SiO2, 6 mm, 20% EtOAc-80% hexane) afforded the title compound (39).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([SiH](CC)CC)C.[OH-].[K+]>FC(F)(F)C(O)=O>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: CC[SiH](CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnn2c1NCCC2c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of 3.44 g of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Ex. 24) in 40 ml of trifluoroacetic acid was stirred under nitrogen and heated to 60° C. in an oil bath. Then 5.0 ml of triethylsilane was added and the mixture was stirred at 60° C. for 24 hours. The reaction mixture was cooled and carefully poured into a beaker containing a 25% aqueous solution of potassium hydroxide and cracked ice. The product which precipitated was extracted into chloroform. The chloroform was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo and gave crystals which were recrystallized from toluene-hexane to give the desired product, mp 152°-154° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[CH2:8][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[CH2:8][C:2]([CH3:4])([OH:3])[CH3:1]
Reactant: CC(C)=O
Reactant: Fc1ccc(C[Mg]Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(F)cc1F

Procedure:
11.0 mL acetone, diluted with 50 mL diethyl ether, is added dropwise to a solution of 500 mL of 0.25 molar 2,4-difluorobenzylmagnesium bromide in diethyl ether within 20 minutes. Then the mixture is refluxed for 1.5 hours and then hydrolyzed with 10% ammonium chloride solution. The ether phase is separated off, washed with water, dried with sodium sulfate, and evaporated down. The fractional distillation of the residue yields the alcohol as a colorless liquid (boiling point: 70° C.-73° C./2 mmbar). Yield: 20.0 g (86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH2:47])[CH2:43][N:44]([CH3:46])[CH3:45])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH2:32]([O:39][C:40](=[O:48])[CH2:41][C@@H:42]([NH:47][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]1[CH:17]=[CH:18][C:19]([F:20])=[C:2]([F:1])[CH:3]=1)[CH2:43][N:44]([CH3:45])[CH3:46])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)CCCCCCCOCc1ccc(F)c(F)c1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
A solution of 8-(3,4-difluoro-benzyloxy)-octanoic acid (153 mg, 0.53 mmol), N,N-diisopropylethylamine (414 mg, 3.21 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetrametbyluronium-hexaflurophophate (244 mg, 0.64 mmol) in N,N-dimethylformamide was stirred for 1 h at room temperature, then a solution of (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride (198 mg, 0.64 mmol) in N,N-dimethylformamide (1 mL) was added. The reaction mixture was stirred for 16 h at room temperature, then evaporated. Chromatography (SiO2, dichloromethane-[dichloromethane/methanol/25% aq. ammonia solution 110:10:1] gradient) produced (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester (136 mg, 50%). Light yellow oil, m/e=505.4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:13](Cl)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([O:9][CH3:13])=[O:8]
Reactant: CC(=O)Cl
Reactant: O=C(O)C=Cc1cccc(Br)c1
Solvent: CO
Product: COC(=O)C=Cc1cccc(Br)c1

Procedure:
To a solution of 50.0 g (220 mmol, Aldrich) of 3-bromocinnamic acid in 1 L sieve-dried methanol (Burdick & Jackson), stirred at 0° C., was added dropwise a solution of acidic methanol (prepared by the addition of 2.5 mL acetyl chloride to 250 mL methanol). The reaction
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2O.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][C:6]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(F)cc2c1O
Product: CCOC(=O)c1cnc2ccc(F)cc2c1Cl
Temperature: 25 °C

Procedure:
The starting material for the latter is prepared as follows: The mixture of 28.9 g of ethyl 6-fluoro-4-hydroxy-quinolin-3-carboxylate [J.A.C.S., 69, 371 (1947)] and 240 ml of phosphorus oxychloride is refluxed under nitrogen for 3 hours. After cooling to room temperature, the solution is evaporated and the residue treated with ice-water and chloroform. The organic layer is dried and evaporated. The residue is taken up in aqueous sodium bicarbonate and diethyl ether, the ethereal layer is dried and evaporated, to yield the ethyl 4-chloro-6-fluoroquinolin-3-carboxylate melting at 55°-57°.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CN(C)C1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]