Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1CCN([C:15]([O:17]C(C)(C)C)=[O:16])CC1)(=O)C1C=CC=CC=1.[OH:22][C:23]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[N:43]=[C:42]([C:47]([F:50])([F:49])[F:48])[C:41]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[C:40]2[C:57]([F:60])([F:59])[F:58])[CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1>>[C:61]1([C:23]([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[C:42]([C:47]([F:48])([F:49])[F:50])[C:41]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[C:40]3[C:57]([F:59])([F:60])[F:58])([CH:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]2)[OH:22])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.[C:15]([OH:17])([C:47]([F:50])([F:49])[F:48])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccccc2)c2ccc3nc(C(F)(F)F)c(-c4ccccc4)c(C(F)(F)F)c3c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)CC1
Product: O=C(O)C(F)(F)F
Product: OC(c1ccccc1)(c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C(F)(F)F)c2c1)C1CCNCC1

Procedure:
The precursor of the title compound was prepared essentially as described for Example 164, using tert-butyl 4-benzoylpiperidine-1-carboxylate (commercial; e.g., Matrix Scientific) in place of (1-methyl-1H-imidazol-5-yl)(pyridin-4-yl)methanone to provide, after heptanes/acetone flash chromatography, tert-butyl 4-(hydroxy(phenyl)(3-phenyl-2,4-bis(trifluoromethyl)quinolin-6-yl)methyl)piperidine-1-carboxylate as a clear yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1.Cl.N1CC[CH:24]([C:27]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=CC=CC=3)[CH:30]=2)=[O:28])[CH2:23][CH2:22]1>>[ClH:2].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:22][CH2:23][CH2:24][C:27]([C:29]3[CH:38]=[CH:37][CH:36]=[CH:31][CH:30]=3)=[O:28])[CH2:18][CH2:19]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccc2ccccc2c1)C1CCNCC1
Reactant: Clc1ccc(CC2CCNCC2)c2ccccc12
Agent: Cl
Product: O=C(CCCN1CCC(Cc2ccc(Cl)c3ccccc23)CC1)c1ccccc1

Procedure:
When in the procedure of Example 19, 4-[(4-chloro-1-naphthyl)methyl]piperidine hydrochloride is substituted for 2-naphthyl 4-piperidyl ketone hydrochloride, 4-[4-((4-chloro-1-naphthyl)methyl)-1-piperidyl]-1-phenyl-1-butanone hydrochloride is produced.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1.[C:19](=[O:30])([O:25][C:26](Cl)(Cl)Cl)OC(Cl)(Cl)Cl.O[C@H]1[CH2:51][N:35]2[C:36](=[O:50])[N:37]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=3)[CH2:38][C@@H:34]2[CH2:33]1>ClCCl.O>[O:50]=[C:36]1[N:35]2[CH2:51][C@H:26]([O:25][C:19](=[O:30])[NH:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=3)[CH2:33][C@H:34]2[CH2:38][N:37]1[C:39]1[CH:40]=[CH:41][C:42]([O:45][C:46]([F:49])([F:47])[F:48])=[CH:43][CH:44]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](O)CN12
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(F)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(F)cc1)O[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
Diisopropylethylamine (800 mg, 6.2 mmol) and (4-fluorophenyl)methanamine (400 mg, 3.2 mmol) was dropped into a solution of bis(trichloromethyl) carbonate (300 mg, 1 mmol) in anhydrous dichloromethane (30 mL) at −78° C., the mixture was stirred for 2 hours at room temperature. Then (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (50 mg, 0.165 mmol) was added into the mixture, the mixture was refluxed for 2 days. The mixture was cooled and poured into water (50 mL), extracted with ethyl acetate (3×30 mL), the organic layers was combined washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to yield 25 mg (33%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.60 (d, 2H, J=9.3 Hz), 7.29-7.24 (m, 2H), 7.19 (d, 2H, J=8.4 Hz), 7.03 (t, 2H, J=8.7 Hz), 5.38 (t, 1H, J=5.7 Hz), 5.04 (s, 1H), 4.34 (d, 2H, J=5.7 Hz), 4.15 (dd, 1H, J1=13.5 Hz, J2=6.0 Hz), 4.05-4.00 (m, 1H), 3.74 (d, 1H, J=6.9 Hz), 3.2 (d, 1H, J=13.5 Hz), 2.27-2.21 (m, 1H), 1.78-1.63 (m, 1H); LC-MS: 454.1 [M+1]+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[OH-].[Na+].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Temperature: 25 °C

Procedure:
The intermediate from step A (890 mg, mmol) was suspended in POCl3 (5 mL) and refluxed for 1 hour. The reaction was cooled to room temperature and poured into an erlenmeyer flask containing ice and 5 N NaOH (30 mL). The resulting mixture was extracted with ethyl acetate (3×). The organic layer was washed with saturated NaHCO3, saturated NaCl solution dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate-hexanes to afford the product as a white solid. 1H NMR (500 MHz, CDCl3): 9.19 (s, 1H), 8.33 (s, J=9.2 Hz, 1H), 7.46 (d, J=2.5 Hz, 1H), 7.36 (dd, J=2.5, 9.1 Hz, 1H), 4.53 (q, J=7.1 Hz, 2H), 4.01 (s, 3H), 1.5 (t, J=7.4 Hz, 3H). LC-MS: 3.22 min; (M+H)=266.1.
Reaction SMILES: [C:1](=[O:6])([O:3][CH2:4][CH3:5])[NH2:2].[CH3:7][C:8]([CH3:11])([O-])[CH3:9].[K+].C1C[O:16]CC1>>[C:7]([NH:2][C:1](=[O:6])[O:3][CH2:4][CH3:5])(=[O:16])[C:8]([CH3:11])=[CH2:9]
Reactant: CCOC(N)=O
Reactant: CC(C)(C)[O-]
Reactant: C1CCOC1
Agent: [K+]
Product: C=C(C)C(=O)NC(=O)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
To the solution of 8.9 g of ethyl carbamate in 100 g of THF, 11.2 g of potassium t-butoxide was mixed and the reaction mixture was stirred for 1 hour at 60° C. The resulting slurry was added dropwise to the solution of 5.43 g of methacryloyl acid chloride in 50 g of THF heated at 60° C. in 2 hours. After removing THF by vacuum evaporation, the residue was extracted with 1000 ml of water and 500 ml of ethyl acetate. The organic phase was concentrated in vacuo and the residue was subjected to column chromatography for purification, thereby isolating 1.0 g of ethyl methacryloylcarbamate.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)([CH3:14])[CH3:13])[CH:7]=1>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)([CH3:13])[CH3:14])[CH:7]=1
Reactant: COc1ccc(C(C)(C)c2cc(Br)ccn2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(c1ccc(O)cc1)c1cc(Br)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
BBr3 (1 M in DCM, 23 mmol, 8 eq) is added dropwise to a cold (0° C.) solution of 4-bromo-2-[1-(4-methoxy-phenyl)-1-methyl-ethyl]-pyridine (Step 55.3) (0.878 g, 2.87 mmol) in DCM (42 mL), under an argon atmosphere. The reaction mixture is stirred for 1 h at 0° C., allowed to warm to rt, stirred for 18 h, cooled to 0° C. and quenched by addition of anhydrous MeOH. The mixture is concentrated, diluted with a 6M aqueous solution of HCl, stirred for 1 h, neutralized to pH 7 and extracted with DCM. The organic phase is dried (Na2SO4), filtered and concentrated. The residue is used without purification.
Reaction SMILES: [C:1](OC(NC(C)(C)C/C=C/C(O)=O)=O)(C)([CH3:3])[CH3:2].ON1[C:23]2[N:24]=[CH:25][CH:26]=C[C:22]=2N=N1.Cl.[CH2:29](N=C=NCCCN(C)C)C>C(Cl)Cl>[CH:1]([N:24]([CH:23]([CH3:22])[CH3:29])[CH2:25][CH3:26])([CH3:3])[CH3:2]
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Reactant: On1nnc2cccnc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(C(C)C)C(C)C
Reaction time: 0.5 h
Yield: 250 %

Procedure:
To a solution of (2E)-5-(tert-butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.35 g, 1.42 mmol) in methylene chloride (5 ml) was added a mixture of 1-hydroxy-7-azabenzotriazole (0.193 g, 1.42 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.272 g, 1.42 mmol) and stirred for 30 min. Then a mixture of the obtained crude (2R)-N-[(1R)-1-(N',N'-dimethylhydrazinocarbonyl)-2-phenylethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide and diisopropylethylamine (0.61 ml, 3.55 mmol) was added and the mixture was stirred overnight. The mixture was concentrated in vacuo and chromatographed on silica (40 g) with ethyl acetate (95):methanol/10% ammonia (5) to give 0.37 g of ((3E)4-[N-((1R)-1-(N-[(1R)-1-(N',N'-dimethylhydrazinocarbonyl)-2-phenylethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester as an oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[OH:12]O>C(O)=O.O>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:12]
Reactant: OO
Reactant: ClCCCSc1ccccn1
Solvent: O=CO
Solvent: O
Product: O=S(CCCCl)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.5 %

Procedure:
2-(3-Chloropropyl)thiopyridine (4.4 g) prepared in Reference Example 3 is dissolved in formic acid (40 ml). 30% Aqueous hydrogen peroxide (2.7 g) is added to the solution and the mixture is stirred at room temperature for 3 hours. The mixture is allowed to stand at room temperature for overnight, diluted with water and extracted with chloroform. The chloroform solution is washed with water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with chloroform-methanol (50:1) to obtain 2-pyridyl 3-chloropropyl sulfoxide (2.7 g) as colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(Cl)Cl.[Pd]>[O:14]1[C:13]2([CH2:18][CH2:19][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A mixture of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spiro[4.5]decane (Synthesis, 606, 1981) (3.5 g, 13.3 mmol) and 10% Pd/C (0.5 g) in 100 mL of ethanol/methylene chloride(2:1) was pressurized with 30 psi hydrogen and shaken over 1 hours. The catalyst was then removed by filtering through a short pad of silica gel to give the title compound (2.8g, 90%) as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.85-2.00 (m, 4H), 3.00-3.10 (m, 4H), 3.93 (s, 4H), 6.60 (d, J=6.0 Hz, 2H), 6.80 (d, J=6.0 Hz, 2H); MS (ES) m/z: 235.2 (MH+); HRMS Calcd. for C13H18N2O2: 234.1380. Found: 234.1371.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:9][C@@H:10]1[C@@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[O:34][C@H:11]1[O:12][C:13]1[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][OH:29])=[CH:21][C:20]=2[CH3:30])=[C:16]([CH:31]([CH3:33])[CH3:32])[NH:15][N:14]=1)(=[O:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:29][CH2:28][CH2:27]/[CH:26]=[CH:25]/[C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[C:13]([O:12][C@@H:11]3[O:34][C@H:35]([CH2:46][O:47][C:48](=[O:50])[CH3:49])[C@@H:36]([O:42][C:43](=[O:45])[CH3:44])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:10]3[O:9][C:6](=[O:8])[CH3:7])=[N:14][NH:15][C:16]=2[CH:31]([CH3:33])[CH3:32])=[C:20]([CH3:30])[CH:21]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCOS(C)(=O)=O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 69.8 %

Procedure:
Add methanesulfonyl chloride (0.54 mL, 7 mmol) to a solution of 4-{4-[(1E)-4-hydroxybut-1-en-1-yl]-2-methylbenzyl}-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (3.7, 5.87 mmol) in dichloromethane (15 mL) and triethylamine (4 mL, 29 mmol) at 0° C. After refluxing at room temperature for 30 min, concentrate to remove the solvent under the reduced pressure. Purify residue by flash chromatography to yield the title compound (2.9 g, 4.1 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][C@@H:18]2[C:31]([O:33][CH3:34])=[O:32])[C:13]1=[O:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
Example 13a, Step 1 (Isomerization of the cis ester to the corresponding trans ester): To a solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonylamino)-cyclohexanecarboxylate (281 mg, 0.573 mmol, see Example 12a, Step 3) in anhydrous DMF was added cesium carbonate (747 mg, 2.29 mmol), and the mixture was stirred for 16 h at rt. At the end of the stirring the mixture was poured into water, and extracted with EtOAc (3×). The combined extracts were washed with water, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatograpy on silica gel with elution by EtOAc to afford pure trans isomer, (1S,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonyl)amino-2-oxopyrrolidin-1-yl)-5-(tert-butoxycarbonyl)amino-cyclohexanecarboxylate (214 mg) as an oil.
Reaction SMILES: [Br-].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:10][C:5]=2[O:4][CH2:3]1.[C:31]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]([CH3:45])[CH:43]=O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32].CC(O)=O>C1COCC1>[C:31]([C:35]1[CH:36]=[CH:37][C:38]([CH2:41][CH:42]([CH3:45])[CH:43]=[CH:11][C:9]2[CH:8]=[CH:7][C:6]3[O:2][CH2:3][O:4][C:5]=3[CH:10]=2)=[CH:39][CH:40]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: c1ccc([P+](Cc2ccc3c(c2)OCO3)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C=Cc1ccc2c(c1)OCO2)Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.8 %

Procedure:
Potassium t-butylat (1 Min THF, 11 mL, 11.0 mmol, 1.1 equiv.) was added to a solution of (benzo[d][1,3]dioxol-5-ylmethyl)triphenylphosphonium bromide (4.77 g, 10.0 mmol, 1.0 equiv.) in THF (20 mL) at 25° C. After the dark red suspension was stirred at 25° C. for 10 min, 3-(4-tert-butylphenyl)-2-methylpropanal (2.04 g, 10.0 mmol, 1.0 equiv.) in THF (10 mL) was added, and the mixture was stirred at 70° C. for 1.5 h. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was extracted with hexanes, the combined organic phases were dried (MgSO4), filtered and the filtrate was concentrated. The residue was purified by flash chromatography on SiO2 (hexanes/EtOAc 19:1) to yield 2.83 g (88%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C@H:15]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:14][C@H:15]([C:23]([NH:25][C@H:26]([CH:39]=[O:40])[CH2:27][C:28](=[N:34][NH:35][C:36]([NH2:38])=[O:37])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CC(C)(C)OC(C[C@@H](C=O)NC(=O)[C@@H](N)Cc1ccccc1)=NNC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@H](C=O)CC(=NNC(N)=O)OC(C)(C)C)cc2ccccc21
Reaction time: 4 h
Yield: 81.7 %

Procedure:
1-Methylindole-2-carboxylic acid (72 mg, 0.41 mmol) and 3(S)-(phenylalaninyl]amino4-oxobutanoic acid, t-butyl ester semicarbazone (154 mg, 0.41 mmol) were dissolved in methylene chloride (2 mL) and both DMAP (53 mg, 0.43 mmol) and EDAC (109 mg, 0.57 mmol) were added to the solution under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and an additional 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution, successively, dried over sodium sulfate, and concentrate to give a white solid. Trituration of the solid with ether afforded the title product as a white powder (179 mg, 82%) TLC: (methanol/methylene chloride: 5/95, silica gel): Rf=0.44.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]O)[CH:5]=[CH:6][CH:7]=1.[CH2:31]([N:33](CC)[CH2:34]C)C.CS(Cl)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[N:10]([C:26]([CH2:29][CH3:30])=[CH:27][CH:28]=3)[N:11]=[C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:33]([CH3:34])[CH3:31])[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCO)c(-c3ccccc3)nn12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCc1ccc2c(-c3cccc(Cl)c3)c(CCCCCN(C)C)c(-c3ccccc3)nn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-1-pentanol (55 mg) and triethylamine (19.9 mg) in dichloromethane (3 mL) was added methanesulfonyl chloride (165 mg) under ice-water cooling and the mixture was stirred at 0° C. for 1 hour. The solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. To the residue in 1,2-dichloroethane (3 mL) was added 2 M dimethylamine in tetrahydrofuran (3 mL) and the mixture was stirred at 60° C. for 120 hours. The solution was diluted with chloroform, washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (20:1-5:1) to give 5-[4-(3-chlorophenyl)-7-ethyl-2-phenylpyrrolo[1,2-b]pyridazin-3-yl]-N,N-dimethyl-1-pentanamine as an yellow oil (38 mg).
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:25]1[CH:29]=[C:28]([C:30]2[C:31]3[CH:38]=[CH:37][N:36](COCC[Si](C)(C)C)[C:32]=3[N:33]=[CH:34][N:35]=2)[CH:27]=[N:26]1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17](C#N)=[CH:16][C:15]=2[F:22])=[O:13])[CH2:8][CH:7]1[CH2:23]O)#[N:2].[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48].C(N)CN>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[F:22][C:15]1[CH:16]=[C:17]([OH:48])[CH:20]=[CH:21][C:14]=1[C:12]([N:9]1[CH2:8][CH2:7][CH2:23][N:6]([CH2:5][CH:4]([N:25]2[CH:29]=[C:28]([C:30]3[C:31]4[CH:38]=[CH:37][NH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH:27]=[N:26]2)[CH2:3][C:1]#[N:2])[CH2:11][CH2:10]1)=[O:13]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCN(C(=O)c5ccc(C#N)cc5F)CC4CO)c3)ncnc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(CN1CCCN(C(=O)c2ccc(O)cc2F)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 0.5 h
Yield: 60 %

Procedure:
4-{[4-{3-cyano-2-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propyl}-3-(hydroxymethyl)piperazin-1-yl]carbonyl}-3-fluorobenzonitrile (9 mg, 0.01 mmol; peak 1 from Step 5) was stirred in a solution of 1:1 TFA:DCM (2 mL) for 1 h. Solvents were removed in vacuo. The residue was dissolved in methanol (1.0 mL), and ethylenediamine (0.050 mL, 0.75 mmol) was added. After 30 min, the product was purified via preparative HPLC-MS (C18, eluting first with a gradient of H2O/MeCN containing 0.15% NH4OH, then repurified eluting with a gradient of H2O/MeCN containing 0.1% TFA) and lyophilized to afford product as the (2.66×) trifluoroacetate salt (6.3 mg, 60%). 1H NMR (500 MHz, DMSO-d6, 90° C.): δ 12.11 (br s, 1H), 8.77 (s, 1H), 8.74 (s, 1H), 8.38 (s, 1H), 7.84 (d, 1H), 7.71 (d, 1H), 7.63-7.60 (m, 1H), 7.55 (t, 1H), 6.99 (br d, 1H), 4.92-4.85 (m, 1H), 3.85-2.35 (m, 13H); 19F NMR (400 MHz, DMSO-d6): δ −74.94 (s, 8F), −114.23 to −114.96 (m, 1F); LCMS (M+H)+: 514.2.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[O:46][CH2:47][CH2:48][O:49][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[O:46][CH2:47][CH2:48][O:49][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c4c(c3)OCCO4)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc2c1OCCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.4 mg (0.06 mmol) LiOH in 0.5 mL water was added to a solution of 28 mg (0.04 mmol) (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(8-methyl-2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 6.5) in 0.5 mL THF and the reaction solution was stirred for 3 h at RT. The reaction mixture was purified by HPLC without any further working up. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:22]([OH:24])=[O:23])[CH2:20][OH:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].ClC(Cl)(Cl)C(=N)O[C:29]([CH3:32])([CH3:31])[CH3:30]>CCOC(C)=O.C1CCCCC1>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][CH:19]([CH2:20][OH:21])[C:22]([O:24][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:23])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.3 %

Procedure:
To a solution of commercial N-Fmoc-L-serine (1.5 g, 4.58 mmol) in EtOAc (40 ml), a solution of t-butyl 2,2,2-trichloroacetimidate (4.00 g, 18.32 mmol) in cyclohexane (18 ml) was added dropwise. After stirring at room temperature for 24 hrs, the solution was evaporated and the residue was purified by flash chromatography (n-Hexane/EtOAc 70:3), yielding the title compound (1.20 g, 68%).