Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.Cl.[CH2:38]([O:40][CH:41]1[CH2:44][NH:43][CH2:42]1)[CH3:39]>>[CH2:38]([O:40][CH:41]1[CH2:44][N:43]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:42]1)[CH3:39]
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Reactant: CCOC1CNC1
Agent: Cl
Product: CCOC1CN(Cc2ccc(C#Cc3ccc(C(=O)N(C)[C@@](C)(C(=O)NC)C(=O)NOC4CCCCO4)cc3)cc2)C1
Yield: 73.9 %

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.30 g) as obtained in Example 16-(1) and 3-ethoxyazetidine hydrochloride (0.11 g), there was obtained (2S)-2-{[4-({4-[(3-ethoxyazetidin-1-yl)methyl]phenyl}ethynyl)benzoyl](methyl)amino}-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.26 g, 74%) in the same manner as in Example 16-1-(3).
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[NH:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]>CCCCCC>[ClH:3].[NH:6]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:5])=[O:15])=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Product: N=C(N)Nc1ccc(C(=O)Cl)cc1

Procedure:
To 100 ml of thionyl chloride, was added 21.6 g of 4-guanidinobenzoic acid hydrochloride. The mixture was heated with stirring under reflux for one hour. n-Hexane was added to the reaction mixture to obtain pale yellow crystals of 4-guanidinobenzoyl chloride hydrochloride. Into 200 ml of pyridine, was dissolved 28.2 g of 6-amidino-2-naphthol methanesulfonate. To the resulting solution, while being cooled in ice, was added 4-guanidinobenzoyl chloride hydrochloride which was obtained above. The mixture was stirred under cooling in ice for one hour and then at room temperature overnight. After completion of the reaction, the reaction mixture was mixed with about 300 ml of ethyl ether. The oily substance which was separated was dissolved in about 300 ml of water and the insolubles were removed by filtration. A saturated aqueous sodium hydrogencarbonate solution was added to the filtrate to precipitate pale yellow crystals. The crystals were collected by filtration and washed with water and acetone to obtain 30 g (63.7% yield) of 6-amidino-2-naphthyl 4-guanidinobenzoate carbonate. The carbonate was suspended in 100 ml of methanol. Upon addition of 17 g of methanesulfonic acid to the suspension, a clear solution was formed accompanied by effervescence. About 200 ml of ethyl ether was added to the solution to precipitate white crystals which were collected by filtration to obtain 6-amidino-2-naphthyl 4-guanidinobenzoate dimethanesulfonate.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[NH:34][N:33]=[C:32]([CH2:35][C:36](O)=[O:37])[N:31]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH3:24])[N:18]=[C:17]3[CH:25]2[CH2:28][CH2:27][CH2:26]2)[CH2:11][CH2:12][N:13]1[C:36](=[O:37])[CH2:35][C:32]1[NH:33][N:34]=[C:30]([CH3:29])[N:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCn1nc(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc21
Reactant: Cc1nc(CC(=O)O)n[nH]1
Product: CCn1nc(C2CCC2)c2cc(N3CCN(C(=O)Cc4nc(C)n[nH]4)[C@@H](Cc4ccccc4)C3)ccc21
Yield: 37 %

Procedure:
Prepared using the same procedure described in Example 189 from 5-((S)-3-benzyl-piperazin-1-yl)-3-cyclobutyl-1-ethyl-1H-indazole and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (61 mg, 37%). LC/MS (Method B) 3.32 min, [M+1]+ 498.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].C([O:27][P:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.C(#N)C>CCOC(C)=O>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[P:28](=[O:27])([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOP(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccc2ccccc2c1

Procedure:
1-(trimethylsilyl)naphthalen-2-yl trifluoromethanesulfonate (25 mg, 0.071 mmol), Cesium Fluoride (60 mg, 0.395 mmol), Ethoxydiphenylphosphane (68 mg, 0.287 mmol), Acetonitrile (1 ml): Reaction Time: 16 h; Rf: 0.4 (1:3 EtOAc:Pet Ether); Thick oil; 19.5 mg, 83%; 1H NMR (400 MHz, CDCl3, TMS) δ 8.28 (d, J=13.8 Hz, 1H), 7.95-7.84 (m, 3H), 7.79-7.40 (m, 13H); 13C NMR (100 MHz, CDCl3, TMS) δ 134.7 (d, J=2.3 Hz), 134.0 (d, J=9.3 Hz), 133.0, 132.3, 132.1 (d, J=10.0 Hz), 132.0 (d, J=1.5 Hz), 131.3 (d, J=243.5 Hz), 128.9, 128.5 (d, J=12.3 Hz), 128.4, 128.2, 127.4 (d, J=87.9 Hz), 126.8 (d, J=10.8 Hz); 31P NMR (162 MHz, CDCl3) δ 29.3; HRMS-ESI (m/z) calcd (C22H17OP+H)+: 329.1090. found: 329.1086; Known compound, Lit. Y. -L. Zhao, G. -J. Wu, Y. Li, L. -X. Gao, F.-S. Han, Chem. Eur. J. 2012, 18, 9622.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20]Br>>[Br:18][CH2:19][CH2:20][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: BrCCBr
Product: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 2.1, 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-ol and 1,2-dibromoethane were converted to yield 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole as off-white solid, 105° C., MS: 411 (M, 2Br).
Reaction SMILES: [C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:20]([N:22](CC)CC)[CH3:21].C(N)C>O1CCCC1>[C:1]([CH:3]([NH:9][C:10]([C:12]1[S:16][C:15]([NH:22][CH2:20][CH3:21])=[N:14][C:13]=1[CH2:18][CH3:19])=[O:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCN(CC)CC
Reactant: CCc1nc(Br)sc1C(=O)NC(C#N)c1cccs1
Agent: CCN
Solvent: C1CCOC1
Product: CCNc1nc(CC)c(C(=O)NC(C#N)c2cccs2)s1
Yield: 70 %

Procedure:
1.0g of 2-bromo-4-ethyl-thiazole-5-carboxylic acid (cyano-thiophen-2-yl-methyl)-amide, 0.40ml of triethylamine and 0.55ml of ethylamine were added to 10ml of tetrahydrofuran. The reaction mixture was stirred under reflux for 4 hours and then treated according to the same procedure as EXAMPLE 10 to obtain 0.63g (Yield 70%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])(=O)=O>C(Cl)Cl>[Si:41]([O:1][CH2:2][C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@H:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)/[CH:5]=[CH:6]/[CH3:7])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C/C=C/[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 78.2 %

Procedure:
Tert-butyl (2S,3S,E)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (1.94 g, 5.4 mmol) was taken up in 50 mL of DCM and chilled to 0° C. N,N-diisopropylethylamine (2.4 mL, 13 mmol) was added, followed by slow addition of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (1.5 mL, 6.5 mmol). After 45 minutes, an additional 0.20 mL of TBSOTf was added. After an addition 20 minutes, the reaction was quenched with 50 mL of aq NaHCO3. The mixture was partitioned, and the aqueous portion was extracted twice with 50 mL of DCM. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (1% to 7.5% EtOAc/hexanes) afforded tert-butyl (2S,3S,E)-1-(tert-butyldimethylsilyloxy)-3-(4-(trifluoromethyl)phenyl)hex-4-en-2-ylcarbamate (2.0 g, 78% yield) as a clear oil. The oil crystallized on the bench top over 12 hours. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (d, J=8.02 Hz, 2H) 7.35 (d, J=8.02 Hz, 2H) 5.61 (s, 1H) 5.59 (d, J=5.87 Hz, 1H) 4.62-4.60 (m, 1H) 3.97-3.92 (m, 1H) 3.79-3.76 (m, 1H) 3.66-3.59 (m, 2H) 1.69 (d, J=5.28 Hz, 3H) 1.26 (s, 9H) 0.92-0.97 (m, 9H) 0.06 (s, 6H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1.S(=O)(=O)(O)O.[C:30](=O)([O-])O.[Na+].C(Cl)(Cl)Cl>CO>[CH3:30][O:1][CH2:2][C:3]1[S:24][C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[C:11](=[N:12][N:13]([C:17]4[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=4)[C:14](=[O:16])[CH:15]=3)[C:5]=2[CH:4]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCCc2sc(CO)cc2-3)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COCc1cc2c(s1)CCCc1cc(=O)n(-c3ccc(C)cc3)nc1-2

Procedure:
To a suspension of 0.75 g of 9-hydroxymethyl-2-(4-methylphenyl)2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in methanol was added 0.1 ml of conc. sulfuric acid at room temperature and the mixture was refluxed under heating for 3 hours. The mixture was poured into aqueous sodium hydrogen carbonate solution and extraced with chloroform. The extract was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using chloroform as an eluent. The solid was recrystallized from a mixed solvent of ethanol and isopropyl ether to give 0.7 g of 9-methoxymethyl-2-(4-methylphenyl)-2,5,6,7-tetrahydro-3H-thieno-[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one as a white powder, melting at 109°-110° C.
Reaction SMILES: [CH3:1][NH2:2].O.[Cl:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Cl>CN(C)C=O>[Cl:4][C:5]1[CH:6]=[C:7]([CH2:8][NH:2][CH3:1])[CH:10]=[CH:11][CH:12]=1
Reactant: CN
Reactant: ClCc1cccc(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: CNCc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of methylamine (2.0 M solution in tetrahydrofuran, 30 ml) in N,N-dimethylformamide (30 ml), 3-chlorobenzyl chloride (2.5 ml) was added, and the mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of the title compound, which was used in the next reaction without being purified.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(-c2ccc3ccccc3c2)cc1F
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3ccccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 2-(3-fluoro-4-methoxyphenyl)naphthalene (0.22 g, 0.87 mmol) with boron tribromide (1.75 mL of 1 N solution, 1.75 mmol) according to method D to yield 0.13 g (63%) of a white solid: mp 110-112° C.; 1H NMR (DMSO-d6): δ 7.05-7.11 (1H, m), 7.47-7.54 (3H, m), 7.65 (1H, dd, J=2.20 Hz, J=12.92 Hz), 7.82 (1H, dd, J=1.80 Hz, J=8.62), 7.90-7.98 (3H, m), 8.17 (1H, bs), 10.07 (1H, bs); MS (ESI) m/z237 (M−H)−.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.S(O[CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[F:46])(=O)(=O)C>C(O)C>[F:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[CH2:39][CH2:38][CH2:37][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: CS(=O)(=O)OCCCc1ccccc1F
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(NCC1CCN(CCCc2ccccc2F)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
Under nitrogen gas, 0.38 ml (4.90 mM) of methanesulfonyl chloride was added to a solution of 499 mg (3.24 mM) of 2-fluorophenylpropanol and 0.90 ml (6.47 mM) of triethylamine in methylene chloride (6 ml) at 0° C. and the mixture was stirred at the prevailing temperature for 20 minutes. The reaction was stopped by adding saturated aqueous solution of sodium hydrogen carbonate. The reaction mixture was then extracted with diethyl ether. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over MgSO4. The solvent was then distilled off under reduced pressure to provide 0.722 g (3.24 mM) of 2-fluorophenylpropyl mesylate. To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.2 mM) of triethylamine in ethanol was added 0.60 g (2.69 mM) of 2-fluorophenylpropyl mesylate at room temperature, and the mixture was refluxed under nitrogen for 16 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic -layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 20-50%) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1cc(F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cc(F)cc2cccnc12)c1ccccc1
Yield: 35.8 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-amine (Intermediate 48) (60 mg, 0.37 mmol), benzenesulfonyl chloride (78 mg, 0.44 mmol) and DMAP (cat.) gave the title compound (40 mg, 36%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:17][C@@H:10]2[CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C@H:15]2[CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]3[CH2:17][CH2:16]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](COc3ccc(F)cc3)CC[C@@H]2C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(OC[C@@H]2CC[C@@H]3CNCCN3C2)cc1
Yield: 102.5 %

Procedure:
A solution of 0.20 g (0.55 mmol) of (7R,9aR)-2-BOC-7-(4-fluorophenoxy)methyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 10 mL of trifluoroacetic acid and 3 mL of water was stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo and the residue diluted with water. The solution was adjusted to pH 12 with 15% NaOH, and extracted with ethyl acetate (2×). The organic phase was dried (magnesium sulfate), filtered and evaporated to give 0.149 g of the title compound which was used without further purification for subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)cc1
Yield: 52.3 %

Procedure:
The title compound (D151) (56 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (70 mg, 0.216 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (49.18 mg, 0.216 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:27]1C(C)=NC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:19]3[C:20]([CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:16][CH:15]=[C:14]([CH3:25])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1ncccc1Br
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1
Product: Cc1ccc(Nc2cccnc2C)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide (example 11) in accordance with the general method of example 20 using 3-Bromo-2-methylpyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as a light yellow crystalline solid, MS (ISP): m/e=352.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].Br[C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[C:16]([CH3:23])([O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Product: CCOC(=O)C(C)(C)Oc1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 52A], 3-nitro-5-trifluoromethyl-phenol [PCT Int. Appl. (1994), WO 94/20467A1] was reacted with ethyl bromoisobutyrate to yield the title compound as yellow oil.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9].[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23](O)=[O:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C>[CH2:12]([O:19][CH2:20][CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([NH:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([O:10][CH3:11])=[O:9])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1c(Br)ccn1N
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(Br)ccn1NC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Yield: 102.7 %

Procedure:
Methyl 1-amino-3-bromo-1H-pyrrole-2-carboxylate (2.83 g, 12.92 mmol) was treated with (S)-4-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoic acid (4 g, 12.93 mmol), N,N-diisopropylethylamine (7.4 mL, 42.6 mmol) and T3P® (50% in ethyl acetate, 10.8 mL, 18.14 mmol) according to the method of Preparation 5a to give 6.77 g (84% yield) of the desired compound. Purity 81%.
Reaction SMILES: C[C:2]([CH3:36])([CH2:6][C@@:7]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1)[C:3](N)=O.CC#[N:39].O>>[NH2:39][C:2]([CH3:36])([CH3:3])[CH2:6][C@@:7]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH3:29])[CH:23]=3)=[CH:20][CH:21]=2)[CH3:15])[CH2:9][CH2:8]1
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)C(N)=O)(c2ccccc2)OC1=O
Reactant: CC#N
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)N)(c2ccccc2)OC1=O
Reaction time: 24 h

Procedure:
A foil covered flask charged with 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (20 mg, 0.04 mmol) in 1:1 CH3CN/H2O (1 mL) was treated with PhI(O2CCF3)2 (31 mg, 0.07 mmol). The reaction was complete after 24 h. The solvent was removed and the crude material purified by prep HPLC to afford (S)-6-(2-amino-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (16 mg). LC/MS ES+=460 (M+1). LC-MS Method 1 tR=1.06 min, m/z=460 (M+1); 1H NMR (CDCl3) 7.60 (dd, 1H, J=9 Hz, 2 Hz), 7.46 (d, 1H, J=3 Hz), 7.39-7.27 (m, 5H), 7.20 (d, 2H, J=7 Hz), 7.1 (d, 2H, J=8 Hz), 6.78 (d, 1H, J=9 Hz, 5.61 (q, 1H, J=7 Hz), 3.65 (s, 3H), 2.87 (m, 1H), 2.80 (d, 1H, J=16 Hz), 2.23 (d, 1H, J=16 Hz), 2.19-2.08 (m, 3H), 1.54 (d, 3H, J=7 Hz), 1.41 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25](=[O:31])[N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][C:25](=[O:31])[N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-{3-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2,4-oxadiazol-5-yl}hexanoate (Preparation 52) (309 mg, 0.71 mmol) was treated with trifluoroacetic acid (2 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound as a pale yellow oil (200 mg).