Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=C1CCC2(OCCO2)CC1.O=[C:13]1[CH2:18][CH2:17][C:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.O1C2(CCC(=O)CC2)OCC1>>[CH2:1]=[C:13]1[CH2:18][CH2:17][C:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)CC1
Reactant: C=C1CCC2(CC1)OCCO2
Agent: O=C1CCC2(CC1)OCCO2
Product: C=C1CCC(C(=O)OCC)(C(=O)OCC)CC1

Procedure:
The title compound was prepared following the method reported herein for Compound 31a. As starting material diethyl 4-oxocyclohexane-1,1-dicarboxylate replaced 1,4-dioxaspiro[4.5]decan-8-one. After the usual work-up procedure the residue was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 1:0 to 8:2) to give the title compound as a colorless oil. Yield: 88.1%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:22])[N:16]([CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:17]=2)=[N:31]\[OH:32])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(CC2CC2)c1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(CC2CC2)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-3-o-tolyl-propionyl]-1-cyclopropylmethyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless foam, MS (ESI+): m/z=465.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].O>CN(C)C=O>[C:21]1(=[O:30])[N:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][C:9]3=[O:12])=[CH:4][CH:3]=2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: O=C1CCCc2ccc(O)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCc2ccc(OCCCN3C(=O)c4ccccc4C3=O)cc21
Reaction time: 0.05 h

Procedure:
7-Hydroxy-1-tetralone (33.3 g) is dissolved in dimethylformamide (325 ml) and the mixture is cooled in an ice bath. Sodium methoxide (11.07 g) is added to the mixture. After the mixture is stirred for 3 min., N-(3-bromopropyl)phthalimide (54.96 g) is added to the mixture; stirring is continued and the reaction mixture stirred overnight. The resulting mixture is poured into H2O (650 ml), stirred for 1 hour, filtered, washed with H2O and air dried. The resulting fluffy near-white solid (62.8 g) is crystallized from ethyl acetate to give the desired product, a fluffy white solid (M.P. 149°-150° C.)
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([NH:10]C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4].C(Cl)Cl.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[CH3:1][O:2][C:3]([C@@:5]1([NH2:10])[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C[C@@H]1C[C@]1(N)C(=O)OC

Procedure:
N-Boc-(1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid methyl ester (125 mg, 0.52 mmol) stirred in CH2Cl2/TFA (1:1, 2 mL) at RT for 90 minutes. Solvents removed under vacuum to yield (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid methyl ester trifluoroacetic acid salt.
Reaction SMILES: C([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(OC(C)(C)C)=O.O1CCOCC1.Cl.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([N:8]1[CH2:31][CH2:30][C@@:15]23[C:16]4[CH:17]=[C:18]([O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:21]=4[CH2:22][C@@H:9]1[C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14]3)(=[O:42])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OC(=O)C(C)(C)C)cc13
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)Oc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(S(C)(=O)=O)CC3
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of compound 31 (5 mg, 0.012 mmol) in dry CH2Cl2 (0.2 mL) was added 4 M HCl dioxane solution (0.5 mL) and stirred for 2 h at 0° C. The solvent was evaporated under reduced pressure. The crude amine salt 32 was dissolved in CH2Cl2 (0.5 mL) and slowly added methanesulfonyl chloride (2 μL, 0.030 mmol) and TEA (9 μL, 0.064 mmol) at 0° C. After 1 h stirring, the reaction mixture was concentrated under reduced pressure. The crude product was purified on a silica gel column chromatography (3:1 n-Hexane/EtOAc) to give a colorless oil (3 mg, 82% yield): 1H NMR (300 MHz, CDCl3) 1.08˜1.87 (m, 20H); 2.36 (d, J=12.4 Hz, 1H); 2.77˜2.92 (m, 5H); 3.51˜3.54 (m, 1H); 4.10˜4.15 (m, 1H); 6.86˜6.96 (m, 2H); 7.13 (d, J=8.3 Hz, 1H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:21]3[N:22]=[C:23]4[C:29]([C:30](O)=[O:31])=[CH:28][N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:24]4=[N:25][CH:26]=3)=[N:16][N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[F:72][C:73]([F:84])([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C@H:74]([NH2:76])[CH3:75]>CN(C=O)C>[F:72][C:73]([F:84])([CH2:77][C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[C@H:74]([NH:76][C:30]([C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:15]3[C:14]4[C:18](=[CH:19][C:11]([F:10])=[CH:12][CH:13]=4)[N:17]([CH3:20])[N:16]=3)[N:22]=2)[N:27]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[CH:28]=1)=[O:31])[CH3:75]
Reactant: C[C@@H](N)C(F)(F)Cc1ccccc1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a round-bottomed flask, (R)-2,2-difluoro-1-methyl-3-phenyl-propylamine trifluoroacetate (crude from Step 3) was dissolved in DMF (1.1 ml) and N,N-diisopropylethylamine (0.25 ml, 1.43 mmol) was added. Then 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 23 mmol) was added followed by HATU (95 mg, 0.25 mmol). The yellow reaction was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was triturated with petroleum ether to afford 136 mg (94%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2,2-difluoro-1-methyl-3-phenyl-propyl)-amide as an off-white powder.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)#[N:7].BrC1C=CC(C2C=CC(CCCCC)=CC=2)=CC=1.C(NC(C)C)(C)C.BrCCC>CCCCCC.C1COCC1>[C:6]([C:8]1([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)#[N:7]
Reactant: [Li]CCCC
Reactant: CCCCCc1ccc(-c2ccc(C3CCC(C#N)CC3)cc2)cc1
Agent: CCCCCc1ccc(-c2ccc(Br)cc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc(C3CCC(C#N)(CCC)CC3)cc2)cc1
Reaction time: 0.33 h

Procedure:
62.5 ml (0.1 mole) of a 1.6M solution of n-butyl-lithium in hexane and 33.1 g (0.1 mole) of 4-(4-cyanocyclohexyl)-4'-pentylbiphenyl (obtainable by Grignard reaction of 4-bromo-4'-pentyl-biphenyl with 4-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-cyclohexanone (J. Org. Chem. 39 (18), 2787-93 (1974)), detachment of water and simultaneous removal of the oxazolyl protective group by boiling with ethanolic H2SO4, hydrogenation of the double bond and subsequent conversion of the ester into the nitrile) in 40 ml of THF are successively added dropwise to 10.1 g (0.1 mole) of diisopropylamine in 70 ml of THF at -10°, with exclusion of moisture and under a nitrogen atmosphere. The reaction mixture is then stirred for 20 minutes. 13.5 g (0.11 mole) of 1-bromopropane are then added, also at -10°, and the mixture is subsequently stirred at room temperature for a further 20 minutes. After customary working up, 4-(4-cyano-4-propylcyclohexyl)-4'-pentylbiphenyl is obtained.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([OH:34])=O)[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]2[CH2:19][CH2:20]2)[C:7]1(/[CH:30]=[CH:31]/[C:32]([NH2:38])=[O:34])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(=O)O)CNC(=O)OC(C)(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC1c2ccccc2C(=O)N(CC2CC2)C1(/C=C/C(N)=O)CNC(=O)OC(C)(C)C
Yield: 94.7 %

Procedure:
A solution of (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenic acid (0.71 g, 1.5 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.58 g, 3 mmol) and 1-hydroxybenzotriazole ammonium salt (0.46 g, 3 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide (0.67 g, 95.7%) as crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[NH:20][N:19]=[C:18]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[CH:17]=2)[CH:11]=1.C(C1C=NC=CC=1)(=O)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:59][C:60]([F:73])([F:72])[C:61]1[CH:62]=[C:63]([CH:69]=[CH:70][CH:71]=1)[O:64][CH:65]1[CH2:68][NH:67][CH2:66]1>CN(C=O)C.O>[O:27]=[C:25]([N:67]1[CH2:68][CH:65]([O:64][C:63]2[CH:69]=[CH:70][CH:71]=[C:61]([C:60]([F:59])([F:73])[F:72])[CH:62]=2)[CH2:66]1)[CH2:24][NH:23][C:21]([C:18]1[CH:17]=[C:16]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[NH:20][N:19]=1)=[O:22]
Reactant: O=C(O)CNC(=O)c1cc(-c2cccnc2)[nH]n1
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Agent: CC(=O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1)c1cc(-c2cccnc2)[nH]n1
Reaction time: 0.03 h
Yield: 32 %

Procedure:
DIPEA (158.2 mg, 1.22 mmol) was added to a stirred solution of [(5-pyridin-3-yl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (prepared by the method used for the synthesis of Intermediate 30, starting from 3-acetylpyridine) (76 mg, 0.30 mmol) in DMF (2 mL) followed by HOBt (43.4 mg, 0.32 mmol) and EDCI (61.6 mg, 0.32 mmol). After 2 minutes of stirring, 3-(3-trifluoromethyl-phenoxy)-azetidine hydrochloride (77.5 mg, 0.3 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure The residue obtained purified by column chromatography (using silica gel 60- and 100% ethyl acetate as eluent) to afford 43 mg (32% Yield) of 5-pyridin-3-yl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[3-(3-trifluoromethyl-phenoxy)-azetidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 446.14, 93.76%. 1H NMR (300 MHz, DMSO-d6): δ 9.44 (s, 1H), 9.2 (d, 1H), 8.72 (m, 2H), 8.38 (m, 1H), 7.64 (m, 1H), 7.52 (t, 1H), 7.35 (d, 1H), 7.16 (m, 2H), 5.2 (m, 1H), 4.7 (m, 1H), 4.3 (m, 1H), 4.2 (m, 1H), 3.95 (d, 2H), 3.8 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH2:30][CH3:31])[C:24]2=[O:32])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].C(O)CCC>O>[CH2:30]([N:25]1[C:26](=[O:29])[CH:27]=[CH:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:16]3[CH2:14][CH2:13][N:4]([C:5]4[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=4)[CH2:3][CH2:2]3)=[CH:18][CH:19]=2)[C:24]1=[O:32])[CH3:31]
Reactant: CCn1c(=O)ccn(-c2ccc(N)cc2)c1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCn1c(=O)ccn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Reaction time: 24 h
Yield: 37 %

Procedure:
A mixture of 17.47 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 16.3 parts of 1-(4-aminophenyl)-3-ethyl-2,4(1H,3H)-pyrimidinedione, 11.83 parts of sodium hydrogen carbonate and 240 parts of 1-butanol was stirred for 24 hours at reflux temperature. After cooling, 150 parts of water were added. The product was filtered off and crystallized from methylbenzene. The product was filtered off and dried in vacuo at 60° C., yielding 10.6 parts (37.0%) of 3-ethyl-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4(1H,3H)-pyrimidinedione; mp. 210.2° C. (int. 26).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>>[O:10]1[CH2:11][CH2:12][N:7]([CH2:2][CH:3]([OH:6])[CH2:4][OH:5])[CH2:8][CH2:9]1
Reactant: OCC(O)CCl
Reactant: C1COCCN1
Product: OCC(O)CN1CCOCC1
Temperature: 80 °C
Yield: 72.7 %

Procedure:
33 g of 3-chloropropylene glycol was added dropwise to 65 g morpholine, with stirring, while maintaining the temperature at 80° C. The 3-chloropropylene glycol reacted quickly with the morpholine exothermically. The reaction mixture was stirred for 3 hours, with the temperature maintained at 80° C. The salt of morpholine, which separated from the reaction mixture, was filtered out. The filtrate was distilled under reduced pressure. This distillation gave 35 g of the desired product, 3-morpholino propylene glycol (bp. 135°-138° C./11 mmHg), in a 75.5% yield.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][CH2:16][C:15](=[O:18])[N:14]2[CH3:19])(=O)=O)=CC=1.[N-:20]=[N+]=[N-].[Na+].[H-].[Na+].[I-].[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N.C(O)(=O)C(O)=O>C(OCC)C.C(O)(C)C.O.CN1CCCC1=O>[NH2:20][CH2:12][CH:13]1[N:14]([CH3:19])[C:15](=[O:18])[CH2:16][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(=O)N2C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: N
Agent: O=C(O)C(=O)O
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)O
Product: CN1C(=O)CCC1CN
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of (1-methyl-5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (196 g, 0.73 mol), sodium azide (142 g, 2.19 mol) and N-methyl-2-pyrrolidinone (800 ml) was heated to 80° C. for two hours, cooled, diluted with diethyl ether (3 L) and filtered through a pad of silica gel. The silica gel pad was washed with 1 L of a mixture of methanol:diethyl ether (5:1). The combined filtrates were concentrated in vacuo. The residue was subsequently treated with a suspension of sodium hydride in mineral oil (60%, 44 g, 1.1 mol) at 10-15° C. under rapid stirring for two hours followed by the addition of lithium iodide (155 g, 1.1 mol). The reaction mixture was allowed to warm to 25° C. for 3 hours. The unreacted sodium hydride was quenched with water. The mixture was diluted with dioxane (1.5 L) and diethyl ether (5 L) and filtered through a plug of silica gel. The silica gel plug was then washed with ether. The combined filtrates were concentrated, the residue was dissolved in dioxane (2 L), cooled to 0° C., and triphenylphosphine (191 g, 0.73 mol) was added at 0° C. for 1 hour. The reaction mixture was stirred at 25° C. for 10 hours, then water (25 mL) and aqueous ammonia (1 mL, 25%) were added, and the mixture was refluxed for two hours, cooled, and evaporated. The residue was dissolved in isopropanol (2.5 L), and to the solution was added a solution of oxalic acid (88 g, 0.7 mol) in isopropanol (1 L). The precipitate that formed was filtered, washed with isopropanol (1 L), and dried to give the title compound as the oxalate salt.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([O:25][CH3:26])[C:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[C:18]3[Cl:38])([C:7]2[C:8]([CH3:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[OH:6])[CH2:2]1.N1CC(C(C2C(C)=NC(C)=CC=2)(O)C2C=C3C(=CC=2)N=[C:49]([OH:54])[C:48](CC2C=CC(C(F)(F)F)=CC=2)=C3Cl)C1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:38][C:18]1[C:17]2[C:22](=[CH:23][CH:24]=[C:15]([C:5]([C:7]3[C:8]([CH3:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)([OH:6])[CH:3]3[CH2:4][N:1]([C:49](=[O:54])[CH3:48])[CH2:2]3)[CH:16]=2)[N:21]=[C:20]([O:25][CH3:26])[C:19]=1[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=1
Reactant: Cc1ccc(C(O)(c2ccc3nc(O)c(Cc4ccc(C(F)(F)F)cc4)c(Cl)c3c2)C2CNC2)c(C)n1
Reactant: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CNC3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)C3CN(C(C)=O)C3)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 40 °C

Procedure:
To a flask containing crude azetidin-3-yl(4-chloro-2-methoxy-3-(4-(trifluoromethyl)-benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanol and 6-(azetidin-3-yl(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)-4-chloro-3-(4-(trifluoromethyl)benzyl)-quinolin-2-ol (630 mg, 1.16 mmol, Example 126) was added DCM (20 mL) which gave a suspension at room temperature. Triethylamine (1 mL, 6.9 mmol) was added, followed by acetic anhydride (0.30 mL, 3 mmol) and the initial suspension became homogeneous after about 2 minutes. The mixture was heated to 40° C. for 4 hours then quenched with brine and extracted with DCM (3×25 mL). The combined organics were dried over MgSO4, filtered and concentrated to dryness. The residue was purified by FCC (5% MeOH-EtOAc increasing to 10% MeOH) to provide the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (dd, J=4.1, 2.0 Hz, 2H), 7.81-7.71 (m, 4H), 7.53 (d, J=8.2 Hz, 4H), 7.46-7.37 (m, 6H), 7.25-7.17 (m, 2H), 4.45-4.33 (m, 5H), 4.30-4.07 (m, 4H), 4.04 (d, J=1.3 Hz, 5H), 4.01-3.97 (m, 1H), 3.85 (t, J=8.6 Hz, 1H), 3.77-3.59 (m, 3H), 2.49 (d, J=1.6 Hz, 6H), 2.18 (s, 6H), 1.83 (d, J=13.7 Hz, 6H); MS (ESI): mass calcd. Chemical Formula: C31H29ClF3N3O3, Exact Mass: 583.2. m/z found 583.9 [M+H]+. 1-(3-((4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(hydroxy)methyl)azetidin-1-yl)ethanone was purified by chiral SFC (Stationary phase: CHIRALPAK AD-H 5 μm 250×20 mm, Mobile phase: 75% CO2, 25% i-PrOH (0.3% iPrNH2)) to give two enantiomers. The first eluting enantiomer was Example 87b and the second eluting enantiomer was Example 87c.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[Li+].[OH-]>C1COCC1.O>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(CN)cc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 3-aminomethyl-5-nitrobenzoate (5890 mg, 28 mmol) in THF (100 mL) was added a solution of LiOH (2350 mg, 56 mmol) in water (100 mL) and the mixture was stirred at r.t. for 2.5 hours. THF was evaporated and the aqueous solution was washed with Et2O (100 mL). The solution was neutralized with concentrated HCl (6 mL) and evaporated in vacuo. To a solution of evaporated residue in water (150 mL) and concentrated HCl (3 mL) was added 1N LiOH (50 mL). Brown fine needles were precipitated out and collected on a glass filter (5300 mg, 96%): 1H NMR (300 MHz, D2O) δ 8.645 (s, 1H), 8.412 (s, 1H), 8.232 (s, 1H), 4.332 (s, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br-].[Li+].[C:13]([C:17]1[S:21][C:20]2=[C:22]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:23]=[CH:24][N:19]2[C:18]=1[CH2:31][O:32][Si:33]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:34][CH3:35])(=[O:16])[CH2:14][CH3:15].C(O[C@H:44]1[NH:47][C:46](=[O:48])[C@H:45]1[C@H:49]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[CH3:50])(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[Si:52]([O:51][C@@H:49]([C@@H:45]1[C@@H:44]([CH:14]([CH3:15])[C:13]([C:17]2[S:21][C:20]3=[C:22]([C:25]4[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=4)[N:23]=[CH:24][N:19]3[C:18]=2[CH2:31][O:32][Si:33]([CH2:34][CH3:35])([CH2:38][CH3:39])[CH2:36][CH3:37])=[O:16])[NH:47][C:46]1=[O:48])[CH3:50])([C:55]([CH3:56])([CH3:57])[CH3:58])([CH3:53])[CH3:54]
Reactant: CCC(=O)c1sc2c(-c3cccnc3)ncn2c1CO[Si](CC)(CC)CC
Reactant: CC(=O)O[C@H]1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OCc1c(C(=O)C(C)[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)sc2c(-c3cccnc3)ncn12
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
A 1 M tetrahydrofuran solution (5.2 ml) of lithium bistrimethylsilylamide was added to a solution of 2.05 g of lithium bromide in 10 ml of tetrahydrofuran under an argon atmosphere, and the mixture was cooled to −78° C. A solution of 0.95 g of 2-propionyl-7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazole in 4.7 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for one hr. A solution of 0.81 g of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one in 3.8 ml of tetrahydrofuran was added thereto, and the mixture was stirred at that temperature for 2 hr. A 10% aqueous citric acid solution was added to the reaction mixture to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution and saturated brine in that order and was then dried over anhydrous magnesium sulfate. The extract was then concentrated by removing the solvent, and the concentrate was purified by column chromatography on silica gel (5 to 10% methanol/methylene chloride) to give 0.80 g of a crude product of (3S,4R)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[1-methyl-2-[7-(pyridin-3-yl)triethylsilyloxymethylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl]azetidin-2-one.