Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[C:74]([CH2:75][NH:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[N:73][CH:72]=[N:71]1>C(Cl)Cl.CN(C=O)C>[C:79]([O:78][C:77]([NH:76][CH2:75][C:74]1[N:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=[CH:72][N:73]=1)=[O:83])([CH3:80])([CH3:82])[CH3:81]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCc1ncnn1C[C@H]1NC(=O)[C@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ncnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 1 h
Yield: 58.1 %

Procedure:
To a slurry of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (160 mg, 0.373 mmol) in DCM:DMF (30:1, 3.1 mL) at 0° C. was added DIPEA (163 μL, 0.933 mmol) followed by HATU (142 mg, 0.373 mmol). To the resulting solution was added a solution of tert-butyl ((1-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-1,2,4-triazol-5-yl)methyl)carbamate (92 mg, 0.311 mmol) in DCM:DMF (30:1, 3.1 mL). After 1 h of stirring it was concentrated in vacuo and taken up in EtOAc/brine. The layers separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (Acetone-DCM, 70%) to afford the title compound (128 mg, 58%). LCMS: Rt=0.97 min, m/z=708.2 (M+1) Method 2m_acidic.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([CH3:11])[CH3:10].O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:9]([CH3:11])[CH3:10])[CH:17]=2)=[CH:7][N:6]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(-c2ccc(Cl)nc2)c1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
To a stirred solution of 5-bromo-2-chloropyridine (1.27 g, 6.63 mmol) in toluene (30 mL) was added an ethanolic solution (10 mL) of 3-isopropyl-phenylboronic acid (1.8 g, 11.28 mmol) followed by water (10 mL) and potassium carbonate (2.76 g, 20.0 mmol). The resulting mixture was degassed for 15 min (by purging with argon). At this time, Pd(PPh3)4 (0.613 g, 0.53 mmol) was added under argon and the reaction mixture was heated at 80° C. for 4 h. The reaction mixture was then cooled to room temperature and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (2×10 mL), dried over Na2SO4 and concentrated in vacuo to obtain the crude product, which was purified over silica gel (Biotage column chromatography, 2% ethyl acetate in hexane) to afford 0.900 g (59%) of 2-chloro-5-(3-isopropyl-phenyl)-pyridine.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][C:4]=1[CH3:10].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>Cl.C(O)(=O)C>[Cl:2][C:3]1[CH:9]=[CH:8][C:6]([S:15]([Cl:1])(=[O:17])=[O:16])=[CH:5][C:4]=1[CH3:10]
Reactant: Cl
Reactant: O=S=O
Reactant: Cc1cc(N)ccc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: -5 °C
Reaction time: 1 h

Procedure:
4-Chloro-3-methylaniline hydrochloride (75 g, 0.54 mol) was dissolved in 200 mL concentrated hydrochloride acid (200 mL) and acetic acid (60 mL). The mixture was cooled to −5° C. and NaNO2 (40.9 g, 0.59 mmol) was added. The mixture was stirred between −10° C. to −5° C. for 1 h. While the diazotization was in progress, glacial AcOH (600 mL) was placed in a 4000-mL beaker and stirred magnetically. Sulfur dioxide was introduced by a bubbler tube with a fritted end immersed below the surface of the AcOH until saturation was evident. Cuprous chloride (15 g) was added to the solution. The introduction of sulfur dioxide was continued until the yellow-green suspension becomes blue-green. The mixture was then placed in an ice bath and cooled to 10° C. The diazotization reaction mixture was subsequently added in portions over a 30 min period to the sulfur dioxide solution, ensuring the temperature of the solution did not exceed 30° C. After all the diazonium salt mixture was added, the mixture was poured into ice water (2 L). The resulting precipitate was filtered and re-dissolved in hexane (500 mL). The mixture was filtered through a pad of silica gel (100 g) and the filter pad was washed with hexane (300 mL). The combined filtrate was concentrated to yield 50 g of 4-chloro-3-methylbenzenesulfonyl chloride as slightly yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([OH:18])=O)[CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.FC(F)(F)C(O)=O.[NH2:51][C:52]1[S:53][CH:54]=[C:55]([C:57]2[CH:68]=[CH:67][C:60]([C:61]([NH:63][CH:64]3[CH2:66][CH2:65]3)=[O:62])=[CH:59][CH:58]=2)[N:56]=1>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:18])[NH:51][C:52]2[S:53][CH:54]=[C:55]([C:57]3[CH:58]=[CH:59][C:60]([C:61](=[O:62])[NH:63][CH:64]4[CH2:66][CH2:65]4)=[CH:67][CH:68]=3)[N:56]=2)[CH2:14][O:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1COCN1C(=O)OCc1ccccc1
Reactant: Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)c1ccc(-c2csc(NC(=O)[C@@H]3COCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
(S)-Oxazolidine-3,4-dicarboxylic acid 3-benzyl ester (51.3 mg, 0.20 mmol) was dissolved in DMF (1.5 mL). Triethylamine (56 μL, 0.40 mmol) and pentafluorophenyl trifluoroacetate (35 μL, 0.20 mmol) were added, and the reaction was allowed to stir at ambient temperature for 25 minutes. Then 4-(2-Amino-thiazol-4-yl)-N-cyclopropyl-benzamide trifluoroacetic acid salt (148.8 mg, 0.40 mmol) was added, and the reaction was stirred at ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product. Yield 10.2 mg. MS: 493.1 (M+H+); H1 NMR (DMSO-d6): δ(ppm) 0.52-0.74 (m, 4H), 4.05-4.37 (m, 2H), 4.58-4.69 (m, 1H), 4.90-5.17 (m, 4H), 7.00-7.45 (m, 4H), 7.72-7.98 (m, 5H), 8.37-8.48 (m, 1H), 12.48-12.51 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH:3]1[O:5][CH2:4]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:4][CH:3]([OH:5])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:4][CH:3]([OH:5])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: NCCCCCCN
Reactant: CC(C)(C)C1CO1
Product: CC(C)(C)C(O)CNCCCCCCNCC(O)C(C)(C)C

Procedure:
Condensation of 3,3-dimethyl-1-butene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3,3-dimethylbutylamine] (I: R = (CH3)3C, R' = H, X = (CH2)6, Z = H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[P:23](Cl)(Cl)([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].C1C[O:47]CC1>>[P:23]([OH:47])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)=[O:24]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: C1CCOC1
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=P(O)(Oc1ccccc1)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), phenyl dichlorophosphate (0.211 mL, 1.1 mmol), and lithiumhexamethyidisilazide (0.183 g, 1.1 mmol) in 10 mL of THF was stirred for 1 hour at ambient temperature. The reaction mixture was quenched with H2O and concentrated in vacuo. The residues were purified by reversed phase HPLC (Column: HS Hyperprep C18 8 u ID 22 mm; solvent gradient 40% to 100% acetonitrile (0.1% TFA) in H2O; flowrate 10 mL/min) to give 0.120 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:19])[C:6]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=1.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:20][CH2:13][C:11]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][N:8]=[C:7]([C:6]2[N:5]([CH3:19])[N:4]=[CH:3][C:2]=2[Cl:1])[N:12]=1
Reactant: CCOC(=O)c1cnc(-c2c(Cl)cnn2C)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(-c2c(Cl)cnn2C)nc1CBr
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of ethyl 2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-methylpyrimidine-5-carboxylate (1 g, 3.56 mmol) in carbon tetrachloride (20.0 mL) was added N-bromosuccinimide (697 mg, 3.92 mmol) and 2,2′-azo-bis-isobutyronitrile (30 mg, 0.2 mmol), and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by combi-flash chromatography to afford 0.78 g (61% yield) of the desired product. LC-MS found: 361.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]\[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[F:20])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:21]1([C@@H:27]2[NH:32][CH2:31][C:30](=[O:33])[O:29][C@@H:28]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH3:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH:43]=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C@@:6]3([C@H:43]([CH2:42][C:41]([CH3:46])([CH3:45])[CH3:40])[N:32]4[C@H:31]([C:30](=[O:33])[O:29][C@H:28]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C@@H:27]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C@H:12]3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[F:20])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC=O
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C\c1cccc(Cl)c1F
Reactant: O=C1CN[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Solvent: Cc1ccccc1
Product: CC(C)(C)C[C@@H]1N2[C@H](C(=O)O[C@H](c3ccccc3)[C@@H]2c2ccccc2)[C@@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Yield: 56 %

Procedure:
To a suspension of 496 mg (1.61 mmol) of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one in toluene under argon, were added 408 mg (1.61 mmol) of (5S,6R)-5,6-diphenylmorpholin-2-one and 213 μL (1.61 mmol) of 3,3-dimethyl-butyraldehyde. The reaction mixture was heated at reflux temperature for 6 hours, upon which it was cooled down to room temperature and concentrated to dryness under reduced pressure. The residue was purified by flash chromatography on a 70 g silica cartridge (15-40 μm silica gel; eluting solvent: cyclohexane/ethyl acetate 90/10 v/v; flow: 50 mL/min). 0.58 g of (3R,3′R,4′S,6′S,8′R,8a′S)-6-chloro-8′-(3-chloro-2-fluorophenyl)-6′-neopentyl-3′,4′-diphenyl 3′,4′,8′,8a′-tetrahydrospiro[indoline-3,7′-pyrrolo[2,1-c][1,4]oxazine]-1′,2(6′H)-dione was obtained as an amorphous yellow solid. LC-MS: tR (min)=1.81; [M+H]+: m/z 643[M−H]−: m/z 641 (WATERS UPLC-SQD apparatus; Ionization: electrospray in positive mode and/or negative mode (ES+/−); Chromatographic conditions: Column: ACQUITY BEH C18 1.7 μm-2.1×50 mm; Solvents: A: H2O (0.1% formic acid) B: CH3CN (0.1% formic acid); Column temperature: 50° C.; Flow: 0.8 ml/min; Gradient (2.5 min): from 5 to 100% of B in 1.8 min; 2.4 min: 100% of B; 2.45 min: 100% of B; from 100 to 5% of B in 0.05 min; Retention time=tR (min); referred to herein as “Method C”); 1H NMR (400 MHz, DMSO-d6): 0.39 (s, 9 H); 1.30 (dd, J=4.0 and 15.2 Hz, 1 H); 1.93 (dd, J=6.3 and 15.2 Hz, 1 H); 3.49 (dd, J=4.0 and 6.3 Hz, 1 H); 4.47 (d, J=11.2 Hz, 1 H); 5.04 (d, J=4.2 Hz, 1 H); 5.08 (d, J=11.2 Hz, 1 H); 6.53 (d, J=8.1 Hz, 1 H); 6.66 to 6.76 (m, 3 H); 6.96 (m, 2 H); 7.10 to 7.26 (m, 9 H); 7.34 (t broad, J=7.9 Hz, 1 H); 7.62 (t broad, J=7.9 Hz, 1 H); 10.71 (s broad, 1 H).
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][C:25](OC)=[O:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1.[BH4-].[Li+]>C1COCC1.CCOCC>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][CH2:24][CH2:25][OH:26])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:6])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9])[CH2:2][CH2:3]1
Reactant: COC(=O)CCc1cc(CN(C(=O)OC(C)(C)C)C2CC2)c2ncccc2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(Cc1cc(CCCO)cc2cccnc12)C1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 3-{8-[(cyclopropyl{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-6-quinolinyl}propanoate (1 eq.) from the previous step in THF (0.08 M) was added lithium borohydride (5 eq.). The resulting mixture was stirred at RT for 14 h before it was diluted with ether and quenched with 1 N aq. NaOH. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][C:53]=1[S:59][CH:60](C)[CH2:61]O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:61][CH2:60][S:59][C:53]2[CH:54]=[C:55]([CH3:58])[CH:56]=[CH:57][C:52]=2[CH3:51])=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1ccc(C)c(SC(C)CO)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCSc4cc(C)ccc4C)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 44.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (97 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-propanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (51 mg, yield 42%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.Cl[CH:7]([Cl:9])Cl.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16](=[O:22])[CH2:15][CH2:14]2.C([O-])(=O)C.[Na+]>O.CN(C)C=O>[Cl:9][C:7]1[NH:17][C:18]2[C:13]([CH2:14][C:15]=1[CH:16]=[O:22])=[CH:12][C:11]([F:10])=[C:20]([F:21])[CH:19]=2
Reactant: O=C1CCc2cc(F)c(F)cc2N1
Reactant: ClC(Cl)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=CC1=C(Cl)Nc2cc(F)c(F)cc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
76.9 cm3 of phosphoryl chloride are added in the course of 30 minutes, with stirring, at between 10° and 15° C., to a mixture of 800 cm3Of trichloromethane and 74.35 cm3 of dimethylformamide and the mixture is stirred for 1 hour at a temperature close to 20° C. 65.8 g of 6,7-difluoro-3,4-dihydrocarbostyril are added in the course of 10 minutes, at about 20° C., with vigorous stirring, to the solution obtained The solution obtained is heated to a temperature close to 60° C. and kept at this temperature for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. until a pasty mixture is obtained. A mixture of 500 g of ice and 500 cm3 of water is added, with vigorous stirring. The solid obtained is drained at about 5° C. and washed with 3 times 300 cm3 of water at 5° C. The moist product obtained and 60 g of sodium acetate are added simultaneously, in the course of 1 hour, to 1.5 liters of water at 90° C., in such a way as to maintain the pH at about 6. The mixture is stirred for a further 30 minutes at 90° C., the temperature is allowed to fall to about 50° C. and the product is drained at this temperature and washed with 3 times 300 cm3 of water at about 20° C. 70.18 g of 2-chloro-6,7-difluoro-3-formyl-1,4-dihydroquinoline are obtained in the form of a yellow solid melting at 260° C., which is used in this form for the subsequent steps.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([O:21][C:22]4[C:27]([F:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([F:31])[C:23]=4[F:32])(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:33])[CH:7]=1.[Cl:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([F:43])[CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:36][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([N:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([O:21][C:22]5[C:23]([F:32])=[C:24]([F:31])[C:25]([F:30])=[C:26]([F:29])[C:27]=5[F:28])(=[O:19])=[O:20])=[CH:15][CH:16]=4)[CH:11]=[CH:10][C:9]3=[O:33])[CH:7]=2)[CH:40]=[C:41]([F:43])[CH:42]=1
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cc(F)cc(Cl)c2)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 90 °C
Yield: 38.1 %

Procedure:
Perfluorophenyl 1-(5-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (15.00 g, 26.0 mmol), (3-chloro-5-fluorophenyl)boronic acid (4.99 g, 28.6 mmol), potassium carbonate (10.79 g, 78 mmol), and Pd(PPh3)4 (3.01 g, 2.60 mmol) were combined in 1,4-dioxane (98 ml) and water (32.5 ml). The reaction was heated to 90° C. for 2.5 h. After cooling to room temperature, the reaction was diluted with DCM and washed with water. The organics were dried via phase separator and concentrated in vacuo. The crude oil was dry loaded onto silica gel and purified via MPLC, eluting with 0-100% ethyl acetate (with a 10% DCM additive) to yield perfluorophenyl 1-(3′-chloro-5′-fluoro-4-methoxy-[1,1′-biphenyl]-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (6.20 g, 9.91 mmol, 38.1% yield) as a beige solid. m/z (ESI) 626.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])/[C:5](/[C:14]1[CH:19]=[CH:18][C:17](SC)=[CH:16][CH:15]=1)=[CH:6]/[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].O[O:24][S:25]([O-:27])=O.[K+].[CH3:29]O>>[CH2:1]([O:3][C:4](=[O:22])/[C:5](/[C:14]1[CH:19]=[CH:18][C:17]([S:25]([CH3:29])(=[O:27])=[O:24])=[CH:16][CH:15]=1)=[CH:6]/[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CO
Reactant: O=S([O-])OO
Reactant: CCOC(=O)/C(=C/CC1CCCCC1)c1ccc(SC)cc1
Agent: [K+]
Product: CCOC(=O)/C(=C/CC1CCCCC1)c1ccc(S(C)(=O)=O)cc1

Procedure:
Following the method of example 54d, using (E)-4-cyclohexyl-2-(4-methylsulfanyl-phenyl)-but-2-enoic acid ethyl ester (978 mg, 3.07 mmol) dissolved in methanol 5 h at ambient temperature after the addition of oxone® (2.45 g, 3.99 mmol) gives the title compound as an yellow oil (1.02 g). MS (m/e): 351 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:32][CH3:33])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[OH:31])(=[O:11])=[O:10])[CH:8]=1)#[N:2].C(N(CC)C(C)C)(C)C.Br[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].O>CN(C)C=O>[CH2:48]([O:47][C:45](=[O:46])[CH2:44][O:31][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:19]=[CH:20][C:15]=1[CH2:14][CH2:13][NH:12][S:9]([C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=1[O:32][CH3:33])(=[O:10])=[O:11])[CH3:49]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(C#N)cc1S(=O)(=O)NCCc1ccc(-c2ccccc2S(C)(=O)=O)cc1O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 5.72 g of 5-cyano-N-[2-(3-hydroxy-2′-methanesulfonylbiphenyl-4-yl)ethyl]-2-methoxybenzenesulfonamide in 57 mL of N,N-dimethylformamide were added 2.46 mL of N,N-diisopropylethylamine and 1.37 mL of ethyl bromoacetate. After being stirred at 50° C. for 15 hours, and the reaction mixture was poured into 100 mL of water, and extracted with a mixture of 150 mL of ethyl acetate and 20 mL of toluene. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: ethyl acetate-hexane) to give 2.96 g of ethyl[4-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate as an amorphous material.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]2C(CC(O)C)=CC=C3C([NH:18][C:19](=O)[C:14]=23)=O)[CH2:9][CH2:8]1.NN.C[OH:31]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]([OH:31])[CH2:19][NH2:18])[CH2:9][CH2:8]1
Reactant: CO
Reactant: CC(O)Cc1ccc2c(c1N1CCC(c3ccccn3)CC1)C(=O)NC2=O
Agent: NN
Product: NCC(O)CN1CCC(c2ccccn2)CC1
Yield: 98 %

Procedure:
A mixture of 3-[4-(2-pyridyl)-piperidin-1-yl](2-hydroxypropyl)phthalimide (1.35 g, 3.68 mmol) and hydrazine (0.588 g, 18.4 mmol) in methanol (15 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (0.85 g, 98%).