Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7]([C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=O)=[CH:3][CH:2]=1.S(=O)(=O)(O)O>O1CCCC1>[C:1]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)=[CH:5][CH:6]=1
Reactant: O=C1CC[C@H](C(=O)c2ccc(-c3ccccc3)cc2)N1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=C1CC[C@H](Cc2ccc(-c3ccccc3)cc2)N1
Temperature: 30 °C
Reaction time: 20 h

Procedure:
14 g of (R)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one are suspended in 80 ml tetrahydrofuran. Subsequently 331 mg of concentrated sulphuric acid are added and the reaction vessel is purged with argon. 1.4 g of palladium on carbon 10% m/m (W. C. Heraeus GmbH, Type K-0218) is added and the mixture is stirred under an atmosphere of hydrogen (3 bar) at 30° C. for 20 h. The black suspension is filtered and the filter cake is washed with tetrahydrofuran. After the addition of 50 ml water, the pH of the emulsion is adjusted to pH 5.5 using sodium hydroxide solution (2M). Under reduced pressure, the organic solvent is removed and 100 ml of isopropyl acetate are added. The aqueous layer is then separated and the remaining organic layer is concentrated to approx. half of its original volume. The suspension is cooled to −5° C. and filtered. The filter cake is washed with cooled isopropyl acetate and is dried under reduced pressure to give (R)-5-biphenyl-4-ylmethylpyrrolidin-2-one as colourless crystals. 1H-NMR (CDCl3): 1.93 (1H); 2.37 (3H); 2.80 (1H, dd, J=8.5, 13.5); 2.92 (1H, dd, J=5.4, 13.5); 3.95 (1H); 5.70 (1H); 7.29 (1H, d, J=7.5); 7.38 (1H); 7.47 (2H); 7.59 (4H). MS (ESI, m/e) 252 [M+H]+; 503 [2M+H]+. IR (solution in CH2Cl2, /cm−1): 3191; 3055; 2930; 1692; 1489; 1272; 762; 692.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2C=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[S:9][CH:10]=1)[CH3:2].OC1C(C(=S)N)=[N:22]C=CC=1.ClCC(=O)CC(OCC)=O.[Li+].[Br-]>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[C:12]([OH:17])=[CH:13][CH:14]=[CH:15][N:22]=2)[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(-c2ccccc2O)n1
Reactant: NC(=S)c1ncccc1O
Agent: CCOC(=O)CC(=O)CCl
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1csc(-c2ncccc2O)n1
Yield: 90 %

Procedure:
The procedure used for the preparation of 4a was repeated with 3-hydroxy-2-pyridinecarbothioamide 3c (358 mg, 2.32 mmol), ethyl 4-chloroacetoacetate (0.628 mL, 4.65 mmol), and LiBr (202 mg, 2.32 mmol) in dry THF (6 mL) to give 4c (552 mg, 90%) as a white solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 0-12%) and recrystallization from CH2Cl2 /hexane. mp 85.5°-86.5° C.; IR (KBr) 3400, 1723, 1436, 1202, 1178 cm-1 ; 1H NMR (DMSO-d6) δ1.16 (3H, t, J=7.1 Hz, CH3), 3.93 (2H, s, CH2), 4.08 (2H, q, J=7.1 Hz, CH2), 7.37 (1H, dd, J=8.3 and 4.2 Hz, Ar), 7.45 (1H, d, J=8.3 Hz, Ar), 7.66 (1H, s), 8.15 (1H, d, J=4.2 Hz, Ar), 11.64 (1H, s, OH); FDMS m/z 264 (M+); Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60. Found: C, 54.83; H, 4.66; N, 10.30.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=O)[C:6]([CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:5]2.O=P(Cl)(Cl)[Cl:24]>CN(C)C1C=CN=CC=1>[Cl:24][C:7]1[C:6]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(F)c(F)cc2nc1C=Cc1ccccc1
Agent: CN(C)c1ccncc1
Product: Fc1cc2nc(Cl)c(C=Cc3ccccc3)nc2cc1F
Yield: 56 %

Procedure:
The above 6,7-difluoro-3-styryl-1H-quinoxalin-2-one (2.65 g, 0.93 mmol) was mixed with 4-dimethylaminopyridine (0.27 g) and POCl3 (27 ml) and the mixture was refluxed for 30 minutes. After cooling, the mixture was poured onto ice (400 ml) and the solid was filtered, washed with water (3×) and dried in vacuo overnight. Column chromatography on silica gel, eluting with ethyl acetate:heptane 1:20 afforded 1.6 g (56%) of the title compound.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([CH2:10][C:11]#[N:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([S:7]([C:10]2([C:11]#[N:12])[CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: BrCCCCBr
Reactant: Cc1ccc(S(=O)(=O)CC#N)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: Cc1ccc(S(=O)(=O)C2(C#N)CCCC2)cc1
Yield: 84 %

Procedure:
Similarly to Example 1 paragraph (a), by reaction of 2 g (10.2 mmol) of (toluene-4-sulfonyl)-acetonitrile with 1.35 ml (11.3 mmol) of 1,4-dibromobutane, 50 ml of aqueous soda solution, 233 mg (1 mmol) of benzyltriethylammonium chloride. 2.14 g of 1-(toluene-4-sulfonyl)cyclopentanecarbonitrile is obtained in the form of a brown powder. (Yield=84%)
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6]([C@H:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C@H:9]2[F:21])[CH2:5]1)#[N:2].[NH:22]1[CH:26]=[C:25]([C:27]2[C:28]3[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=3[N:30]=[CH:31][N:32]=2)[CH:24]=[N:23]1.N12CCCN=C1CCCCC2>C(#N)C>[F:21][C@H:9]1[C@@H:8]([N:6]2[CH2:5][C:4]([CH2:3][C:1]#[N:2])([N:22]3[CH:26]=[C:25]([C:27]4[C:28]5[CH:35]=[CH:34][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:29]=5[N:30]=[CH:31][N:32]=4)[CH:24]=[N:23]3)[CH2:7]2)[CH2:13][CH2:12][NH:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N2CC(=CC#N)C2)[C@H](F)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CCNC[C@H]5F)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.5 %

Procedure:
To a solution of tert-butyl cis-4-[3-(cyanomethylene)azetidin-1-yl]-3-fluoropiperidine-1-carboxylate (0.24 g, 0.81 mmol) and 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.31 g, 0.98 mmol) in acetonitrile (8 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 g, 0.98 mmol) by syringe. The resulting solution was stirred at room temperature for 6 hours and concentrated. Purification with combi-flash using 40-100% EtOAc/hexanew as eluent gave 0.30 g (61% yield) of the desired compound as a solid. LCMS found: 611.1 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[CH:19][C:18]=3[NH:29][C:30]([C:32]3[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:31])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[CH:22]=[C:21]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH:20]=[CH:19][C:18]=3[NH:29][C:30]([C:32]3[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=3)[CH2:35][S:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)n2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(2-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propanoate (150 mg, 0.22 mmol, 1.00 equiv) in dichloromethane (4 mL), and trifluoroacetic acid (2 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 85.3 mg (62%) of a white solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.70 (s, 1H), 11.44 (s, 1H), 8.41 (m, 2H), 7.91 (s, 1H), 7.78 (m, 1H), 7.68 (m, 1H), 7.62 (m, 1H), 7.58 (m, 3H), 7.40 (m, 1H), 7.23 (m, 1H), 6.92 (s, 1H), 3.86 (s, 2H), 3.36 (m, 4H), 2.62 (m, 2H), 2.29 (m, 6H), 1.60 (m, 6H). MS (ES, m/z): 612 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH2:20]CS([O-])(=O)=O)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH3:27][C:28]1[N:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:26][C:11]1[C:12]([N:16]2[CH2:17][CH:18]([CH2:20][O:34][C:31]3[CH:32]=[N:33][C:28]([CH3:27])=[CH:29][CH:30]=3)[CH2:19]2)=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: Cc1ccc(O)cn1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(CCS(=O)(=O)[O-])C2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC2CN(c3cccc(CO)c3F)C2)cn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}methylmethanesulfonate (150 mg), 6-methylpyridin-3-ol (70 mg), and DMF (2 ml) were mixed, and potassium carbonate (120 mg) were added thereto, followed by stirring at 80° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and CHCl3 and a saturated aqueous sodium hydrogen carbonate solution were then added thereto. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. THF (2 ml) and a 1 M TBAF/THF solution (0.6 ml) were added to the obtained residue, followed by stirring at room temperature for 1 hour. CHCl3 and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain [2-fluoro-3-(3-{[(6-methylpyridin-3-yl)oxy]methyl}azetidin-1-yl)phenyl]methanol (74 mg).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:5](=[O:6])[CH2:4][C:3]1=[O:7].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=2)[NH:26][CH:25]=1>>[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=2)[NH:26][C:25]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]1[C:5](=[O:6])[C:2]([CH3:1])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[OH:7]
Reactant: Cc1ccc2c(C)c[nH]c2c1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C2(C)C(=O)CC2=O)cc1
Product: Cc1ccc(C2(C)C(=O)C(C(c3ccccc3)c3[nH]c4cc(C)ccc4c3C)=C2O)cc1

Procedure:
Using general procedure C, 2-methyl-2-p-tolyl-cyclobutane-1,3-dione (from Example 4.1) was reacted with benzaldehyde and 3,6-dimethyl-1H-indole (Lit. 4) to give the title compound as a colorless solid. MS: 420.5 ([M−H]−).
Reaction SMILES: [Mg].[CH2:2]([C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1>C1COCC1.Cl[Pd]Cl>[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:10]2[CH:9]=[CH:8][C:7]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=2)=[CH:19][CH:18]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CCCCCc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A Grignard compound is prepared from 1.2 g of magnesium, 50 ml of THF and 11.4 g of 4-pentyl-bromobenzene in 25 ml of THF. When the addition is complete, the mixture is refluxed for a further I hour and cooled to 10°, and 14 g of 4-trifluoromethoxy-bromobenzene in 25 ml of THF and 0.73 g of PdCl2 (dppf) are added. The cooling is removed, but the reaction mixture should not climb above 20°. The mixture is subsequently stirred at room temperature for 16 hours, poured into 100 ml of saturated NH4Cl solution a nd stirred for a further 15 minutes, and the organic phase is then worked up. After purification by crystallization, trifluoromethoxy-4-(4-pentylphenyl)benzene having C 67° I is obtained.
Reaction SMILES: CCCCCC.C([Li])CCC.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>O1CCCC1>[CH3:20][Si:21]([CH3:23])([CH3:22])[N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)[Si:21]([CH3:23])([CH3:22])[CH3:20]
Reactant: Cc1cccc(N)n1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(N([Si](C)(C)C)[Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
A 15% n-hexane solution (636 g.) of n-butyllithium was added to a solution of 2-amino-6-methylpyridin (64.8 g.) in tetrahydrofuran (500 ml.) at -20° to -30° C. over one hour, and stirred at -8° to -10° C. for 30 minutes. To the solution was added trimethylsilylchloride (161.7 g.) at -15° to -5° C. over 40 minutes, and the resultant solution was stirred at room temperature overnight. The solution was filtered through by a column packed with silica gel (180 g.), washed with tetrahydrofuran and then the filtrate was concentrated under reduced pressure. The residue was purified by fractional distillation to give a 2-[N,N-bis(trimethylsilyl)amino]-6-methylpyridine (117.6 g.), b.p. 95° to 97° C./5-6 mmHg.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21]>C(#N)C>[CH2:19]([NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]([CH3:14])[S:12][C:11](=[O:15])[NH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17])[CH:20]([CH3:22])[CH3:21]
Reactant: CC1SC(=O)NN=C1c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)CN
Solvent: CC#N
Product: CC(C)CNc1ccc(C2=NNC(=O)SC2C)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 80.6 %

Procedure:
To 15 ml of acetonitrile are added 2.9 g (10.1 mM) of 5-(4-chloro-3-nitrophenyl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and 5 ml (50 mM) of isobutylamine. The reaction medium is maintained at 60° C. for 20 hours with stirring and is then concentrated under vacuum. The residue obtained is purified on silica using dichloromethane as eluent. The product obtained is taken up and crystallised from diethyl ether. The solid is filtered off and washed to give 2.6 g of 5-[4-(isobutylamino)-3-nitrophenyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)=O)=O)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]2[S:37][C:11]([C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=3)=[CH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C(=O)CNC(=O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccc(-c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1
Temperature: 145 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A mixture of ethyl 4-[2-(4-trifluoromethylbenzoylamino)-1-oxoethyl]benzoate (900 mg), Lawesson's reagent (960 mg) and xylene (5 ml) was stirred at 140 t 145° C. for 2 hours. The reaction mixture was cooled, and precipitated crystals of ethyl 4-[2-(4-trifluoromethylphenyl)-5-thiazolyl]benzoate (378 mg, yield: 43%) were collected by filtration. The product was recrystallized from xylene-isopropyl ether to obtain pale yellow prisms. Melting point: 174 to 176° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[C:4]([O:17][CH3:18])[CH:3]=1.Br[C:20]1[N:24]2[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:31])[CH3:30])=[N:28][C:23]2=[N:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[N:24]3[N:25]=[CH:26][C:27]([C:29]([OH:32])([CH3:30])[CH3:31])=[N:28][C:23]3=[N:22][CH:21]=2)=[C:4]([O:17][CH3:18])[CH:3]=1
Reactant: COc1cc(F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Product: COc1cc(F)ccc1-c1cnc2nc(C(C)(C)O)cnn12
Yield: 91 %

Procedure:
2-(4-Fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)propan-2-ol (from Example 1, step d) under the conditions described in Example 1, step e. The residue was purified by flash column chromatography (silica gel, EtOAc) to give the title compound in 91% yield: 1H NMR (400 MHz, CDCl3) δ 1.70 (6H, s), 3.57 (1H, s), 3.87 (3H, s), 6.78–6.83 (2H, m), 7.87 (1H, dd, J 1.6, 6.6), 8.23 (1H, s), 8.69 (1H, s); MS (ES+) m/z 303 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:23]=[CH:22][C:14]([CH2:15][O:16][C:17](=[O:21])[C:18](Cl)=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:24][Si:25]([CH3:45])([CH3:44])[O:26][C@@H:27]([C@@H:29]1[C@@H:32]([CH:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:36])[CH3:34])[NH:31][C:30]1=[O:43])[CH3:28]>C(Cl)Cl>[CH3:44][Si:25]([CH3:24])([CH3:45])[O:26][C@@H:27]([C@@H:29]1[C@@H:32]([CH:33]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[S:36])[CH3:34])[N:31]([C:18](=[O:19])[C:17]([O:16][CH2:15][C:14]2[CH:22]=[CH:23][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)=[O:21])[C:30]1=[O:43])[CH3:28]
Reactant: O=C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C(=S)c1ccccc1)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=S)c1ccccc1)[C@@H]1[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N1C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -30 °C
Reaction time: 0.58 h

Procedure:
A solution of 0.71 ml of triethylamine and 1.1 g of p-nitrobenzyloxyoxalyl chloride in 10 ml of methylene chloride was added to a solution of 0.9 g of (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-2-azetidinone in 10 ml of methylene chloride, cooled to about -30° C., and the mixture was stirred for 35 minutes at the same temperature. The reaction mixture was worked up and purified in the same manner as in Preparation 1(3), giving (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1RS)-1-(phenylthiocarbonyl)ethyl]-1-(p-nitrobenzyloxyoxalyl)-2-azetidinone as an oil.
Reaction SMILES: ClC(Cl)(Cl)C([NH:5][CH:6]([CH:14]=[CH2:15])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=O>Cl>[NH2:5][CH:6]([CH:14]=[CH2:15])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: C=CC(CCC(=O)OCC)NC(=O)C(Cl)(Cl)Cl
Agent: Cl
Product: C=CC(N)CCC(=O)O
Yield: 139.4 %

Procedure:
A suspension of ethyl 4-trichloroacetoamido-5-hexenoate (0.3 g, 1 mmol) in 6N HCl (10 mL) was heated under reflux 6 H. Then the mixture was concentrated in vacuo, diluted with water (10 mL), washed twice with Acoet, and dried in vacuo to give the title product (0.18 g, 100%). NMR, TLC (NH4OH:EtOH, 3:7) are identical with those of an authentic sample of 4-amino-5-hexenoic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:24][C:25]1([F:33])[CH2:28][N:27]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:12][O:13][C:14]2[CH:15]=[N:16][C:17]([CH:21]3[CH2:23][CH2:22]3)=[C:18]([Cl:20])[CH:19]=2)=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:32][S:29]([N:27]1[CH2:28][C:25]([F:33])([F:24])[CH2:26]1)(=[O:31])=[O:30])=[O:9]
Reactant: NS(=O)(=O)N1CC(F)(F)C1
Reactant: O=C(O)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NS(=O)(=O)N1CC(F)(F)C1)c1cc(Cl)c(COc2cnc(C3CC3)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
To a solution of 5-chloro-4-(((5-chloro-6-cyclopropylpyridin-3-yl)oxy)methyl)-2-fluorobenzoic acid (Preparation 27, 100 mg, 0.28 mmol) and 3,3-difluoroazetidine-1-sulfonamide (Preparation 23, 75 mg, 0.42 mmol) in DCM (10 mL) was added diisopropylethylamine (73 mg, 0.56 mmol) followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (160 mg, 0.42 mmol). The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in DMSO (2 mL) and purified by reverse phase chromatography (0-90% acetonitrile/water containing 0.1% formic acid) to give the title compound as colourless solid (51 mg, 36%).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:19]([CH3:21])[CH3:20])[C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6](OC)=[O:7].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:19]([CH3:21])[CH3:20])[C:12]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][OH:7]
Reactant: COC(=O)c1cc(N(C)C)c(N2CCCCC2)c(N(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1cc(CO)cc(N(C)C)c1N1CCCCC1

Procedure:
A solution of 25 g. of methyl 3,5-bis(dimethylamino)-4-piperidinobenzoate in 150 ml. of absolute tetrahydrofuran was added dropwise to a solution of lithium aluminum hydride in 300 ml. of absolute tetrahydrofuran, and the mixture was boiled under reflux for 3 hours. After cooling, the excess lithium aluminum hydride was cautiously decomposed with 100 ml. of ethyl acetate and then with 3 ml. of water and the sodium evaporated to dryness. The residue was taken up in water, the oily product extracted with ethyl acetate and the ethyl acetate solution dried and evaporated. After recrystallization from high-boiling petroleum ether, there was obtained 3,5-bis(dimethylamino)-4-piperidinobenzyl alcohol having a melting point of 90°-92° C.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=2[O:16][C:15](=[O:24])[CH:14]=1.CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]2[O:16][C:15](=[O:24])[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][S:35]([CH3:34])(=[O:37])=[O:36])[C:18]=2[CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCOc1cc(=O)oc2ccc(Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCCCOc1cc(=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
4-(3-Aminopropoxy)-6-chloro-1-benzopyran-2-one trifluoroacetate salt (0.272 mmol, 0.10 g) is suspended in 2 mL of DCM. DIEA (1.36 mmol, 0.236 mL) is added followed by methanesulfonyl chloride (0.543 mmol, 0.062 g) and the reaction is stirred at ambient temperature for 4 hrs. The solvent is removed under reduced pressure and the residue is redissolved and purified by HPLC to afford the title compound (21 mg, 23%); 1H NMR (DMSO-d6, 300 MHz) δ 7.80 (1H, d, J=2.6 Hz), 7.70 (1H, dd, J=2.5, 8.75 Hz), 7.45 (1H, d, J=8.87 Hz), 7.11 (1H, brt), 5.97 (1H, s), 4.28 (2H, t, J=6 Hz), 3.16 (2H, m), 2.91 (3H, s), 2.01 (2H, m); MS (ESI, Pos.) calcd for C13H14ClNO5S m/z [M+H]=332.0, found 331.9.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].Br[CH2:15][C:16]#[N:17].C(N(CC)CC)C>C(#N)C>[CH3:1][O:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([O:6][CH2:15][C:16]#[N:17])=[O:5]
Reactant: N#CCBr
Reactant: CO[C@@H](Cc1ccccc1)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CO[C@@H](Cc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
(S)-2-Methoxy-3-phenylpropanoic acid (Compounds 7a, 0.50 g, 2.50 mmol) and 2-bromoacetonitrile (1.20 g, 10.00 mmol) were dissolved in acetonitrile (60 ml). Then triethylamine (0.50 g, 4.99 mmol) was added dropwise under ice-cooling. After stirring at room temperature for 40 minutes, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to afford the title compound (0.39 g, 65%).