Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:26][CH2:25][CH2:24][CH2:23][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)=[O:8].[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([NH:1][C:2]2[S:3][C:4]3[CH2:26][CH2:25][CH2:24][CH2:23][C:5]=3[C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)=[O:8])=[O:40])(=[O:35])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1sc2c(c1C(=O)Nc1ccc(Cc3ccncc3)cc1)CCCC2)c1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To a mixture of 9.1 mg of 2-amino-N-[4-(pyridin-4-ylmethyl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, 8.1 mg of 3-(morpholine-4-sulfonyl)benzoic acid, 0.016 mL of N,N-diisopropylethylamine, and 0.5 mL of DMF was added a mixture of 11.4 mg of HATU and 0.1 mL of DMF, followed by stirring at 60° C. overnight. The reaction mixture was separated by the addition of chloroform and water, and then the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to obtain 8.9 mg of 2-{[3-(morpholin-4-ylsulfonyl)benzoyl]amino}-N-[4-(pyridin-4-ylmethyl)phenyl]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH:19]=[CH:18][CH:17]=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:20]>ClCCl.CCOCC>[ClH:20].[N:15]1([CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:18][CH:17]=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: c1cnn(CC2CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-Pyrazol-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (215 mg) in anhydrous dichloromethane (5 ml) was added 2M hydrogen chloride in ether (4.1 ml). The reaction mixture was stirred at room temperature for 6 hours. The solvents were removed in vacuo to yield 4-Pyrazol-1-ylmethyl-piperidine hydrochloride salt.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c(N3CCCC3)cccc12
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Oc1cccc2c(N3CCCC3)cccc12

Procedure:
5-Methoxy-1-pyrrolidinyl-naphthalene (90 g) is dissolved in glacial acetic acid (1 liter). 48% hydrobromic acid is added to the solution and the resulting reaction mixture heated to reflux for 3 hours. The reaction mixture is poured into water and crushed ice and the solution made alkaline to pH 8 to 9. The aqueous mixture is extracted with methylene chloride. The methylene chloride extract is back-extracted with 2% KOH solution and the combined basic layers made acidic by the addition of aqueous HCl. The addition is continued until a white precipitate appears. The aqueous solution is extracted with methylene chloride and the organic layer washed with H2O, dried, filtered and evaporated in vacuo, yielding the desired product.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)=[CH:3][CH:2]=1.CSC.C(#N)C.[Br:24]Br>C(Cl)Cl>[C:1]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[CH:10][C:9]([Br:24])=[CH:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(-n3cccc3)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CSC
Solvent: CC#N
Product: Brc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Temperature: 10 °C
Yield: 40 %

Procedure:
To a mixture of N-biphenyl-4-yl-1H-pyrrole (500 mg, 2.28 mmol), dimethylsulfide (0.25 mL, 3.4 mmol), CH2Cl2 (30 mL), and acetonitrile (10 mL) at -10° C. was added dropwise a solution of bromine in CH2Cl2 (5 mL) over 15 minutes. The mixture was allowed to warm to 10° C. over 2 hours. The resultant mixture was washed with 1M pH 7 phosphate buffer (50 mL) and extracted with CH2Cl2 (25 mL). The combined organic layers were dried over Na2SO4 and concentrated to a crude residue which was purified via flash column chromatography with 0-10% CH2Cl2 /hex gradient eluant to furnish 240 mg (40%) of N-(biphenyl-4-yl)-3-bromo-1H-pyrrole as a white solid, mp 141-3° C. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.59 (d, 2H, J=8.1 Hz), 7.49-7.34 (m, 5H), 7.12 (s, 1H), 7.02 (t, 1H, J=2.6 Hz), 6.36 (dd, 1H, J=3.2, 1.7 Hz). Anal. Calculated for C16H12NBr: C, 64.45; H, 4.06; N, 4.70; Br, 26.80. Found: C, 64.37; H, 4.10; N, 4.64; Br, 26.69.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[CH3:11][C:12]1([CH3:20])[O:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[O:13]1.[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(O)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][CH:1]=[C:16]2[C:17](=[O:18])[O:19][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:15])[CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cccc(Br)c1
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2cccc(Br)c2)C(=O)O1
Temperature: 55 °C

Procedure:
A mixture of triethyl orthoformate (154 grams (g), 1.04 moles (mol) and Meldrum's acid (142 g, 0.983 mol) was heated to 55° C. for 4 hours (h). After cooling to 50° C., a solution of 3-bromoaniline (162.6 g, 0.945 mol) in ethanol (300 mL) was added such that the temperature of the reaction was maintained between 50–55° C. After half of the 3-bromoaniline had been added, stirring became difficult due to the formation of solids, so more ethanol (1 liter (L)) was added to facilitate stirring. Upon complete addition, the reaction was cooled to room temperature (RT), and the solids were collected by filtration. The filter cake was washed with ice cold ethanol until the washings were nearly colorless, and the product was dried at 65° C. under vacuum to afford 287 g of 5-[(3-bromophenylamino)methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as an off-white solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[CH:9]([C:25]1[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)[C:10]1[CH:15]=[C:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:13]=[CH:12][C:11]=1[F:24].[CH2:38](Br)[CH:39]=[CH2:40].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:40]([N:6]1[C@H:5]([CH3:8])[CH2:4][N:3]([CH:9]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[C:10]2[CH:15]=[C:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:13]=[CH:12][C:11]=2[F:24])[C@@H:2]([CH3:1])[CH2:7]1)[CH:39]=[CH2:38]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)N2C[C@@H](C)NC[C@@H]2C)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C=CCN1C[C@H](C)N(C(c2ccc(C(=O)N(CC)CC)cc2)c2cc(O[Si](C)(C)C(C)(C)C)ccc2F)C[C@H]1C
Yield: 78 %

Procedure:
The benzhydrylpiperazine from above (0.44 g, 0.83 mmol) was treated with allyl bromide (0.074 mL, 0.85 mmol) and anhydrous sodium carbonate (0.44 g, 4.2 mmol) as in Example 1. The product was purified by preparative thin layer chromatography (silica gel with dichloromethane:methanol:ammonium hydroxide/90:10:1) to give 0.37 g (78%) of (±)-4-(α-(trans-4-allyl-2,5-dimethyl-1-piperazinyl)-5-(tert-butyldimethylsilyloxy)-2-fluorobenzyl)-N,N-diethylbenzamide as a yellow oil. Reaction with tetraethylammonium fluoride hydrate in acetonitrile as in Example 1, followed by chromatography on silica gel with dichloromethane:methanol/4:1 gave 0.24 g (77%) of (±)-4-α-(trans-4-allyl-2,5-dimethyl-1-piperazinyl)-2-fluoro-5-hydroxybenzyl)-N,N-diethylbenzamide as a light amber resin. NMR (CDCl3): δ 1.0-1.3 (m, 12H); 2.0-2.3 (m, 2H); 2.5-3.05 (m, 5H); 3.2-3.6 (br m, 5H); 5.1-5.3 (m, 2H); 5.25 and 5.55 (s, 1H); 5.7-6.0 (m, 1H); 6.5-7.2 (m, 3H); 7.25 (d, J=8 Hz, 2H); 7.4 (d, J=8 Hz, 2H). A solution of the product in absolute ethanol was titrated to pH 4 with ethanolic hydrochloric acid, concentrated and treated with diethyl ether to precipitate 0.21 g (63%) of the monohydrochloride as an off-white powder. Calc. for C27H36FN3O2HCl 1.25 H2O: C, 63.27; H, 7.77; N, 8.20; Cl, 6.92. Found: 63.33; H, 7.78; N, 8.24; Cl, 7.00. Mass spectrum (Cl--CH4) m/z: 454 (M+1, 100%), 453 (M, 6%), 300 (17%), 153 (95%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.Br.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])=[O:15].C(N(CC)CC)C.Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:10])[NH:12][CH2:13][C:14]([NH:16][C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Agent: Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)Nc1cccc(Cl)c1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of m-chlorophenylisocyanate (756 mg, 4.92 mmol) in tetrahydrofuran (8 ml) is added to a solution of the salt 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (50 ml). Triethylamine (1.67 μl, 12 mmol) is added at 0 ° C., and the mixture is stirred at 0° C. for 30 minutes and then at room temperature overnight. Water and then 10% hydrochloric acid are added, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried (sodium sulfate), and distilled under reduced pressure to remove the solvent. The residue is recrystallized from dichloromethane/diisopropylalcohol to obtain the objective compound 6u (1.43 g; yield 73%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]([OH:18])=O)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:30][C:31]1[CH:32]=[C:33]([CH:52]=[CH:53][CH:54]=1)[O:34][C:35]1[CH:49]=[CH:48][C:38]2[N:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[S:41][C:37]=2[C:36]=1[C:50]#[N:51]>O1CCCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:8]([C:16]([NH:30][C:31]2[CH:54]=[CH:53][CH:52]=[C:33]([O:34][C:35]3[CH:49]=[CH:48][C:38]4[N:39]=[C:40]([NH:42][C:43]([CH:45]5[CH2:47][CH2:46]5)=[O:44])[S:41][C:37]=4[C:36]=3[C:50]#[N:51])[CH:32]=2)=[O:18])[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1ncc(C(=O)O)c1-c1ccccc1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)n1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of 1-tert-butyl-5-phenyl-1H-pyrazole-4-carboxylic acid (67 mg, 0.274 mmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (29 μL, 0.338 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (80 mg, 0.228 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (73 mg, 55%) as a white powder.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].[H-].[Na+].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@@:19]([OH:40])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:20]([N:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27](F)=[CH:28][CH:29]=2)[N:24]=[CH:23]1)[CH3:21].O>CN1C(=O)CCC1.CCOC(C)=O>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C@@:19]([OH:40])([CH2:34][N:35]1[CH:39]=[N:38][CH:37]=[N:36]1)[C@H:20]([N:22]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][C:27]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])=[CH:28][CH:29]=2)[N:24]=[CH:23]1)[CH3:21]
Reactant: C[C@@H](n1cnc2cc(F)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: OCC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](n1cnc2cc(OCC(F)(F)C(F)F)ccc2c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 120 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
A solution of 2,2,3,3-tetrafluoropropanol (381 mg, 2.9 mmol) in anhydrous NMP (10 mL) was treated with NaH (55% in hexane, 126 mg, 2.9 mmol) for 10 min at room temperature. Once H2 ceased to evolve, (1R,2R)-3-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4triazol-1-yl)propyl]-7-fluoroquinazolin-4(3H)-one (400 mg, 0.96 mmol, obtained in example 12) was added and the mixture was stirred at 120° C. overnight. Once the reaction was completed, water and EtOAc were added. The aqueous phase was separated and reextracted with further EtOAc. The combined organic extracts were washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash chromatography to give the title compound as an amorphous white solid (200 mg, 48%): 1H NMR (300 MHz, CDCl3) δ (TMS) 8.56 (s, 1H, N=CH--N), 8.29 (d, J=9.5, 1H, arom), 7.76 (s, 1H, triazole), 7.74 (s, 1H, triazole), 7.48 (dt, Jd =6.5, Jt =8.8, 1H, arom), 7.15 (m, 2H, arom), 6.9-6.7 (m, 2H, arom), 6.08 (tt, J=4.5, J=53, 1H, CHF2), 5.92 (dq, Jd =2, Jq =7.3, 1H, MeCH), 5.51 (d, J=1.5, 1H, OH), 5.16 (d, J=14.3, 1H, CH(H)), 4.49 (tt, J=1.5, J=12, 2H, CH2), 4.01 (d, J=14.3, 1H, CH(H)), 1.29 (d, J=7.3, 3H, CHMe); GC/MS 304 (N-ethylheterocycle group, C13H12F4N2O2), 224 (Tr--CH2COHAr, C10H8F2N3O); [α]D =-16.7° (c 1, CHCl3). Analysis calculated for C23 H19F6N5O3 : C 52.38; H 3.63; N 13.28. Found: C 51.84; H 3.68; N 12.29.
Reaction SMILES: [CH2:1]([Br:3])[CH3:2].[CH2:4]([C:6]1([CH3:30])[CH:11]([CH3:12])[CH:10]([OH:13])[CH2:9][C:8]([CH2:15][CH3:16])([CH3:14])[N:7]1[O:17][C:18]([CH3:29])([CH3:28])[C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[O:20])[CH3:5]>C(#N)C>[Br-:3].[CH2:4]([C:6]1([CH3:30])[CH:11]([CH3:12])[CH:10]([OH:13])[CH2:9][C:8]([CH2:15][CH3:16])([CH3:14])[N:7]1[O:17][C:18]([CH3:29])([CH3:28])[C:19]([NH:21][CH2:22][CH2:23][CH2:24][N+:25]([CH2:1][CH3:2])([CH3:27])[CH3:26])=[O:20])[CH3:5]
Reactant: CCBr
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)(C)C(=O)NCCCN(C)C
Solvent: CC#N
Product: CCC1(C)CC(O)C(C)C(C)(CC)N1OC(C)(C)C(=O)NCCC[N+](C)(C)CC
Product: [Br-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethylbromide (12 ml) is added to a solution of 2-(2,6-diethyl-4-hydroxy-2,3,6-trimethyl-piperidine-1-yloxy)-N-(3-dimethylamino-propyl)-2-methyl-propionamide (20.5 g, 0.053 mol, compound 110) in acetonitrile (35 ml). The mixture is stirred for 18 h at room temperature and is then evaporated to afford 26.63 g of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:33]([O:39][CH2:40]I)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[O:30][CH3:31])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:40][O:39][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[S:25])=[C:15]([CH2:18][CH:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(CC3CCOC3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(CC3CCOC3)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydrofuran-3-yl)methylthio-3-cephem-4-carboxylate (71 mg) was dissolved in dimethylformamide (1 ml) and the solution was cooled to -20° C. The solution, after addition of iodomethyl pivalate (66 mg) thereto, was stirred at a temeprature of -20° to 10° C. for 30 minutes, after which cold water (10 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (10 ml) and the organic layer separated was washed with an aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to leave a yellow oil. The oily residue was purifed by a column chromatography on a silica gel column (40 g) with elution using ethyl acetate as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected under reduced pressure gave the titled compound (77 mg; 92%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:39])[C:24]4[C:29]([C:30]=3[C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[CH:34]=O)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.CC(O)=O.[CH3:44][NH:45][CH3:46].[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:69]>C1COCC1>[ClH:69].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:39])[C:24]4[C:29]([C:30]=3[C:31]3[CH:38]=[CH:37][CH:36]=[C:33]([CH2:34][N:45]([CH3:46])[CH3:44])[CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12
Reactant: CNC
Reactant: CC(c1oc(=O)c2ccccc2c1-c1cccc(C=O)c1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(CN(C)C)c1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Product: Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.3 %

Procedure:
3-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)benzaldehyde (Intermediate F2, 598 mg, 1.147 mmol), AcOH (131 μl, 2.293 mmol) and 2M dimethylamine (1.15 ml) solution in THF were dissolved in DCM (23 ml) followed by a spoon of anhydrous Na2SO4, and the mixture stirred rt for 15 min prior to add NaB(OAc)3H (1215 mg, 5.73 mmol). The resulting mixture was stirred at rt until complete conversion, then quenched with 1M HClaqueous (5 ml), filtered to remove insoluble materials, and the filtrate purified via reverse phase chromatography using a Biotage C18 60 g SNAP with a gradient of water and acetonitrile to give (prior to drying a small amount of 1M HCl aqueous was added) the title compound (460 mg, 68.3% yield) as white solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[CH:7][C:6]=2[CH:5]=[C:4]([Cl:23])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCOCC1.O>[Cl:23][C:4]1[CH:3]=[C:2]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[O:9][C:8]([CH2:11][N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(Br)c2o1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1Cc1cc2cc(Cl)cc(-c3ccccc3)c2o1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of the 2-[(7-bromo-5-chloro-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (0.500 g, 1.28 mmol), dichlorobis(tro-o-tolylphosphine)palladium(II) (0.101 g, 0.128 mmol), and potassium carbonate (0.531 g, 3.84 mmol) in dioxane (20 mL) and water (1 mL) heated to 90° C. was added phenylboronic acid (0.390 g, 3.20 mmol) and the reaction allowed to stir for 1 h. The reaction was cooled to room temperature, filtered (celite), and the solvent removed in vacuo to provide a crude residue. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:4) gave 0.422 g (85%) of 2-[(5-chloro-7-phenyl-1-benzofuran-2-yl)methyl]-1H-isoindole-1,3(2H)-dione as a white solid. mp 163-166° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)O)=[CH:6][CH:5]=1)[CH3:2].C(OC1C=CC(N)=CC=1)C.C(O)(=O)C(C1C=CC=CC=1)O>>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[NH:10][C:11](=[O:20])[CH:12]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCOc1ccc(NC(=O)C(O)c2ccccc2)cc1
Agent: CCOc1ccc(N)cc1
Agent: O=C(O)C(O)c1ccccc1
Product: CCOc1ccc2c(c1)C(c1ccccc1)C(=O)N2

Procedure:
This compound is prepared according to the procedure described in step B of Preparation 66 from N-4-ethoxyphenyl-DL-mandelamide (138° C.), itself obtained according to the procedure described in step A of Preparation 2 from 4-ethoxyaniline and DL-mandelic acid. This gives the expected product. M.p.=125°-130° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N+:8]([O-:12])=[CH:9]2)=[CH:4][N:3]=1.[CH:20]1([C:23]([NH2:25])=[O:24])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.ClCCl.CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:7]1[N+:8]([O-:12])=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][N:3]=[C:2]([NH:25][C:23]([CH:20]1[CH2:22][CH2:21]1)=[O:24])[CH:11]=2
Reactant: NC(=O)C1CC1
Reactant: [O-][n+]1cc2cc(Cl)ncc2cc1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 90 °C
Yield: 84.1 %

Procedure:
A mixture of 7-chloro-3-(2-chlorophenyl)-2,6-naphthyridine 2-oxide (2.0 g, 7.0 mmol), cyclopropanecarboxamide (653 mg, 7.7 mmol), Chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (167 mg, 0.21 mmol), (dicyclohexylphosphino)-3-,6-dimethoxy-2,4′-6′-tri-i-pr-1,1′-biphenyl (281 mg, 0.52 mmol), and cesium carbonate (4.5 g, 13.9 mmol) in 1,4-dioxane (19 mL) was heated at 90° C. for 4 hours. The cooled reaction mixture was diluted with dichloromethane (200 mL) and methanol (100 mL), mixed with Celite, filtered, the solids washed with 15% methanol/dichloromethane (2×100 mL), and the filtrate was dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-10% methanol in dichloromethane) to afford the title compound as an off-white solid (2.0 g, 84%). 1H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 9.13 (s, 1H), 9.09 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 7.62 (m, 1H), 7.58-7.45 (m, 3H), 2.14-2.03 (m, 1H), 0.91-0.82 (m, 4H). LCMS (Method G): RT=8.18 min, M+H+=340.0.