Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:12]2[C:17]([NH2:18])=[N:16][CH:15]=[C:14]([Br:19])[N:13]=2)=[CH:2]1.[N:20]([O-])=O.[Na+].OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O.O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][N:11]2[C:12]3=[N:13][C:14]([Br:19])=[CH:15][N:16]=[C:17]3[N:18]=[N:20]2)=[CH:2]1
Reactant: O=N[O-]
Reactant: Nc1ncc(Br)nc1NCc1c[nH]c2ncccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nnn(Cc3c[nH]c4ncccc34)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.9 %

Procedure:
To the ice-cooled mixture of N2-((1H-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6-bromopyrazine-2,3-diamine (48 mg, 0.15 mmol) in HOAc/H2O (1.5 mL/1.5 mL) was added NaNO2 (31 mg, 0.45 mmol) in water (0.2 mL). The reaction was stirred for 1.5 h in an ice bath, then aqueous H2SO4 (49%, 0.1 mL) was added. The resulting mixture was allowed to warm to room temperature and stir overnight, then was adjusted to pH>8 with 3 N aqueous NaOH solution, and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to give the title compound (46 mg) MS (m/z): 332 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:35][C:36]1[CH:46]=[CH:45][C:39]([C:40]([N:42]([CH3:44])[CH3:43])=[O:41])=[CH:38][C:37]=1[CH3:47].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:44][N:42]([CH3:43])[C:40](=[O:41])[C:39]1[CH:45]=[CH:46][C:36]([NH:35][C:2]2[N:3]=[C:4]([O:29][CH:30]3[CH2:34][CH2:33][O:32][CH2:31]3)[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:6]=3[N:7]=2)=[C:37]([CH3:47])[CH:38]=1
Reactant: Cc1cc(C(=O)N(C)C)ccc1N
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCOC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Nc5ccc(C(=O)N(C)C)cc5C)nc(OC5CCOC5)c34)cc2o1
Temperature: 110 °C
Yield: 72 %

Procedure:
To a suspension of 6-(2-chloro-4-((tetrahydrofuran-3-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv) in 1,4-dioxane (0.24 M) was added 4-amino-N,N,3-trimethylbenzamide (1 equiv), cesium carbonate (3 equiv), palladium acetate (0.3 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalene (0.6 equiv). The resulting reaction mixture was refluxed at 110° C. for 3 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (5% MeOH in DCM) to afford the title compound (72% yield). MS (ESI) m/z 643.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH:16]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[C:26]([O:30][C:31](=[O:43])[NH:32][C:33]1([C:41]#[CH:42])[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.[Cl-].[Na+].O.CC#N.CC#N.Cl[Pd]Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:26]([O:30][C:31](=[O:43])[NH:32][C:33]1([C:41]#[C:42][C:2]2[CH:3]=[CH:4][C:5]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:6]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[CH:16]=2)[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCCCCCCOc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C#CC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 10 h
Yield: 83.5 %

Procedure:
Compound 35-3 (11.1 g), (2,2-dimethyl-5-ethynyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (6.28 g) synthesized by a known method (for example, Tetrahedron vol. 57 (2001) 6531-6538), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (706 mg), bis(acetonitrile)palladium(II) dichloride (128 mg) and cesium carbonate (20.8 g) in acetonitrile (150 ml) were stirred at 80° C. for 10 hr. Brine was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (12.4 g) as a brown oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCC)C.BrC1C(C2C=NC=CC=2)=NNC=1>>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH3:14]
Reactant: CCSSCC
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Brc1c[nH]nc1-c1cccnc1
Product: CCSc1c[nH]nc1-c1cccnc1
Yield: 76 %

Procedure:
Compound 21D was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using ethyldisulfanyl-ethane as the disulfide and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A).
Reaction SMILES: [CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH:15]=[CH:16][C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1>C(O)C.O=[Pt]=O>[CH3:1][C@@:2]1([OH:24])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:23]=[C:14]2[CH2:15][CH2:16][C:17]3[C:18](=[O:22])[NH:19][N:20]=[CH:21][C:12]([C:13]=32)=[N:11]1
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=O)[nH]ncc(n1)c23
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1N1C=C2CCC3=C2C(=N1)C=NNC3=O
Reaction time: 24 h
Yield: 39.9 %

Procedure:
To a solution of the title product from Example 1 (10 mg, 0.030 mmol) in ethanol (20 mL) was added 1-2 mg PtO2. The reaction vessel was flushed with H2 gas and held at 1 atm of H2 via balloon for 24 hours. The platinum catalyst was filtered and the filtrate was concentrated and the crude product was purified on silica gel methanol/methylene chloride (1:20) as the eluent to afford 4.0 mg of the title compound;
Reaction SMILES: Cl.C([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])(C)(C)C.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27](Cl)(=[O:29])=[O:28])=[C:22]([CH3:31])[C:21]=1[CH3:32].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27]([NH:9][C@@H:8]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]([OH:6])=[O:17])(=[O:28])=[O:29])=[C:22]([CH3:31])[C:21]=1[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of 0.5 g of L-phenylalanine t-butyl ester hydrochloride in 4 mL of N,N-dimethylformamide were added 0.67 g of 4-methoxy-2,3,6-trimethylphenylsulfonylchloride and 0.96 mL of N,N-diisopropylethylamine. After stirring for 2 hours at room temperature the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed with aqueous potassium hydrogensulfate (5%), water, aqueous sodium hydrogencarbonate (5%) and brine, dried over magnesium sulfate and concentrated, The residue was dissolved in 16 mL of dichloromethane and 4 mL of trifluoroacetic acid was added. After stirring for 2h at room temperature the reaction mixture was concentrated. Dichloromethane and aqueous sodium hydrogencarbonate (5%) were added to the residue (the mixture was basic), the aqueous layer separated and washed with dichloromethane. The aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3-phenylpropanoic acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.25-1.67 (6H, m), 1.97 and 1.99 (3H, 2x s), 2.12 and 2.17 (3H, 2x s), 2.45-3.54 (8H, m), 2.49 (3H, s), 3.81 and 3.85 (3H, 2x s), 3.82-3.92 (1H, m), 5.13-5.28 (1H, m), 6.61 (1H, s), 6.84-7.07 (5H, m), 7.17-7.21 (1H, m), 7.50-7.56 (1H, m), 7.65-7.69 (1H, m), 7.76-7.82 (1H, m), 8.30-8.35 (1H, m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]#[CH:13].C([O-])(O)=O.[Na+].[Br:19][CH2:20][C:21](Br)=[O:22]>C(Cl)Cl>[Br:19][CH2:20][C:21]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12]#[CH:13])=[O:22]
Reactant: O=C(Br)CBr
Reactant: C#CCOCCOCCOCCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOCCOCCOCCNC(=O)CBr
Yield: 78.1 %

Procedure:
To a solution of 4 (50 mg, 0.27 mmol) in CH2Cl2 (3 mL) was added sat. NaHCO3 (3 mL). Under stirring, bromoacetyl bromide (80 mg, 040 mmol) was added. The pH was controlled in the range 8-9 by adding solid NaHCO3. The reaction was stirred at rt for 15 min. CH2Cl2 (5 mL) was added and the reaction mixture was extracted 5×3 mL CH2Cl2. The organic layers were combined, washed with brine, dried with Na2SO4. The solvent was evaporated and the residue was purified by FCC to afford 5 as clear oil (65 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 2.42 (t, J=2.4 Hz, 1H), 3.48 (dd, J=5.2, 5.2 Hz, 2H) 3.57 (t, J=5.2 Hz, 2H), 3.62 (m, 4H), 3.66-3.70 (m, 4H), 3.85 (s, 2H), 4.18 (d, J=2.4 Hz, 2H). 6.91 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ 29.35, 40.11, 58.65, 69.32, 69.56, 70.53, 70.61, 70.76, 74.90, 79.73, 165.86. ESIMS calcd for C11H18BrNNaO4 [M+Na]+ 330.03, 332.03, found: 330.33, 332.46.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-fluorobenzoic acid.
Reaction SMILES: [O:1]=[C:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[Br:17]Br.S(=O)(=O)(O)O>CO>[Br:17][CH2:16][C:2](=[O:1])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CO
Product: O=C(CBr)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.7 %

Procedure:
Prepare a cold (0° C.) solution of 2-(3-oxobutyl)isoindole-1,3-dione (6.8 g, 31.5 mmol) in methanol (50 mL). Add Br2 (3.2 mL, 63 mmol). Allow the reaction to warm to room temperature and stir for 15 hours. Add 10 M sulfuric acid (26 mL) and stir the mixture for 15 hours. Filter off the solids and dry in vacuo to afford 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione (2.3 g).
Reaction SMILES: [C:1]1([NH:7][S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:20][CH:21]([Cl:29])[C:22]([Cl:28])([S:24](Cl)(=O)=O)[CH3:23]>C(Cl)(Cl)Cl>[Cl:20][CH:21]([Cl:29])[C:22]([Cl:28])([S:24][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH3:23]
Reactant: CC(Cl)(C(Cl)Cl)S(=O)(=O)Cl
Reactant: CCS(=O)(=O)Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)N(SC(C)(Cl)C(Cl)Cl)c1ccccc1
Temperature: 25 °C

Procedure:
To a stirred, cooled solution of 18.5 g. of N-phenyl ethane sulfonamide in 10.1 g. of triethylamine and 200 ml. of chloroform was added at a temperature below 10° C. a solution of 1,1,2-trichloropropane-2 -sulfonyl chloride (21.4 g.) in 50 ml. of chloroform. During the addition, an exothermic reaction took place. When the addition was complete, the mixture was allowed to cool to room temperature. The product was washed twice with water, dried over sodium sulfate and filtered and stripped. A viscous red oil was formed which on evaporation with benzene yielded a solid product of 29.6 g. (92% of theory), m.p. 85°-86° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a stirred solution of m-phenylenediamine (5.0 g, 0.046 mol) and N,N-diisopropylethylamine (8.0 mL, 0.046 mol) in CH2Cl2 (150 mL) at 0° C. was added slowly benzyl chloroformate (6.6 mL, 0.046 mol). The mixture was stirred at 0° C. for 2 h and then warmed to rt for 2 h. Aq. NaHCO3 solution was added and the organic phase was separated, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (8.0 g, 71%) as a syrup. LC-MS: 2.11 min, 243.0 (M+1).
Reaction SMILES: O1CCCC1.[CH3:6][N:7]([CH3:29])[C:8]([C@@H:10]1[CH2:14][C@H:13]([SH:15])[CH2:12][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:17])=[O:9].C(N(CC)C(C1C=CC=CC=1S([C:43]1[C@H:44]([CH3:74])[C@@H:45]2[C@@H:62]([C@H:63]([O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])[CH3:64])[C:61](=[O:73])[N:46]2[C:47]=1[C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=1)=[O:49])=O)=O)C.[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:6][N:7]([CH3:29])[C:8]([C@@H:10]1[CH2:14][C@H:13]([S:15][C:43]2[C@H:44]([CH3:74])[C@@H:45]3[C@@H:62]([C@H:63]([O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:67])[CH3:68])[CH3:64])[C:61](=[O:73])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=2)=[O:49])[CH2:12][N:11]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)=[O:17])=[O:9]
Reactant: CN(C)C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N(C)C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
75 μl of a hexane solution containing 1.6M of butyllithium was added to 1 ml of an ice-cooled toluene solution containing 18 μl (0.13 mmol) of diisopropylamine, and the mixture was stirred for 10 minutes. At the end of this time, 125 μl (0.12 mmol) of a hexane solution containing 0.97M of diethylaluminium chloride was added and the mixture was stirred for a further 20 minutes an this temperature. The diethylaluminium diisopropylamide solution thus obtained was added to 2 ml of an ice-cooled tetrahydrofuran solution containing 43 mg (0.12 mmol) of (2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine, and stirred for 15 minutes at this temperature. At the end of this time, 1 ml of a tetrahydrofuran solution containing 68 mg (0.10 mmol) of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) was added to the reaction mixture, and the mixture was stirred for 105 minutes. A saturated aqueous solution of ammonium chloride and then ethyl acetate were added, and the precipitate which formed was removed. The organic layer was separated, and washed with water and then with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 10 g of silica gel, using a 1:3 by volume mixture of benzene and ethyl acetate as the eluent, to obtain 60 mg of a fraction containing the title compound in a yield of 74%. This fraction showed a purity of 56% as determined by the area ratio according to liquid chromatography.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:21]=[CH:20][C:16]2[N:17]=[CH:18][S:19][C:15]=2[CH:14]=1)(C)C>CO>[C:12]([C:13]1[CH:21]=[CH:20][C:16]2[N:17]=[CH:18][S:19][C:15]=2[CH:14]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccc2ncsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2ncsc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
Potassium carbonate (29.7 g) was added to a solution of 6-trimethylsilanylethynylbenzothiazol (45.1 g) in methanol (600 ml), and the mixture was stirred for 1.5 hours at room temperature. The reaction solution was filtered, and then the resultant was washed with methanol and ethyl acetate successively. The filtrate was concentrated, to which water was added, and then extracted with ethyl acetate. The organic layer, which was washed with a brine, was dried over anhydrous magnesium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to yield 6-ethynylbenzothiazole (30.0 g) as a light yellow solid (mp: 47.5-49.0° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([O:11]C)=[O:10])=[CH:4][CH:3]=1.C1(C(CCC)(CCC)C(OC)=O)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:19])([CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(CCC(C)(C)C)c1ccc(F)cc1
Agent: CCCC(CCC)(C(=O)OC)c1ccccc1
Product: CC(C)(C)CCC(C)(C(=O)O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1C, substituting the compound of Example 24A for the compound of Example 1B. 1H NMR (300 MHz, CDCl3): δ 0.86 (s, 9 H) 1.05 (m, 2 H) 1.52 (s, 3 H) 1.91 (m, 2 H) 7.03 (m, 2 H) 7.32 (m, 2 H).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:34])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:35])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:35][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3cccc(C(F)(F)F)c3)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (97 mg, 0.193 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (92.4 mg, 2.2 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred for four hours under a nitrogen atmosphere. The solvent was evaporated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (3.9 mL). The resulting white precipitate was collected by filtration, washed with water and hexanes, and dried under high vacuum to provide {6-fluoro-3-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (65.8 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1H), 8.97 (br. s, 1H), 8.00-8.22 (m, 1H), 7.97 (s, 1H), 7.90 (dd, J=9.10, 6.50 Hz, 1H), 7.78 (d, J=8.50 Hz, 1H), 7.66-7.73 (m, 1H), 7.49 (t, J=8.30 Hz, 1H), 7.30-7.38 (m, 1H), 7.28 (d, J=8.30 Hz, 1H), 4.28-4.36 (m, 2H), 3.71-3.85 (m, 3H), 3.01-3.18 (m, 2H), 2.43 (s, 3H), 2.17-2.34 (m, 1H), 1.64-1.73 (m, 2H). MS cald. for C26H25F4N2O3 [(M+H)+]: 489, obsd. 489.2.
Reaction SMILES: O[C:2]1([C:10]2[CH:11]=[CH:12][C:13]([Br:16])=[N:14][CH:15]=2)[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.S(=O)(=O)(O)O>>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]23[CH2:3][N:4]([CH2:5][CH2:6]2)[CH2:9][CH:8]=[CH:7]3)=[CH:15][N:14]=1
Reactant: OC1(c2ccc(Br)nc2)CN2CCC1CC2
Agent: O=S(=O)(O)O
Product: Brc1ccc(C23C=CCN(CC2)C3)cn1
Temperature: 190 °C

Procedure:
9.4 g (0.033 mol) of 3-hydroxy-3-(2-bromopyridin-5-yl)-1-azabicyclo[2.2.2]octane and 35 ml of concentrated sulfuric acid are introduced into a 100 ml three-necked flask and the mixture is heated at 190° C. for 1 h 45.
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[CH3:31][NH:32][CH2:33][C:34]([NH2:36])=[O:35].[CH2:37]([C:39]1[CH:40]=[CH:41][C:42]([F:66])=[C:43]([C:45]2[CH:46]=[N:47][C:48]([N:51]3[C:59]4[C:54](=[CH:55][CH:56]=[C:57]([C:60]([OH:62])=O)[CH:58]=4)[C:53]([CH:63]([OH:65])[CH3:64])=[CH:52]3)=[N:49][CH:50]=2)[CH:44]=1)[CH3:38]>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH2:33][N:32]([CH3:31])[C:60]([C:57]1[CH:58]=[C:59]2[C:54]([C:53]([CH:63]([OH:65])[CH3:64])=[CH:52][N:51]2[C:48]2[N:47]=[CH:46][C:45]([C:43]3[CH:44]=[C:39]([CH2:37][CH3:38])[CH:40]=[CH:41][C:42]=3[F:66])=[CH:50][N:49]=2)=[CH:55][CH:56]=1)=[O:62]
Reactant: CNCC(N)=O
Reactant: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)O)cc43)nc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCc1ccc(F)c(-c2cnc(-n3cc(C(C)O)c4ccc(C(=O)N(C)CC(N)=O)cc43)nc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-methylmorpholine (0.107 mL, 0.986 mmol), TBTU (0.191 g, 0.592 mmol) and 2-(methylamino)acetamide hydrochloride (0.123 g, 0.986 mmol) were added to an ice-cooled suspension of 331e) (0.2 g, 0.493 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with ice-cold water. A precipitate was filtered off and dissolved in dichloromethane. The organic phase was washed with sodium hydrogen carbonate solution (20 mL) and brine (20 mL), dried over sodium sulfate and evaporated. The remnant was purified by flash column chromatography [silica gel; dichloromethane with 4% methanol] followed by preparative HPLC. White solid. Yield: 65 mg (28% of theory)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[N:26]=2)=[O:35])=[O:8])[N:6]=1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cn1nc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)c2ccccc21

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1-Methyl-1H-indazole-3-carboxylic acid. LC-MS (basic): tR=0.81 min; [M+H]+=491.2.