Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[N:14]3[C:9]([C:10](=[O:28])[NH:11][C:12]([C:15]4[CH:16]=[C:17]([S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=4[O:21][CH2:22][CH3:23])=[N:13]3)=[C:8]([CH2:29][CH3:30])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:22]([O:21][C:20]1[CH:19]=[CH:18][C:17]([S:24]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)(=[O:26])=[O:25])=[CH:16][C:15]=1[C:12]1[NH:11][C:10](=[O:28])[C:9]2=[C:8]([CH2:29][CH3:30])[N:7]=[C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:14]2[N:13]=1)[CH3:23]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
0.42 g (0.92 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonyl chloride are dissolved in 15 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of 4-dimethylaminopyridine, 0.28 g (2.76 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 0.395 g (80%) of a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[S-:13][CH2:14][CH3:15].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[S:13][CH2:14][CH3:15]
Reactant: CC[S-]
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1ccnc2ccc(Br)cc12
Reaction time: 15 h
Yield: 89.3 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (1.5 g, 6.18 mmol) in DMF (60 mL) was added sodium thioethoxide (624 mg, 7.42 mmol) at 0° C. After addition, it was turned to a dark green solution which then turned to a yellow cloudy solution after 15 h at room temperature. Then, the mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the filtrate was removed under the vacuum and the residue was purified by using a Biotage silica gel column chromatography to afford 1.48 g (89.6% yield) of 6-bromo-4-ethylsulfanyl-quinoline as an yellow solid: EI-HRMS m/e calcd for C11H10BrNS (M+) 266.9717, found 266.9715.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:32])=[O:5])[CH2:3][CH2:2]1.[N+:33]([C:36]1[CH:37]=[N:38][NH:39][CH:40]=1)([O-:35])=[O:34].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:12]([N:38]4[CH:37]=[C:36]([N+:33]([O-:35])=[O:34])[CH:40]=[N:39]4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:32])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2Oc2ccccc2)N1C(=O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@H]1CCc2c(ccc(-n3cc([N+](=O)[O-])cn3)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
A 100-mL round-bottom flask equipped with a balloon filled with air was charged with (5)-cyclopropyl(2-methyl-5-phenoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.240 g, 0.55 mmol), 4-nitro-1H-pyrazole (0.188 g, 1.66 mmol), copper (II) acetate (0.301 g, 1.66 mmol), pyridine (0.2 mL), and N,N-dimethylformamide (5 mL), and the resulting mixture stirred overnight at 90° C. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The filtrate was concentrated, and the residue was purified by preparative thin layer chromatography (eluting with 1:3, ethyl acetate/petroleum ether) to afford (S)-cyclopropyl(2-methyl-6-(4-nitro-1H-pyrazol-1-yl)-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)methanone (0.060 g, 26%) as yellow oil. MS (ESI, pos. ion) m/z 419 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[N:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([NH:21][C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cccc(OCC2CC2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1cccc(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-pyridine-2-carboxylic acid (CAN 1248077-05-5) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 276.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[H-].[Na+].CS(O[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:23]1)(=O)=O.COC1C=C2C(C=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>ClCCl.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]3)[C:6]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(c1)N(CCN1CCC(NC(=O)OC(C)(C)C)CC1)C(=O)CO2
Yield: 66 %

Procedure:
Commercially available 6-methyl-2H-1,4-benzoxazin-3(4H)-one (326 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) (2.2 mmol) as described for Intermediate 2. Chromatography on silica gel with dichloromethane/methanol (20:1) gave the product in 66% yield as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:16]=3[OH:23])[CH2:10][CH2:9]2)[C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(OC([N:38]1[CH2:41][CH:40](I)[CH2:39]1)=O)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[NH:38]1[CH2:41][CH:40]([O:23][C:16]2[CH:17]=[C:18]([Cl:22])[C:19]([Cl:21])=[CH:20][C:15]=2[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:9][CH2:10]2)[CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3O)CC2)c1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc(N2CCN(Cc3cc(Cl)c(Cl)cc3OC3CNC3)CC2)c1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 40.8 %

Procedure:
A reaction mixture of 2-{4-[6-amino-5-(4-fluoro-phenyl)-pyrimidin-4-yl]-piperazin-1-ylmethyl}-4,5-dichloro-phenol (80.0 mg; 0.18 mmol; 1.00 eq.), 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (60.6 mg; 0.21 mmol; 1.20 eq.) and cesium carbonate (116.2 mg; 0.36 mmol; 2.00 eq.) in DMF (1 ml) was stirred at 90° C. overnight. The reaction solution was poured to water and extracted with ethyl acetate, The separated organic layer was washed with brine, dried and concentrated, which was then dissolved in methanol (1 ml) followed by adding 4.0 M HCl in dioxane (2 ml) and stirred at RT overnight. The reaction mixture was concentrated and purified by Waters prep-HPLC (acidic condition) to yield the title compounds (37 mg, yield 33.6%). LC-MS: (M+1=504, obsd.=504/506).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C@@H:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:6]([OH:18])[CH2:5]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])O.[Na+]>C(O)C>[C:12]1([CH2:11][NH:10][C@@H:7]2[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:5][C@H:6]2[OH:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Clc1ncccn1
Reactant: NCCN1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O[C@@H]1CN(CCNc2ncccn2)CC[C@H]1NCc1ccccc1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a stirred solution of 11.2 parts of trans-1-(2-aminoethyl)-4-[(phenylmethyl)amino]-3-piperidinol in 135 parts of ethanol were added 5.7 parts of 2-chloropyrimidine. After the addition of 8.4 parts of sodium hydrogen carbonate, stirring was continued overnight at reflux temperature. After evaporation, the residue was taken up in a mixture of dichloromethane and water. The separated organic layer was washed with water, dried, filtered and evaoporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 11.84 parts (80.3%) of trans-4-[(phenylmethyl)amino]-1-[2-(2-pyrimidinylamino)-ethyl]-3-piperidinol; mp. 126.9° C. (interm. 18).
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][C:3]=1[CH3:16].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6][C:5]1[CH:13]=[C:14]([CH3:15])[C:2]([Br:1])=[C:3]([CH3:16])[CH:4]=1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(OCC(C)(C)CO)cc(C)c1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OCC(C)(C)COS(C)(=O)=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled (0° C.) solution of 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropan-1-ol (251 mg) and triethylamine (160 μL) in dichloromethane (3 mL) is added methanesulfonyl chloride (75 μL). The mixture is stirred for 2 days while warming to room temperature. Then the mixture is diluted with dichloromethane, washed with saturated aqueous NaHCO3 solution and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→50:50) to give the title compound. Yield: 271 mg; LC (method 7): tR=1.18 min; Mass spectrum (ESI+): m/z=365 [M+H]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:25][C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][CH2:25][C:26]([NH2:28])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: NC(=O)CBr
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OCC(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (80 mg, 0.26 mmol) in DMF (3 mL) was added 2-bromoacetamide (53 mg, 0.39 mmol) and cesium carbonate (109 mg, 0.33 mmol). The reaction mixture stirred at RT for 16 h before being diluted with water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield 428 as a white solid (61 mg, 64%). LCMS: RT=6.70 min, [M+H]+=369; 1H NMR (400 MHz, d6-DMSO) 8.28 (1H, d, J=9.8 Hz), 7.85 (1H, s), 7.82 (1H, s), 7.51 (1H, s), 7.35 (1H, s), 6.76 (1H, dd, J=9.8, 2.7 Hz), 6.54 (1H, d, J=2.7 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.49-4.39 (6H, m), 1.43 (6H, d, J=6.6 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49](Cl)(=[O:51])=[O:50]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[S:49]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:51])=[O:50]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 74.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.126 g, 0.274 mmol) was dissolved in acetonitrile (6.0 mL), and the solution was treated with triethylamine (0.0760 mL, 0.548 mmol) and 2-chlorobenzenesulfonyl chloride (0.0867 g, 0.411 mmol) to obtain 4-(2-chlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.130 g, yield 75%).
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:4]=1)#[N:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:17])([F:18])[F:19])=[O:39])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][CH2:23][C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:4]=1)#[N:2]
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C#N)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C#N)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 96.7 %

Procedure:
0.40 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 200mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.40 g of 5-cyano-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.FC(F)(F)S(O[C:22]1[CH:35]=[C:34]2[C:25]([O:26][C:27]3[CH:28]=[CH:29][C:30]([C:41]4[CH:42]=[N:43][CH:44]=[N:45][CH:46]=4)=[CH:31][C:32]=3[C@:33]32[CH2:39][O:38][C:37]([NH2:40])=[N:36]3)=[CH:24][C:23]=1[F:47])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.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>[O:1]1[CH2:2][CH:3]=[C:4]([C:22]2[C:23]([F:47])=[CH:24][C:25]3[O:26][C:27]4[C:32](=[CH:31][C:30]([C:41]5[CH:46]=[N:45][CH:44]=[N:43][CH:42]=5)=[CH:29][CH:28]=4)[C@@:33]4([CH2:39][O:38][C:37]([NH2:40])=[N:36]4)[C:34]=3[CH:35]=2)[CH2:5][CH2:6]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1cc(F)c(OS(=O)(=O)C(F)(F)F)cc12
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1cc(F)c(C3=CCOCC3)cc12
Temperature: 85 °C

Procedure:
A 0.5-2 ml microwave vial was charged with tetrakis(triphenylphosphine)palladium(0) (27.9 mg, 0.024 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (86 mg, 0.411 mmol). A solution of (S)-2-amino-6′-fluoro-2′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (120 mg, 0.242 mmol) in DMF (1612 μL) was added followed by sodium carbonate (2M solution) (363 μL, 0.725 mmol). The vial was sealed and heated in microwave reactor at 85° C. for 1 hr. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, filtered through celite and concentrated to leve brown oil. The crude material was purified by silica gel chromatography on 12 g RediSep column using (15-60% DCM/MeOH/NH4OH 90:10:1 in DCM) to afford (S)-2′-(3,6-dihydro-2H-pyran-4-yl)-3′-fluoro-7′-(pyrimidin-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine. Found MS: MH+=431.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[C:12]1([N:18]2[C:22]([SH:23])=[N:21][N:20]=[N:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]1([N:18]2[C:22]([S:23][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:8]=[O:9])[CH:10]=3)=[N:21][N:20]=[N:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: O=Cc1cc(CCl)ccc1O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=Cc1cc(CSc2nnnn2-c2ccccc2)ccc1O
Temperature: 0 °C

Procedure:
25.6 g of 5-chloromethylsalicylaldehyde and 26.7 g of 1-phenyl-5-mercaptotetrazole were dissolved in 250 ml of dioxane. Then, internal temperature of the solution was lowered to 20° C. or less with ice water and thereto was added dropwise 20.8 ml of triethylamine with stirring followed by stirring at room temperature for 2 hours. After completion of the reaction, the precipitated salt was filtered off and the filtrate was concentrated under reduced pressure. Thus obtained residue was dissolved in 500 ml of ethyl acetate and then washed with water and the organic layer was dried over anhydrous sodium sulfate. Thereafter sodium sulfate was filtered off and the solvent was distilled out under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[N:9]2)[N:3]=1.C([Li])CCC.[Br:19]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Br:19][C:12]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=2)[N:9]=[CH:10][C:11]=1[CH3:13]
Reactant: Cc1cnn(-c2cccc(C)n2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(-n2ncc(C)c2Br)n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a cold (−60° C.) solution of 2-methyl-6-(4-methyl-pyrazol-1-yl)-pyridine (0.52 g) (prepared by Reaction Condition 1 in Step i) in 14 mL of anhydrous THF was added 1.33 mL of a 2.5M solution of n-butyllithium (0.21 g) in hexanes. The reaction mixture was stirred at −60° C. for one hour. A 10 mL solution of N-bromosuccinimide (0.59 g) in THF was added and then the final solution was stirred at −60° C. for 2 hours. Saturated ammonium chloride (20 mL) was added and then the reaction mixture was allowed to warm to 24° C. The reaction mixture was diluted with 300 mL of ethyl acetate and then the aqueous phase was separated. The organic phase was washed with additional saturated ammonium chloride (50 mL) and then with brine (50 mL). The organic layer was separated, dried (sodium sulfate), filtered, and then the filtrate was evaporated to give a crude red oil. Purification by flash chromatography (silica gel, 20% ethyl acetate in heptane) provided, after drying, 0.377 g of the title compound as a yellow oil; 1H-NMR (400 MHz; DMSO-d6) δ 7.88 (t, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 2.50 (s, 3H), 2.02 (s, 3H); MS (APCI+) m/z 254 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[C:21](=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CO>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:21])=[O:8]
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Yield: 87 %

Procedure:
To a solution of 5-hydroxy-4-methoxy-2-nitrobenzoic acid [Sinha J. Ind. Chem. Soc., 47, 925 (1970)] (83.0 g, 0.39 mol) in MeOH (250 ml) was added concentrated H2SO4 (20 ml) and the reaction mixture was heated to reflux for 16 h. On cooling, the reaction mixture was poured into aqueous potassium carbonate solution and acetic acid was added until pH 4 was reached. The mixture was extracted with chloroform, the organic layer washed twice with H2O and dried over MgSO4. Evaporation under reduced pressure afforded the subtitle compound as yellow crystals (77.0 g, 87%). Rf 0.30 (benzene/acetone 4/1, v/v); m.p. 146-9° C.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([CH:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]2=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:27][N:28]1[CH2:32][C@@H:31]([SH:33])[CH2:30][C:29]1=[S:34]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C:12]2[N:16]3[C:17](=[O:22])[C@H:18]([C@H:19]([OH:21])[CH3:20])[C@H:15]3[C@@H:14]([CH3:23])[C:13]=2[S:33][C@@H:31]2[CH2:32][N:28]([CH3:27])[C:29](=[S:34])[CH2:30]2)=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CN1C[C@@H](S)CC1=S
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3CC(=S)N(C)C3)[C@H](C)[C@H]12

Procedure:
In the same manner as described in Example 29-(1), (1R, 5R, 6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-carbapenam-3-carboxylic acid 4-nitrobenzyl ester is treated with (4S)-N-methyl-4-mercaptopyrrolidine-2-thione to give (1R, 5S, 6S)-2-[(4S)-N-methylpyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester as an amorphous powder.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[N:13]([CH2:30][C:31]([F:34])([F:33])[F:32])C(=O)C1C=C(C(F)(F)F)N=C(C(F)(F)F)C=1.[F:36]C1C=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[F:36][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][CH2:30][C:31]([F:34])([F:33])[F:32]
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Fc1ccccc1-c1ccncc1NCC(F)(F)F

Procedure:
The title compound was prepared from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-amine (example 150, intermediate b) and 2-fluorophenylboronic acid (CAS RN 1193-03-9) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (85%). MS (ESI): m/z=271.09 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C(OC(NCCCC(OC1C(C)=CC=CC=1C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][C:20]1[CH:19]=[CH:18][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:22][CH:21]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Agent: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Oc1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-β-alanine and 4-(trifluoromethoxy)phenol in a similar manner as described for 2,6-dimethylphenyl 4-[(tert-butoxycarbonyl)amino]butanoate. Mass Spectrum (M-tert-Bu)+H+ 293.96