Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@:11]([CH2:36][CH2:37]I)([CH2:12][CH2:13][C@@H:14]3[C:23]2=[CH:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C-:39]#[N:40].[K+]>CN(C=O)C>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@:11]([CH2:36][CH2:37][C:39]#[N:40])([CH2:12][CH2:13][C@@H:14]3[C:23]2=[CH:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]4[C@@H]3CC[C@]2(CCI)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@]2(C)C3=CC[C@]4(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]4[C@@H]3CC[C@]2(CCC#N)C1
Temperature: 60 °C
Reaction time: 36 h
Yield: 82.4 %

Procedure:
A suspension of 2.23 g (3.31 mmol) of 3β,17β-bis-(tert-butyldimethylsilyloxy)-5-(2-iodoethyl)-5β-androst-9(11)-ene (Example 4e) and 948 mg (15.11 mmol) of KCN in 48 ml of DMF is stirred for 36 hours at 60° C. under argon. After cooling, it is poured into ice-cold 1N NaOH solution and extracted with dichloromethane. After chromatography of the crude product on silica gel with hexane/ethyl acetate, 1.56 g (75.5% of theory) of the nitrile with a melting point of 194-195° C. (hexane), [α]D +15.0° (CHCl3, c=0.5), is obtained.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:22]([O:26][NH2:27])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][NH:27][C:14]([C:12]1[N:11]=[CH:10][C:9]2[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:2]=3[F:1])[CH:6]=[N:7][C:8]=2[CH:13]=1)=[O:16])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)ON
Reactant: O=C(O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1
Product: CC(C)(C)ONC(=O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1

Procedure:
The title compound can be prepared by coupling of 3-(2,3-difluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-(tert-butoxy)amine under the same conditions as those in step (c) of Example 1.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH2:69]([CH:76]1[CH2:81][CH2:80][NH:79][CH2:78][CH2:77]1)[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>ClCCl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:8]([CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([N:79]3[CH2:80][CH2:81][CH:76]([CH2:69][C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[CH2:77][CH2:78]3)=[O:20])=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)[CH2:24][C@H:25]([OH:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CS(=O)(=O)Nc1cc(OC[C@@H](O)CN(Cc2ccccc2)C2CCC(c3ccc(C(=O)N4CCC(Cc5ccccc5)CC4)cc3)CC2)ccc1OCc1ccccc1
Reaction time: 24 h

Procedure:
A solution of 2 g (2.88 mmol) of trans-4-{4-[benzyl((2S)-3-{4-(benzyloxy)-3-[(methylsulfonyl)amino]phenoxy}-2-hydroxypropyl)amino]cyclohexyl}benzoic acid (Preparation 1), 0.78 g (5.76 mmol) of 1-hydroxybenzotriazole, 1.1 g (5.76 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1.2 ml of triethylamine and 1.01 ml (5.76 mmol) of 4-benzylpiperidine in a mixture of 26 ml of dichloromethane and 5 ml of acetonitrile is stirred for 24 hours. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. N-[5-({(2S)-3-[benzyl(4-{4-[(4-benzylpiperidin-1-yl)carbonyl]phenyl}-cyclohexyl)amino]-2-hydroxypropyl}oxy)-2-(benzyloxy)phenyl]methanesulfonamide is obtained in the form of a white solid (1.355 g, 57%) after purification on silica gel (eluent: dichloromethane/methanol 90/10). [M+H+]=816.6.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][OH:28])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][O:28][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reaction time: 2 h

Procedure:
To a solution of (S)-tert-butyl 4-((S)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxybutyl)-2,2-dimethyloxazolidine-3-carboxylate and TEA in CH2Cl2 at 0° C. was added dropwise a solution of MsCl. The mixture was stirred for 2 h. The mixture was washed with water and dried over Na2SO4. The organic phase was distilled off to give the crude product (S)-tert-butyl 4-((S)-2-((tert-butyldimethylsilyloxy)methyl)-4-(methylsulfonyloxy)butyl)-2,2-dimethyloxazolidine-3-carboxylate (6.2 g). 1H NMR (CDCl3, 400 MHz) δ 0.06 (s, 6H, 0.89 (s, 9H), 1.46 (s, 12H), 1.50 (s, 3H), 1.53 (m, 3H), 2.94 (s, 3H), 3.49 (m, 2H), 3.50 (m, 2H), 3.7 (m, 2H), 3.9 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.CO[C:15](OC)([CH3:17])[CH3:16].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH:6][CH:15]([CH3:17])[CH3:16])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COC(C)(C)OC
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cc(F)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
4,5-difluoro-2-nitroaniline (3.48 g, 20 mmol), 2,2-dimethoxypropane (11.9 mL, 100 mmol), and trifluoroacetic acid (1.6 mL, 21 mmol) were dissolved in toluene (40 mL) and stirred at room temperature for 1 h. A boron-pyridine complex (2.12 mL, 21 mmol) was slowly added. The reaction mixture was stirred for 20 h. The solvent was evaporated in vacuo, and the residue was taken up into water and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on a column of aminopropyl-silica gel eluting with hexane/ethyl acetate (30:1) to give 2.42 g (56%) of the title compound as a bright orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([C@H:23]5[CH2:28][CH2:27][N:26]([CH3:37])[CH2:25][C@@H:24]5[F:29])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@H]1CCNC[C@@H]1F
Reactant: C=O
Product: CN1CC[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@@H](F)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,4S)-3-fluoro-1-methyl piperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3S,4S)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (from Example 382) and formaldehyde following General Procedure R.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>CCOC(C)=O>[OH:9][N:8]=[C:17]([NH2:18])[C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: NC(=NO)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 86.88 %

Procedure:
Potassium carbonate and hydroxylamine hydrochloride were added to an ethanolic solution of 4-nitrobenzonitrile. The solution was refluxed at 80° C. for 5 hours. After completion of the reaction the solvent was evaporated and the crude so obtained was dissolved in EtOAc and washed with water, brine, then dried by sodium sulfate and concentrated to give a solid. It was the purified by column chromatography and further recrystallized from EtOAc: petroleum ether to obtain the title product in 86.88% yield. 1H NMR (DMSO-d6) δ: 6.071 (s, 2H, NH2) 8.24 (d, 2H, CH), 8.317 (d, 2H, CH), 10.138 (S, 1H, OH), ms (m/z) 180 (M−−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([F:34])[CH:33]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][N:12]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[O:9]C(=O)[NH:7]1.[Li+].[OH-]>CCO.O>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:12]2[C@@H:11]([C@@H:10]([OH:9])[C@@H:6]([NH2:7])[CH2:5][C:4]3[CH:31]=[C:32]([F:34])[CH:33]=[C:2]([F:1])[CH:3]=3)[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN2Cc3ccccc3C[C@@H]2[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)cc1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((R)-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-3-yl)oxazolidin-2-one (Step A (8), 420 mg, 0.9 mmol) in EtOH (20 mL) was added a solution of LiOH (217 mg, 9 mmol) in H2O (5 mL). This reaction mixture was brought to 60° C. and stirred overnight. The mixture was then concentrated in vacuo. Ethyl ether (100 mL) was added to the mixture and washed with 1N HCl (80 mL) twice. The aqueous phase was basified to pH 12 with 50% aqueous NaOH solution. This mixture was extracted with ethyl acetate (100 mL) twice. The combined organic layer was dried (Na2SO4), and concentrated in vacuo to give 345 mg of the title compound of Preparation A: 1H NMR (CDCl3, 500 MHz) δ 1.78 (2H, brd s), 2.44 (1H, dd, J=10, 15 Hz), 2.93 (1H, m), 3.01-3.07 (3H, m), 3.36 (1H, s), 3.60-3.69 (3H, m), 3.80 (3H, s), 6.69 (1H, m), 6.77-6.81 (2H, m), 6.86 (2H, d, J=10 Hz), 6.98 (1H, d, J=5 Hz), 7.12-7.18 (3H, m), 7.24 (2H, d, J=10 Hz). MS (ESI)(M+H)+ 439.12.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH2:11]Cl.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]2[C:3]([CH:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[NH:1]2)=[CH:4][CH:5]=1
Reactant: Br[Mg]C1CC1
Reactant: Nc1c(C(=O)CCl)ccc(Cl)c1F
Solvent: Cc1ccccc1
Product: Fc1c(Cl)ccc2cc(C3CC3)[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
To a stirred solution of compound 2 (4.5 g, 20.3 mmol) in toluene (50 mL) was added cyclopropyl magnesium bromide (0.5 M in THF; 102.0 mL, 50.9 mmol) at 0° C. under inert atmosphere. The reaction mixture was stirred at 0° C. for 15 min and then warmed to RT and stirring was continued for additional 1 h. After completion of the reaction by TLC, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel chromatography; 1% EtOAc/Hexanes) to afford compound 3 (2.7 g, 63%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 11.55 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.97 (dd, J=8.5, 6.5 Hz, 1H), 6.16 (s, 1H), 2.03-1.99 (m, 1H), 0.99-0.96 (m, 2H), 0.83-0.80 (m, 2H); LC-MS (ESI): 91.6%; m/z 208.1 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.32 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=O)=[O:4].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.Cl.[CH:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)([CH3:35])[CH3:34].O>C(Cl)Cl.CCN(CC)CC>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14](=[O:16])[NH:42][CH:39]1[CH2:40][CH2:41][N:36]([CH:33]([CH3:35])[CH3:34])[CH2:37][CH2:38]1)=[O:4]
Reactant: CC(C)N1CCC(N)CC1
Reactant: COC(=O)c1ccc2[nH]nc(C(=O)O)c2c1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc2[nH]nc(C(=O)NC3CCN(C(C)C)CC3)c2c1
Reaction time: 3 h

Procedure:
To a solution of 1 g 1H-Indazole-3,5-dicarboxylic acid 5-methyl ester in 8 mL DCM, 2.5 mL NEt3, 1.15 g BOP-Cl and 0.98 g 1-Isopropyl-piperidin-4-ylamine hydrochloride were added at RT. The mixture was stirred for 3 h. After addition of 20 mL of water the reaction mixture was extracted with DCM (3×50 mL). The combined organic layers were dried over MgSO4. After removal of the solvent under reduced pressure the crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([NH:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[C:14]([CH:16]=3)[NH2:15])=[N:7][C:6]=2[CH:24]=1.[CH:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31])=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[N:17]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)[C:25]([C:27]5[CH:36]=[CH:35][CH:34]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=5)=[N:15][C:14]=4[CH:16]=3)=[N:7][C:6]=2[CH:24]=1
Reactant: Nc1cc(-c2nc3cc(Cl)ccc3o2)ccc1NC1CCOCC1
Reactant: COC(=O)c1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc3cc(-c4nc5cc(Cl)ccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 5-chloro-2-(2-(tetrahydropyran-4-yl)aminoanilin-5-yl)benzoxazole (see Working Example 100-2) (250 mg, 0.727 mmol) in dimethylformamide (3 mL) was added methyl 3-formylbenzoate (143 mg, 0.872 mmol) and oxone (313 mg, 0.509 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (220 mg, 62% yield) as yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[C:18](=[O:19])[N:4]2[CH:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][S:7][C@H:3]12.COC(OC)OC.[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl.CO>[N+:27]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[N:1][C@@H:2]2[C:18](=[O:19])[N:4]3[CH:5]([C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:6][S:7][C@H:3]23)=[CH:32][CH:31]=1)([O-:29])=[O:28]
Reactant: N[C@@H]1C(=O)N2C(C(=O)OCc3ccccc3)CS[C@H]12
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: COC(OC)OC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CS[C@@H]2[C@H](N=Cc3ccc([N+](=O)[O-])cc3)C(=O)N12

Procedure:
Benzyl 6β-aminopenam-3-carboxylate (1.11 g, 4 m mol) in dry dichloromethane (4ml) with trimethylorthoformate (0.42 g, 0.44 ml, 4 m mol) was treated with 4-nitrobenzaldehyde (0.61 g, 0.4 m mol) in dry methanol (10 ml) at room temperature for 1.5 h. The mixture was then evaporated to dryness, triturated with ethanol and the solid material collected by filtration. Renystallisation from ethanol/ethylacetate gave almost colourless needles (1.2 g 74%); m.p. 95-96 C; νmax (CH2Cl2) 1795, 1750, 1530, 1360 cm-1 ; δ(CDCl3) 8.68 (1H, d, J 2Hz, CH=N), 8.27 and 7.94 (4H, 2d, J 9Hz, nitrophenyl), 7.38 (5H, s, phenyl), 5.51 (1H, d, J 4Hz, 5-H), 5.45 (1H, dd, J 2Hz and 4 Hz, 6-H), 5.23 (2H, s, CH2Ph), 4.93 (1H, t, J 5.5Hz, 3-H) and 3.45 (2H, d, J 5.5H±, 2-H)
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([N:22]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:10]=1.Cl.[O:36]1CCOCC1>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:23]([OH:28])=[O:36].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([N:22]([CH:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:23](=[O:28])[C:24]([F:25])([F:27])[F:26])[CH:10]=1
Reactant: CN1CCC[C@H]1COc1ccc(C(=O)OC(C)(C)C)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: ClCCl
Product: CN1CCC[C@H]1COc1ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C2CCOCC2)c1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Tert-butyl 4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-2-[tetrahydro-2H-pyran-4-yl(trifluoroacetyl)amino]benzoate (480 mg, 1 mmol) was dissolved in 20 ml of DCM. Anhydrous HCl 4M in dioxane was added (2.5 ml, 10 mmol). The reaction was stirred at room temperature for 5 days after that the HPLC analysis showed the formation of the desired product but with almost 30% of the detrifluoroacetylated by-product. Solvents were removed under vacuum and the resulting yellow powder was suspended in 15 ml of DCM and TFAA (0.28 ml, 2 mmol) was added. The solid immediately dissolved and the mixture was stirred for 2 hours after that the HPLC analysis showed the complete disappearance of the by product. Solvents were evaporated to dryness to yield a dark yellow solid which was used in the next synthetic step without any further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH3:35])=[N:33][N:34]=[C:30]3[C@H:29]([CH2:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])[N:28]=[C:27]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=3)[C:26]=2[CH:49]=1)(=O)=O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:48][C:45]1[CH:44]=[CH:43][C:42]([C:27]2[C:26]3[CH:49]=[C:22]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:23]=[CH:24][C:25]=3[N:31]3[C:32]([CH3:35])=[N:33][N:34]=[C:30]3[C@H:29]([CH2:36][C:37]([NH:39][CH2:40][CH3:41])=[O:38])[N:28]=2)=[CH:47][CH:46]=1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3cccnc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
3-Pyridinylboronic acid (27.2 mg), sodium carbonate (43.0 mg) and bis(triphenylphosphine)palladium(II) chloride (12.95 mg) were added to a 2-5 ml microwave vial. A solution of (4S)-6-(4-chlorophenyl)-4-[2-(ethylamino)-2-oxoethyl]-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl trifluoromethanesulfonate (for a preparation see Intermediate 3) (100 mg) in DME (3 ml) and water (1 ml) was added and the reaction mixture was heated at 120° C. for 20 min (microwave). The reaction mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with water (10 ml) and brine (10 ml). The organic phase was dried and the solvent evaporated. The residue was chromatographed (0-10% methanol:DCM) product was further purified by MDAP (formate modifier) to give 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(3-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide as a white oil (11.9 mg).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7]2.C1COCC1.O.[OH-].[Li+:28]>C1COCC1>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][C:14]([O-:16])=[O:15])=[CH:7]2.[Li+:28]
Reactant: CCOC(=O)Cc1cc2cc(OC(F)(F)F)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])Cc1cc2cc(OC(F)(F)F)ccc2[nH]1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
A solution of ethyl 2-(5-(trifluoromethoxy)-1H-indol-2-yl)acetate (96 mg, 0.33 mmol) in 2:1 THF/water (6 mL) was treated with lithium hydroxide (10 mg, 0.4 mmol), and the reaction was stirred overnight. The THF was stripped, and the aqueous was freeze-dried to yield 90 mg of an off-white solid as product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:3]=1[CH:4]=[O:5].[S-2].[Li+].[Li+].[OH2:14].[CH3:15]S(C)=O>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:15]=[O:14])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cc(F)ccc1F
Reactant: O
Reactant: CS(C)=O
Agent: [Li+]
Agent: [S-2]
Product: O=Cc1cccc(F)c1C=O
Reaction time: 1.5 h
Yield: 59 %

Procedure:
To a stirred solution of 17.5 g (123 mmol) of 2,5-difluorobenzaldehyde (Aldrich) in 615 mL of DMSO at ambient temperature was added 6.2 g (135 mmol) of lithium sulfide (Aldrich). The dark red solution was stirred at 75 C. for 1.5 hours, or until the starting material was completely consumed, and then 34 g (135 mmol) of dibutyl mesylate aldehyde was added at about 50 C. The reaction mixture was stirred at 75 C. for three hours or until the reaction was completed. The cooled solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water several times, dried (MgSO4) and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 23.6 g (59%) of fluorobenzene dialdehyde as a yellow oil: 1H NMR (CDCl3) d 0.87 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.78 (m, 4H), 3.09 (s, 2H), 7.2-7.35 (m, 1H), 7.5-7.6 (m, 2H), 9.43 (s, 1H), 10.50 (d, J=2.62 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:18][O:17][C:15](=[O:16])[CH:14]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:13]([O:20][CH3:21])=[O:19]
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 12 h

Procedure:
To a solution of 2-fluoro-4-methoxy-1-nitro-benzene (84.1 g, 0.49 mol) and dimethyl malonate (129.9 g, 0.98 mol) in DMF (490 ml), potassium carbonate (135.9 g, 0.98 mol) is added at ambient temperature. The reaction mixture is stirred at 70 C.° for 12 h. The reaction mixture is added to toluene (393 ml) and 12 N HCl (123 ml) and extracted with ethyl acetate. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 2-(5-methoxy-2-nitro-phenyl)-malonic acid dimethyl ester.