Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:49])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH2:40][O:41]C3CCCCO3)[CH:35]=2)[CH:29]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:41][CH2:40][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:27]3[CH2:26][C:25](=[O:49])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[CH:38][N:37]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(isobutyl-methyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M279) (5.82 g, 8.34 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (2.84 g, 69%).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1.P([O-])([O-])([O-])=O>O1CCCC1.C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Reactant: O=Cc1cnc2ccccc2c1
Agent: CN(C)C(=N)N(C)C
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: -45 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
1,1,3,3-Tetramethylguanidine (0.5 mL, 4.0 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 1.00 g, 1.9 mmol) in tetrahydrofuran (8 mL) at −45° C. The solution was stirred at −45° C. for 5 min and then quinoline-3-carboxaldehyde (300 mg, 1.9 mmol) was added. After the reaction was allowed to proceed at −40° C. for 30 min, the mixture was warmed to room temperature and was stirred for another 2 h. Ethyl acetate and pH 6 phosphate buffer (200 mL each) were added and the resulting solid was filtered to furnish (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (500 mg, 47% yield). The layers in the filtrate were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (MgSO4), filtered through a bed of silica gel and the filtrate was evaporated to give an additional quantity of (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (520 mg, 49% yield) as a colorless solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[NH2:11][C:12]([C:14]1[C:18]([NH:19][C:20](=O)[C:21]2[CH:26]=[C:25]([I:27])[CH:24]=[N:23][C:22]=2[O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:17]([CH2:34][CH3:35])[N:16]([CH2:36][CH2:37][O:38][CH3:39])[N:15]=1)=[O:13].C(OCC)(=O)C>C(O)CCC>[CH2:29]([O:28][C:22]1[C:21]([C:20]2[NH:11][C:12](=[O:13])[C:14]3[C:18](=[C:17]([CH2:34][CH3:35])[N:16]([CH2:36][CH2:37][O:38][CH3:39])[N:15]=3)[N:19]=2)=[CH:26][C:25]([I:27])=[CH:24][N:23]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCOc1ncc(I)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Yield: 42.3 %

Procedure:
Potassium hexamethyldisilazide (46 mg, 0.23 mmol) was added to N-[3-(aminocarbonyl)-5-ethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]-2-butoxy-5-iodonicotinamide (Preparation 13) (100 mg, 0.19 mmol) in degassed n-butanol (2 mL) and the solution stirred under a nitrogen atmosphere. The reaction was heated at reflux for 9 h and then cooled. The butanol was removed in vacuo and the residue partitioned between dichloromethane and 1N hydrochloric acid. The organic phase was separated and washed with brine, dried (MgSO4) and concentrated to give a white solid. Trituration with ethyl acetate gave the title compound (40 mg, 42%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:22]=[CH:21]4)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CCOC(=O)C(C)(C)Cn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(cnn4CC(C)(C)C(=O)O)c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
Ethyl 3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indazol-1-yl]-2,2-dimethylpropanoate (D107) (50 mg, 0.106 mmol) was dissolved in Ethanol (10 ml). Sodium hydroxide (2N in H2O, 0.264 ml, 0.528 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. Most of the solvent was removed in vacuo, and the residue was diluted with water. The aqueous phase was neutralised with a 2N HCl aqueous solution then extracted with EtOAc. The organic phase was washed with H2O, dried over MgSO4 and concentrated in vacuo to give the title compound (15 mg, 30%) as a light yellow solid. MS (ES): C23H24N5O4 requires 445; found (MH+) 446.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]([O:15][C:16]([CH3:47])([CH3:46])[CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([N:31]3C(=O)C4C(=CC=CC=4)C3=O)[C:21]=2[N:20]=[C:19]1[CH2:42][O:43][CH2:44][CH3:45])=[O:14].NN.O.Cl>C(Cl)Cl.C1COCC1>[NH2:3][CH2:12][C:13]([O:15][C:16]([CH3:46])([CH3:47])[CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=[C:19]1[CH2:42][O:43][CH2:44][CH3:45])=[O:14]
Reactant: CCOCc1nc2c(N3C(=O)c4ccccc4C3=O)nc3ccccc3c2n1CC(C)(C)OC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OC(=O)CN
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62.9 %

Procedure:
1-(4-(1,3-Dioxoisoindolin-2-yl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yl 2-(1,3-dioxoisoindolin-2-yl)acetate (300 mg, 475 μmol) was combined with THF (5 mL) to give a white suspension. To this suspension was added hydrazine in water (1000 μl, 11.2 mmol) and the solution was stirred for 0.75 hour at room temperature. The mixture was cooled to 0° C., 1N hydrochloric acid (30 mL) and DCM (50 mL) were added. The white precipitate a (phtalylhydrazide) was removed by filtration and the organic phase was discarded. The aqueous phase was lyophilized and the residue was taken up with acetonitrile (20 mL) and DIEA (pH 10). After evaporation of solvent, the residue was purified by preparative HPLC (Gemini NX 3u 50×4.6mm; acetonitrile/water/Et3N) to give the title compound (111 mg, 63%) as amorphous white solid; LC-MS (UV peak area, ESI) 99%, 372.4 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[C:32]([CH:42]=[CH:43][CH:44]=4)[C:33]([NH:35][C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)=[O:34])=[CH:26][C:20]=3[C:21]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:13][CH:12]=1.[CH3:45][C:46]1[NH:50][N:49]=[C:48]([NH2:51])[CH:47]=1.[H-].[Na+]>CN(C=O)C.CO>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:18][C:19]3[CH:29]=[CH:28][C:27]([C:30]4[CH:44]=[CH:43][CH:42]=[C:32]([C:33](=[O:34])[NH:35][C:36]([CH3:40])([CH3:41])[C:37]([NH:51][C:48]5[CH:47]=[C:46]([CH3:45])[NH:50][N:49]=5)=[O:39])[CH:31]=4)=[CH:26][C:20]=3[C:21]=2[C:22]([NH:23][CH3:24])=[O:25])=[CH:15][CH:16]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)Nc4cc(C)[nH]n4)c3)cc12
Reaction time: 0.5 h
Yield: 21.8 %

Procedure:
DIEA (28 μL, 0.158 mmol) was added to a stirring solution of 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (25 mg, 0.053 mmol), 5-methyl-1H-pyrazol-3-amine (11 mg, 0.105 mmol) in DMF (527 μL) at rt. It was allowed to stir for 30 min. NaH (11 mg, 0.263 mmol) was added and the reaction was allowed to stir overnight. The mixture was treated with a drop of MeOH and was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (6.4 mg, 21%). 1H NMR (500 MHz, DMSO-d6) d ppm 11.90 (1H, br. s.), 9.84 (1H, br. s.), 8.51-8.56 (1H, m), 8.41 (1H, br. s.), 8.23-8.28 (1H, m), 7.98-8.03 (2H, m), 7.86-7.93 (3H, m), 7.76-7.83 (2H, m), 7.59 (1H, t, J=7.63 Hz), 7.37-7.43 (2H, m), 6.28 (1H, br. s.), 2.87 (3H, d, J=4.88 Hz), 2.17 (3H, s), 1.54 (6H, s). LC-MS retention time: 1.56 min; m/z (MH+): 554. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=10.47 min, purity=97%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=9.58 min, purity=96%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][NH:25][C:26]([O:28]C)=[O:27])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[OH:39][C:33]([C:35]([F:38])([F:37])[F:36])=[O:34].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[O:22][CH2:23][CH2:24][NH:25][C:26](=[O:27])[OH:28])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCNC1

Procedure:
The solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (2.247 g, 5.26 mmol) in mixed solvent of DCM/TFA (24 mL, 3:1, v/v) was stirred at rt for 30 min. The solvents was removed in vacuo to produce 2-((R)-(3-chlorophenyl)((R)-piperidin-3-yl)methoxy)ethylcarbamate TFA salt in quantitative yield. MS ESI+ve m/z 327 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1.NN.[OH-].[K+]>C(O)CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[C:18]([CH2:19][CH2:20][CH3:21])=[CH:17][C:16]([Cl:22])=[C:15]([OH:23])[C:12]=3[C:13]=2[CH3:14])=[CH:24][CH:25]=1
Reactant: CCCc1cc(Cl)c(O)c2c(C)c(C(=O)c3ccc(OC)cc3)oc12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCc1cc(Cl)c(O)c2c(C)c(Cc3ccc(OC)cc3)oc12
Yield: 54.5 %

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-chloro-7-propylbenzofuran (90 mg; 0.25 mmole), hydrazine (80 μl) and potassium hydroxide (98 mg) in ethylene glycol (2 mL) was heated at 145° C. for a period of 5 hours. The reaction mixture was cooled, poured in water, and extracted with ether. The organic phase was washed with 20% citric acid, with brine, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel using 20% ethylacetate in hexane as eluent to yield 47 mg (50%) of 2-(p-methoxybenzyl)-3-methyl-4hydroxy-5-chloro-7-propylbenzofuran.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:16][CH2:15][CH2:14][C@@:13]2([CH3:17])[C@H:8]1[CH2:9][CH2:10][CH2:11][C@@H:12]2[C@H:18]([CH3:26])[CH2:19][CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])(C)(C)C.C(#N)C.O>O1CCCC1>[OH:24][C:22]([CH3:23])([CH3:25])[CH2:21][CH2:20][CH2:19][C@H:18]([C@H:12]1[CH2:11][CH2:10][CH2:9][C@@H:8]2[C@:13]1([CH3:17])[CH2:14][CH2:15][CH2:16][C@@H:7]2[OH:6])[CH3:26]
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@H](CCCC(C)(C)O)[C@H]1CCC[C@H]2[C@@H](O)CCC[C@]12C
Reaction time: 72 h
Yield: 55.5 %

Procedure:
To a stirred solution of 267 mg (0.65 mMol) of (R)-6-[(1R,4aR,5S,8aR)-5-(tert-butyl-dimethyl-silanyloxy)-8a-methyl-decahydronaphtalen-1-yl]-2-methyl-heptan-2-ol in 2.5 ml of tetrahydrofuran are added 7.5 ml of acetonitrile and 2.5 ml of an aqueous HF solution (40%). The reaction mixture is kept for 72 hours, poured unto water and extracted three times with diethylether, the combined organic extracts are washed with a saturated aqueous NaHCO3 solution, with water, dried over Na2SO4, filtered and evaporated in vacuo. The residue is chromatographed over 40 g of silicagel with toluene/diethylether 4/1 to yield 107 mg (56%) of crystalline pure (1S,4aR,5R,8aR)-5-[(R)-5-Hydroxy-1,5-dimethyl-hexyl]-4a-methyl -decahydro-naphtalen-1-ol. The material crystallized with diisopropylether has m.p.: 85.1-86.9°.
Reaction SMILES: [CH2:1]1[CH2:20][O:19][CH:18]2[CH:3]([C@@H:4]([C@@H:16]([CH2:21][CH2:22][C:23]([OH:30])([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])[O:2]1.[OH-].[K+].OP([O-])(O)=O.[Na+]>CO.O>[CH2:1]1[CH2:20][O:19][CH:18]2[CH:3]([C@@H:4]([C@@H:16]([CH2:21][CH2:22][C:23]([OH:30])([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:17]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[O:2]1
Reactant: CCCCCC(C)(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(C)(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)O

Procedure:
A solution of 1.33 g. of ethyl 9-ethylenedioxy-15-hydroxy-15-methyl prostanoate (Example 57) in 20 ml. of methanol-water (1:1) containing 500 mg. of potassium hydroxide is stirred at room temperature for 18 hours. The solution is neutralized with 30% aqueous sodium phosphate monobasic and extracted with ether. The ether extract is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.23 g. (99%) of viscous oil; λ max. 2.94-4.00 (broad) (hydroxyl and carboxyl groups) and 5.85 μ (acid carbonyl group).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1.S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:8][N:7]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(F)(F)F)cn1
Yield: 84 %

Procedure:
A solution of 5-(trifluoromethyl)-pyridine-2-carboxylic acid (CAN 80194-69-0, 3 g, 15.7 mmol) and sulfurous dichloride (0.1 mL) in methanol (30 mL) was stirred under reflux conditions overnight. Removal of the solvent provided the crude title compound which was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to obtain the title compound (2.7 g, 84%) as white solid; MS (EI): m/e=206.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].O.[NH2:12][NH2:13]>O>[NH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:9]=2)[NH:13][N:12]=1
Reactant: NN
Reactant: N#Cc1cc(Br)ccc1F
Solvent: O
Product: Nc1n[nH]c2ccc(Br)cc12
Reaction time: 48 h
Yield: 91 %

Procedure:
A mixture of 5-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) and hydrazine hydrate (10 mL) was heated at reflux for two hours and then it was allowed to stand at room temperature for two days. The reaction was treated with water (50 mL) and the solids were collected by filtration to give 3-Amino-5-bromo-indazole as a white solid (4.82 g, 91%): mp 165-175° C.; MS [M+H]+ 212, 214.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:15]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([Si:5]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[C:9]#[CH:15])([CH3:14])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)(C=O)CO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionaldehyde (0.84 g, 3.9 mmol) in methanol (20 mL) was added (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (0.9 g, 4.7 mmol) and K2CO3 (1.1 g, 7.8 mmol). The solution was stirred overnight at room temperature and then the reaction mixture was washed with water. The crude residue was purified by flash chromatography (eluted with: petroleum ether:EtOAc=100:2) to afford the title compound (0.17 g, 21%): 1H NMR (CDCl3, 400 MHz) delta 0.05 (s, 6H), 0.90 (s, 9H), 1.19 (s, 6H), 2.06 (s, 1H), 3.45 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].[N+](=[CH2:13])=[N-]>CCOCC>[CH3:13][O:9][C:8](=[O:10])[C@H:5]([CH2:6][SH:7])[NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)[C@H](CS)NC(C)=O
Reaction time: 8 h

Procedure:
N-Acetyl-L-cysteine (5 g, 30.6 mM) was treated with excess diazomethane (generated from N-nitrosomethyl urea) in ether for 6 hr at RT. Unreacted starting material was removed by filtration and the resulting yellow filtrate was allowed to stand overnight. The solvent was removed in vacuo and the residue crystallized from Et2O/Pet. ether to give pure N-acetyl-L-cysteine methyl ester (650 mg); mp 73°-76° C. compared to a literature mp of 81°-82° C. in the Journal of Organic Chemistry, Vol. 35, p. 3542 (1970) and 79°-80° C. in the Canadian Journal of Chemistry, Vol. 44, p. 2517 (1966).
Reaction SMILES: [N+](=CC([C:6]1([N:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=[CH:12]2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=O)=[N-].[C:20]([O:23]CC)(=[O:22])[CH3:21]>O1CCOCC1.O.CCCCCC>[N:11]1([C:6]2([CH2:21][C:20]([OH:23])=[O:22])[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=[CH:12]1
Reactant: CCOC(C)=O
Reactant: [N-]=[N+]=CC(=O)C1(n2ccc3cccnc32)CCCC1
Solvent: O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C(O)CC1(n2ccc3cccnc32)CCCC1
Reaction time: 2 h
Yield: 54 %

Procedure:
To a stirred solution of 2-diazo-1-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-ethanone (396) (0.95 g, 3.82 mmol) in dioxane:water (10:1) (27.5 mL) was added silveracetate (319 mg, 1.91 mmol) and stirring was continued for 2 h at room temperature (TLC, 30% ethyl acetate in hexane, Rf=0.2). The mixture was filtered over a celite bed, washed with ethyl acetate (3×20 mL) and concentrated. The crude product was purified by Combi-Flash column (eluted at 30% ethyl acetate in hexane) to get (1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentyl)-acetic acid (397) (0.5 g, 54%) as a brown solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[OH:25][C@@H:26]([C@H:28]1[C:48](=[O:49])[N:30]2[CH:31]([C:35]([O:37]CC3C=CC([N+]([O-])=O)=CC=3)=[O:36])[C:32](=O)[CH2:33][C@H:29]12)[CH3:27].Cl.[C:51]([O:54][C@@H:55]1[CH2:59][CH2:58][N:57]([C:60](=[NH:63])[CH2:61][SH:62])[CH2:56]1)(=[O:53])[NH2:52]>C(#N)C.CS(C)=O.O1CCCC1.P([O-])([O-])([O-])=O.[C].[Pd].CCOCC>[C:51]([O:54][C@@H:55]1[CH2:59][CH2:58][N:57]([C:60](=[NH:63])[CH2:61][S:62][C:32]2[CH2:33][C@@H:29]3[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:48](=[O:49])[N:30]3[C:31]=2[C:35]([OH:37])=[O:36])[CH2:56]1)(=[O:53])[NH2:52]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: N=C(CS)N1CC[C@@H](OC(N)=O)C1
Agent: [Pd]
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SCC(=N)N3CC[C@@H](OC(N)=O)C3)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
0.183 ml of diisopropylethylamine and 0.218 ml of diphenylphosphoryl chloride were added dropwise to an ice-cooled solution of 348 mg of p-nitrobenzyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-oxo-1-carbapenam-3-carboxylate in 5 ml of anhydrous acetonitrile, and the mixture was stirred for 60 minutes with ice-cooling. A solution of 0.183 ml of diisopropylethylamine and 380 mg of 2-[(3R)-3-carbamoyloxypyrrolidin-1-yl]-2-iminoethylmercaptan hydrochloride in 2.5 ml of dimethylsulfoxide was then added dropwise, and the resulting mixture was stirred for a further 30 minutes with ice-cooling. The reaction mixture was poured into 200 ml of anhydrous ether, and the solvent was decanted off from the gummy material which formed. This material was dissolved in a mixture of 35 ml of tetrahydrofuran and 35 ml of 0.1M phosphate buffer (pH 7.0), and the solution was subjected to catalytic hydrogenation for 3 hours at room temperature in the presence of 0.55 g of 10% palladium-carbon. The hydrogenated solution was filtered over "Celite" (Trade Mark) filter aid, and the filtrate was extracted with 80 ml of ether. The aqueous layer was concentrated under reduced pressure, and the concentrate was subjected to chromatography through a 160 ml of column of "Dowex 50W" (Trade Mark) cation exchange resin (Na+ type), giving 70 mg of the title product from the fraction eluted with water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:30])[NH:21][C:22]([CH3:29])=[CH:23][C:24]=1[CH:25]([CH2:27][CH3:28])[CH3:26]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:30])[NH:21][C:22]([CH3:29])=[CH:23][C:24]=2[CH:25]([CH2:27][CH3:28])[CH3:26])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Reactant: CCC(C)c1cc(C)[nH]c(=O)c1CN
Product: CCC(C)c1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.50 g, 1.77 mmol) and 3-(aminomethyl)-4-(sec-butyl)-6-methylpyridin-2(1H)-one (0.446 g, 2.296 mmol). The product was collected as 0.81 g (98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (s, 1H), 8.62 (t, J=4.7 Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.70 (d, J=1.5 Hz, 1H), 5.96 (s, 1H), 5.05 (quin, J=6.6 Hz, 1H), 4.41 (d, J=4.3 Hz, 2H), 2.95 (q, J=7.1 Hz, 1H), 2.15 (s, 3H), 1.48 (m, 8H), 1.07 (d, J=6.6 Hz, 3H), 0.74 (t, J=7.3 Hz, 3H). LC-MS (ES) [M+H]+ 459.2.