Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:3]=1[CH3:29].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:32][CH2:31]1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[CH3:39][O:38][C:36]([CH:33]1[CH2:34][CH2:35][N:30]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:3]=2[CH3:29])[CH2:31][CH2:32]1)=[O:37]
Reactant: Cc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ncnc(NC[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)c2C)CC1
Yield: 25 %

Procedure:
A mixture of 80 mg (0.19 mmoles) of (1,1-dimethylethyl) 3-[(6-chloro-5-methyl-4-pyrimidinyl)amino]-N-[(phenylmethoxy)carbonyl]alaninate and 3 ml of methyl 4-piperidinylcarboxylate is heated under reflux for 3 hours. After cooling down the reaction medium is taken up in water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent eliminated under vacuum. The residue is chromatographed on silicagel eluting with a gradient of heptane (100%) to heptane-ethyl acetate (50-50). 25 mg (Yield=25%) of the expected product is obtained in the form of oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)=[C:8]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-:36].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][F:36])=[C:8]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: Cc1ccc(S(=O)(=O)OCc2c(SCc3ccc(C(C)(C)C)cc3)cnn(C(C)(C)C)c2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CF)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 15 ml round bottom flask charged with 2-tert-butyl-4-p-toluenesulfonyloxymethyl-5-(4-tert-butylbenzyl)thio-3(2H)-pyridazinone (0.5 g, 0.972 mmol) is added 4.86 ml of tetra-butylammonium fluoride solution (1M in THF, 4.86 mmol). The mixture is first stirred at room temperature for 15 minutes after which it is heated for 15 minutes at 100° C. The solution is then cooled to room temperature and to it is added dichloromethane followed by water. The layers were separated and the organic layer is washed with water and then dried. The organic layer is then concentrated and subjected to purification using silica gel flash chromatography (ethyl acetate/hexanes) to obtain the above compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:29]([CH2:28][C@@H:25]2[CH2:24][CH2:23][C:22]3[S:21][C:20]4[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]5[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]5)[C:27]=4[C:26]2=3)=[O:30])=[N:38][CH:39]=1
Reactant: Nc1ccc(F)cn1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of intermediate 22.4 (200 mg, 0.43 mmol, 1.00 equiv) in distilled DMF (8 mL) at room temperature under nitrogen was added 5-fluoropyridin-2-amine (55 mg, 0.49 mmol, 1.13 equiv), HATU (200 mg) and DIPEA (170 mg). The resulting solution was stirred for 2 h at room temperature and quenched with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to give tert-butyl N-(4-[[(3S)-3-[[(5-fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (23.1, 195 mg, 81%) as a yellow oil. MS: m/z 556 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([OH:13])[C:10]2[C:5](=[C:6]([C:14]([OH:16])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl.[CH3:26]COCC>CO>[F:24][C:2]([F:1])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[C:6]([C:14]([O:16][CH3:26])=[O:15])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(O)c1cccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc12
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Yield: 51 %

Procedure:
2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)-3-carbamoylbenzoic acid (28.5 g, 81 mmol) in MeOH (1000 mL) was treated with 2M HCl/ether (4 mL) and then heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (17.5 g, 62%). Separately, 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-hydroxyquinazoline-8-carboxylic acid (10.5 g, 31 mmol) in MeOH (200 mL) was treated with 2M HCl/ether (1 mL) and was heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (5.5 g, 51%). The filtrates from the two procedures above were concentrated at 65° C. and allowed to cool. The solid was collected by filtration to afford additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (3 g). Purification of the filtrate by silica gel chromatography eluting with EtOAc/hexanes afforded additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (4 g). The isolated solids were combined to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate as a solid (30 g). LC-MS (ESI) m/z 350 (M+H+).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][C:17]([CH3:20])([CH3:19])[CH:16]=[CH:15][C:14]=2[CH:21]=1.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>C(O)(=O)C>[CH3:8][O:9][C:10]1[C:11]([N+:22]([O-:24])=[O:23])=[CH:12][C:13]2[O:18][C:17]([CH3:19])([CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]=1
Reactant: COc1ccc2c(c1)C=CC(C)(C)O2
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixed solution of acetic acid (6.2 mL) and acetic anhydride (6.2 mL) containing 6-methoxy-2,2-dimethyl-2H-1-benzopyran (3.1 g, 16.4 mmol) was cooled with ice, nitric acid (1.37 mL, 18.0 mmol) was added dropwise and then the mixture was stirred at 0° C. for 1 hour. Upon the completion of the reaction, an aqueous solution of 1 mol/L sodium hydroxide was added to the reaction solution, the resulting solution was extracted with ethyl acetate (150 mL). The organic phase was washed twice with 1 mol/L sodium hydroxide aqueous solution and once with saturated sodium chloride solution. Then, the organic phase was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=6/1) and the aimed product was obtained as yellow crystal (yield: 79%).
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:12][CH3:13])=[CH:7][CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([N:21]2[C:20]([C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)([O:12][CH3:13])[C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:36])=[O:3])=[CH:10][CH:9]=3)=[C:28]3[C:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:22]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1ccc(C(OC)(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(c1ccc(C(=O)O)cc1)(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-methoxymethyl}-benzoic acid ethyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as off-white solid. MS: m/e=479.3 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)[NH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH2:66])=[O:65])=[CH:62][CH:61]=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([NH:59][C:60]3[CH:68]=[CH:67][C:63]([C:64]([NH2:66])=[O:65])=[CH:62][CH:61]=3)=[O:17])[NH:12][CH:13]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2c[nH]c(C(Cc3ccccc3)C(=O)O)n2)cc1
Reactant: NC(=O)c1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2c[nH]c(C(Cc3ccccc3)C(=O)Nc3ccc(C(N)=O)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
The acid from Example 59 Part A (100 mg, 0.32 mmol), triethylamine (150 μL, 1.2 mmol), and BOP reagent (210 mg, 0.48 mmol) were dissolved in THF (9 mL). The mixture was stirred at rt for 15 min and 4-aminobenzamide (47 mg, 0.35 mmol) was added. The resulting mixture was heated at 70° C. under N2 for 1 h. The mixture was concentrated and then re-dissolved in EtOAc. It was washed with water and brine, dried over Na2SO4, concentrated, and purified by flash chromatography (silica gel, EtOAc/hexane) to give 45 mg of the desired product (32%). MS 436.3 (M+H)+.
Reaction SMILES: [OH:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:6][N:7]1[C@@H:24]2[CH2:25][C:12]3=[CH:13][CH:14]=[C:15](O)[C:16]4[O:17][C@H:18]5[C:19]([CH2:21][CH2:22][C@@H:23]2[C@:10]5([C:11]=43)[CH2:9][CH2:8]1)=[O:20].C(#N)C.[OH-].[Na+]>CCO>[CH3:6][N:7]1[C@@H:24]2[CH2:25][C:12]3=[CH:13][CH:14]=[C:15]([O:3][S:2]([OH:5])(=[O:1])=[O:4])[C:16]4[O:17][C@H:18]5[C:19]([CH2:21][CH2:22][C@@H:23]2[C@:10]5([C:11]=43)[CH2:9][CH2:8]1)=[O:20]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC#N
Product: CN1CC[C@]23c4c5ccc(OS(=O)(=O)O)c4O[C@H]2C(=O)CC[C@H]3[C@H]1C5
Temperature: 81 °C

Procedure:
Morphine base (30.0 g, wet, 75% wt, 78.85 mmol) was dried in a vacuum oven at 90° C. for 3 h. The dried solid was added to a reaction flask, along with water (30 mL) and EtOH (60 mL). The reaction mixture was stirred to form a suspension. The reactor was flushed with nitrogen and the reaction mixture was kept under nitrogen throughout the reaction. The reaction flask was charged with H2SO4 (98%, 7.73 g, 78.85 mmol) and the catalyst (RuCl3.xH2O, 0.20 g). The reaction mixture was heated to reflux (80-82° C.) for 16 h. HPLC analysis indicated that 96.8% (area) hydromorphone was formed. The reaction mixture was cooled down overnight. Acetonitrile (30 mL) was added to the reaction mixture and the mixture was heated at reflux for 1 h. The pH of the reaction mixture was adjusted the pH to 1.6 with 50% NaOH. EtOH (90 mL) was added to the mixture, which as cooled down to 15° C. for 1 h. The mixture was filtered, and the solid was washed with 95% EtOH (2×15 mL). The solid was dried under vacuum at 65° C. for 18 h to give 11.6 g of hydromorphone sulfate as solids (purity>99% area).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:22])([F:21])[CH:17]([OH:20])[CH2:18][CH3:19]>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:20][CH:17]([C:16]([F:22])([F:21])[F:15])[CH2:18][CH3:19])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CCC(O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CCC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F

Procedure:
Prepared in analogy to Example B4(c) from 2-Fluoro-5-methanesulfonyl-benzoic acid (example B4(b)) and rac-1,1,1-Trifluoro-butan-2-ol (CAS: 431-36-7). White solid. MS (m/e): 325.0 ([M−H], 100%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[CH:2]1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc2cc[nH]c2c1
Solvent: ClCCl
Product: N#Cc1ccc2c(Br)c[nH]c2c1
Yield: 100.5 %

Procedure:
To a solution of 1H-indole-6-carbonitrile (1.6 g, 11.25 mmol) in DCM (60 mL) was added NBS (2.0 g, 11.25 mmol) in portions over a period of 5 minutes. The resultant mixture was stirred for 1 h. The reaction mixture was quenched with saturated sodium thiosulfate solution (25 mL) and further diluted with DCM (60 mL). The organic layer was washed with water (2×25 mL) followed by brine solution and dried over anhydrous sodium sulfate, filtered and concentrated to afford 2.50 g (99%) of the title compound, 1H NMR (300 MHz, CDCl3): δ 7.43 (d, J=7.4 Hz, 1 H), 7.45 (s, 1 H), 7.67 (d, J=6.9 Hz, 1 H), 7.79 (s, 1 H), 8.67 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17]CC3C=CC=CC=3)[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5].C(=O)(O)[O-].[Na+].O>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5]
Reactant: Nc1ncccc1C(=O)NCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ncccc1C(=O)NCc1cc2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a trifluoroacetic acid solvent of 2-amino-N-(6-benzyloxy-benzofuran-2-ylmethyl)-nicotinamide (323 mg, 865 mmol) described in Example 58 at 0° C., which was stirred at room temperature for 3 hours. Sodium bicarbonate and water were added to the reaction solution at 0° C. followed by extraction with ethyl acetate. The organic layer was washed with sat. NaCl followed by drying by adding anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (219 mg, 89%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:1]1[CH2:2][CH:3]([C:5]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4]1)=[O:27]
Reactant: O=C(Cl)CCl
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCl)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 1-(azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (330 mg, 1.39 mmol) and Na2CO3 (590 mg, 5.56 mmol) in dichloromethane (10 ml) at 0° C. was added chloroacetyl chloride (107 μl, 1.39 mmol). After 10 mins the reaction temperature was raised to RT and stirred for a further hour. The reaction was then filtered and concentrated at reduced pressure to give the title compound as colourless oil (411 mg, 91% yield), which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[C:10](O)=[O:11].CCN=C=NCCCN(C)C.C1C=CC2[N:53]([OH:54])N=NC=2C=1.NO>CN(C=O)C.C(OCC)(=O)C>[OH:54][NH:53][C:10]([C@@H:4]1[C@H:3]([N:2]([CH3:1])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:20][CH:21]=2)(=[O:14])=[O:15])[C@@H:8]2[CH2:9][C@H:5]1[CH2:6][CH2:7]2)=[O:11]
Reactant: CN(C1C2CCC(C2)C1C(=O)O)S(=O)(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C(=O)NO)S(=O)(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution of 3-{methyl-[4-(quinolin-2-ylmethoxy)-benzenesulfonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.268 mmol) in DMF (1 mL) were added EDCI (103 mg, 0.536 mmol), HOBT (72.5 mg, 0.536 mmol) and hydroxylamine (50% in water, 82 μL, 1.34 mmol) at room temperature. The mixture was stirred for 20 h, diluted with ethyl acetate (5 mL), and washed with water (3×3 mL) and brine (3 mL). The organic layer was concentrated and the residue was purified by RP-HPLC to give (1R,2S,3R,4S)-N-hydroxy-3-(methyl{[4-(quinolin-2-ylmethoxy)phenyl]sulfonyl}amino)bicyclo[2.2.1]heptane-2-carboxamide (50% yield). MS (ESI) [M+H] 482.2
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:21]=[CH:22][C:23]=1[F:24].C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[N:31]=[C:30]3[S:32][C:33]([NH:35][C:36]([CH:38]4[CH2:40][CH2:39]4)=[O:37])=[N:34][C:29]3=[CH:28][CH:27]=2)[CH:21]=[CH:22][C:23]=1[F:24])=[O:5]
Reactant: CC(C)(C#N)Oc1cccc(C(=O)Cl)c1Cl
Reactant: Nc1cc(Nc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)Oc1cccc(C(=O)Nc2cc(Nc3ccc4nc(NC(=O)C5CC5)sc4n3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethoxy)benzoyl chloride synthesized above in N,N-dimethylacetamide (4.0 mL) was added N-{5-[(3-amino-4-fluorophenyl)amino][1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.582 mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (20 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (20 mL) and saturated brine (20 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→0/100) and crystallized from hexane/ethyl acetate to give the title compound (216 mg, 66%) as pale-purple crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:19](Cl)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:19]([O:20]/[C:19](/[C:18]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:17]=2)=[CH:8]\[C:7]2[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Product: COc1ccc(C(=O)O/C(=C\c2c(Cl)cncc2Cl)c2ccc(OC)c(OC3CCCC3)c2)cc1OC1CCCC1

Procedure:
The compound was obtained starting from 3,5-dichloro-4-methyl-pyridine and 3-cyclopentyloxy-4-methoxybenzoyl chloride following the procedure of Example 31.
Reaction SMILES: [Cl:1][C:2]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][N:5]([CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][CH:17]=O)[CH:13]=[CH:14][CH:15]=1.[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH2:45].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:41][O:42][C:43](=[O:46])[CH2:44][NH:45][CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:40])[F:39])[C:2]=2[Cl:1])[CH2:19][CH:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1
Reactant: O=CCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)CNCCc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-acetaldehyde (76 mg, 0.13 mmol) and glycine methyl ester (34 mg, 0.27 mmol) in 1,2-dichloroethane (15 ml) was stirred as room temperature for 10 minutes, and sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added. Next two drops of glacial acetic acid was added. The reaction mixture was stirred at room temperature for 18 hour and then quenched with 0.01N aqueous HCl (15 ml) The biphasic mixture was separated and the aqueous layer was extracted with dichloromethane (3×). The organic layers were combined with the 1,2-dichloroethane solution and were washed with brine (1×), dried over sodium sulphate, filtered and concentrated in vacuo. Preparative HPLC (YMC 75×30 mm, 25 ml/min, 90-100% CH3CN) afforded title compound as an oil, 70 mg (81%).
Reaction SMILES: N#N.[N:3]([C@H:6]1[C@H:10]([OH:11])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+:4]=[N-:5].[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[N:3]([C@H:6]1[C@H:10]([O:11][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[N+:4]=[N-:5]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N#N
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])cc1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of trans-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (J. Med. Chem. 2010, 53, 6730-6746) (320 mg, 1.40 mmol) in pyridine (3 mL) was added TsCl (588 mg, 3.00 mmol). The mixture was stirred at 5° C. overnight. The solvent was removed under reduced pressure and the mixture was partitioned between CH2Cl2 and 10% aq. NaHCO3. The organic layer was washed with water, dried over MgSO4, and the solvent removed under reduced pressure. The residue was purified by FC (Hept/EA, 9.5:0.5→8:2) to afford trans-tert-butyl 3-azido-4-(tosyloxy)pyrrolidine-1-carboxylate as a colorless oil. LC-MS-conditions 08: tR=0.96 min; [M-CH3+H]+=368.10. TLC: rf (Hept/EA, 8:2)=0.22.