Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11]([NH:13][C:14]2[C:15]([NH2:21])=[CH:16][CH:17]=[C:18]([F:20])[CH:19]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C@@H:30]([CH3:34])[C:31](O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:22]([O:26][C:27](=[O:28])[NH:29][C@H:30]([C:31]1[N:13]([C@H:11]2[CH2:12][C@@H:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:10]2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[N:21]=1)[CH3:34])([CH3:25])([CH3:24])[CH3:23]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1N[C@H]1C[C@@H](OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of N2-(cis-3-benzyloxycyclobutyl)-4-fluorobenzene-1,2-diamine (1.13 g, 3.95 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (0.83 g, 4.35 mmol) and HOAt (0.59 g, 4.35 mmol) in DCM (20 mL) was cooled to 0° C. under nitrogen atmosphere. To this mixture N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.83 g, 4.35 mmol) was added portion wise and the reaction mixture stirred at RT for 1 h. The reaction mixture allowed to warm to RT then partitioned between DCM and a 10% aq. citric acid. The organic fraction was washed with brine (20 mL), dried (MgSO4), concentrated in vacuo and the resulting dark brown residue purified by column chromatography (Si—PCC, gradient 0-40% EtOAc in cyclohexane) to afford the title compound as a yellow gum, which solidified on standing (1.93 g, 93%). 1H NMR (CDCl3, 400 MHz): δ 7.46 (1H, s, br), 7.36-7.30 (5H, m), 7.11 (1H, q, J=14.8 Hz, 2.5 Hz), 6.37 (1H, dt, J=19.5 Hz, 2.8 Hz), 6.25 (1H, dd, J=14 Hz, 2.82 Hz), 4.94 (1H, d, J=5.83 Hz), 4.43 (2H, s), 4.23-4.07 (1H, m), 3.93-3.81 (1H, m), 3.47-3.35 (1H, m), 2.88-2.75 (1H, m), 2.03-1.85 (1H, m), 1.45 (3H, d, J=2.46 Hz), 1.43 (9H, s). LCMS (Method B): RT 3.88 min [M+H]+ 458. 110183151. The compound thus obtained (1 g, 2.19 mmol) was dissolved in AcOH (15 mL) and heated at 70° C. for 18 h. After cooling to RT, the volatiles were evaporated under reduced pressure and the residue partitioned between DCM (40 mL) and a saturated solution of NaHCO3 (20 mL). The organic fraction was washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting dark yellow residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in cyclohexane) to afford the title compound as pale red gum (570 mg, 60%). LCMS (Method B): RT 3.61 min [M+H]+ 440.0. 1H NMR (CDCl3, 400 MHz): δ 7.70-7.60 (2H, m), 7.44-7.37 (5H, m), 7.05-6.96 (1H, m), 5.38-5.26 (1H, m), 5.20-5.05 (1H, m), 4.82-4.68 (1H, m), 4.55 (2H, s), 4.10-3.97 (1H, m), 3.02-2.77 (4H, m), 1.47 (3H, d, J=2.44 Hz), 1.44 (9H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[I:12]Cl.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:7]([I:12])[CH:8]=1
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(I)cc(Cl)cc1[N+](=O)[O-]
Yield: 14.2 %

Procedure:
A solution of 4-chloro-2-nitroaniline (34.5 g) in acetic acid (500 ml) was refluxed with iodine monochloride (65.0 g) for 7 h with stirring, then was cooled and added to excess water. The precipitate was filtered off, washed with aqueous sodium sulphite and after column chromatography yielded 4-chloro-2-iodo-6-nitroaniline (8.5 g). δ (360 MHz, DMSO-d6) 7.13 (2H, bs, NH2), 8.08 (1H, d, 3-H) and 8.13 (1H, d, 5-H).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.CN1CCOCC1.[CH3:35][NH:36][C@H:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1>ClCCl.O>[CH3:35][N:36]([C@H:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][CH2:38]1)[C:21]([C:18]1[CH:19]=[CH:20][N:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:26])([F:25])[F:27])=[N:5]3)[CH2:15][CH2:14]2)[N:17]=1)=[O:23]
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ccc(C(=O)O)n2)CC1
Reactant: CN[C@@H]1CCCc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ccc(C(=O)N(C)[C@@H]3CCCc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.9 %

Procedure:
A mixture of 1-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-1H-pyrazole-3-carboxylic acid (270 mg, 0.7 mmol) (i.e. the product of Example 18, Step E), N-(3-dimethylaminopropyl)-Y-ethylcarbodiimide hydrochloride (EDC) (147.61 mg, 0.77 mmol) and N-methylmorpholine (0.088 mL, 0.8 mmol) in 5 mL of dichloromethane was stirred at room temperature for 15 minutes. (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (124.16 mg, 0.77 mmol) (i.e. the product of Example 6, Step A) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was poured in water, and the organic layer was subsequently washed with water, 1 M aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate, brine. The filtered reaction mixture was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by medium-pressure liquid chromatography on silica gel using 75-100 of ethyl acetate in hexanes as eluant to give 55 mg of the title compound, a compound of the present invention as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH2:11]Cl)=[C:9]([CH3:13])[C:6]([O:7][CH3:8])=[C:5]([CH3:14])[C:4]=1[CH3:15].[Mg].[CH2:17](Br)[C:18]#[CH:19]>C1COCC1.CCOCC.[I-].[Na+]>[CH2:11]([C:10]1[C:3]([O:2][CH3:1])=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]([O:7][CH3:8])[C:9]=1[CH3:13])[CH2:19][C:18]#[CH:17]
Reactant: COc1c(C)c(C)c(OC)c(CCl)c1C
Reactant: C#CCBr
Agent: [I-]
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CCCc1c(C)c(OC)c(C)c(C)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
A solution of chloromethyltrimethylhydroquinone dimethyl ether (7.5 g; 32 mmol) in THF (20 ml) was treated dropwise at 0° with a freshly Prepared solution of a Grignard reagent Prepared from 1.9 g of magnesium shavings and 4.91 ml (65 mmol) of propargyl bromide. After the addition of solid sodium iodide (0.42 g) the mixture was warmed to room temperature and stirred overnight. Thereafter, the reaction mixture was diluted with ether and washed with 2N hydrochloric acid. The ethereal solution was deacidified with bicarbonate, dried and freed from solvent. Distillation (0.04 mbar; 140° C.) of the residue gave 7.16 g of 1-(3-butynyl)-3,6-dimethoxy-2,4,5-trimethylbenzene; melting point: 54° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2ccccc2n1Cc1cccc(C(F)(F)F)c1
Yield: 88.6 %

Procedure:
A suspension of 0.492 g (2.6 mmol) of ethyl 1H-indole-2-carboxylate, of 0.683 g (2.86 mmol) of 3-trifluoromethylbenzyl bromide and of 0.898 g (6.5 mmol) of potassium carbonate in 50 ml of dimethylformamide is stirred at 60° C. for 24 hours. The reaction mixture is cooled and is poured into a mixture of ice-cold water and of ethyl acetate. After settling, the organic phase is separated and is then washed with two times 50 ml of water and then with 50 ml of a saturated sodium chloride solution. The solution is dried over magnesium sulfate and filtered, and then the filtrate is concentrated under reduced pressure. 0.8 g of an oil is obtained, which oil is used as is in the following stage.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc2ccccc2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-naphthylamine (1.43 g, 10 mmol) and triethylamine (1.11 g, 11 mmol) in 10 mL of CH2Cl2 is cooled to 0° C. under an atmosphere of nitrogen. To this solution is added dropwise a solution of acetyl chloride (0.86 g, 11 mmol) in 10 mL of CH2Cl2. The mixture is allowed to warm to room temperature and stirred overnight. The mixture is concentrated in vacuo and then 1 N HCl is added to the residue to bring the mixture to pH 4. The mixture is extracted 3 times with 20 mL of EtOAc and the combined organic layers are washed with 20 mL each of H2O, saturated aqueous NaHCO3 and saturated brine. The organic layer is dried over MgSO4, filtered and the solvents are removed in vacuo to give 2-acetylaminonaphthalene as a solid which is used without further purification. A solution of NaClO3 in (0.33 g, 30 mmol) in 0.77 mL of H2O is added dropwise to a mixture of 1.0 g of 2-acetylaminonaphthalene in 5 mL of concentrated HCl and 6 mL of HOAc at 0° C. The mixture is allowed to warm to room temperature and stirred overnight under an atmosphere of nitrogen. The mixture is poured over 20 g of ice and is extracted three times with 20 mL of CH2Cl2. The combined organic layers are washed with 20 mL each of water, saturated aqueous sodium bicarbonate and saturated brine, and dried over magnesium sulfate. The mixture is filtered and the solvents are removed in vacuo to give an oil which is purified by flash chromatography on silica gel (CH2Cl2) to give 1-chloro 2-acetylaminonaphthalene as a solid. A mixture of 0.17 g (0.77 mmol) of 1-chloro 2-acetylaminonaphthalene in 3.9 mL of 6 N HCl is heated to 85° C. and is stirred for 8 hours. The mixture is cooled to 0° C. and solid Na2CO3 is carefully added to bring the mixture to pH 8. The mixture is extracted 3 times with 20 mL of CH2Cl2. The combined organic layers are washed with 15 mL of saturated brine, dried over Na2SO4 and the solvents are removed in vacuo to give 1-chloro 2-aminonaphthalene as a solid.
Reaction SMILES: [OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].CO[C:14](OC)([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:16])([CH3:15])[O:1]1)=[O:4]
Reactant: CON(C)C(=O)[C@@](C)(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CON(C)C(=O)[C@]1(C)COC(C)(C)O1

Procedure:
The compound prepared in Example 130(a) (12.4 g), acetone (150 mL), acetone dimethylacetal (18 mL) and p-toluenesulfonic acid monohydrate (290 mg) were stirred at room temperature for an hour. The reaction mixture was concentrated, poured into a cold aqueous solution of sodium hydrogen carbonate and extracted with a mixed solution of ethyl acetate-hexane (1:1). The obtained organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuum condition and dried to give the title compound (8.4 g) having the following physical data.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][NH:23][CH3:24])[CH2:17][CH2:16]2)=[N:11][CH:12]=[CH:13][N:14]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:8][C:9]1[C:10]([N:15]2[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][N:23]([CH3:24])[S:32]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)(=[O:34])=[O:33])[CH2:19][CH2:20]2)=[N:11][CH:12]=[CH:13][N:14]=1
Reactant: CNCCN1CCN(c2nccnc2Cl)CC1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91 %

Procedure:
Add triethylamine (0.426 mL, 3.058 mmol) to a stirring solution of [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amine (0.200 g, 0.612 mmol) in dichloromethane (5 mL). Add pyridine-3-sulfonyl chloride hydrochloride salt (0.157 g, 0.734 mmol) at room temperature. Stir at room temperature for 20 min. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate and extract the aqueous fraction with dichloromethane. Combine the organic fractions, dry over sodium sulfate, filter, and concentrate. Purify the resulting material by silica gel chromatography eluting with hexanes:acetone 4:1 to afford the title preparation (0.220 g, 91% yield). MS ES: m/z=397 [M+H]+.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CN(C=O)C>[OH:1][CH:2]([CH2:28][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: CC(C)N
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CNC(C)C
Temperature: 70 °C
Yield: 15.3 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol), (prepared as described for the starting material in Example 162), and isopropylamine (100 μl, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1) to give 7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (18 mg, 16%).
Reaction SMILES: [C:1]([O:6][CH:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4].CCCCCC>CC(OC)(C)C.O>[C:1]([O:6][C@@H:7]([O:11][C:12]([CH3:14])=[S:13])[CH:8]([CH3:10])[CH3:9])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OC(OC(C)=S)C(C)C
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: O
Product: CCCC(=O)O[C@@H](OC(C)=S)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
2-Methyl-1-methylthiocarbonyloxypropyl butanoate (2d) (1 g) was dissolved in 20 mL of MTBE, saturated with 1% of water, 1.3 g of PLE/MPEG (7.5% , 60 mg/1 g) was added, and the mixture shaken at room temperature for 24 hrs. Hexane was added to the reaction mixture and after filtration through a CELITE® 545 pad, the organic solution was washed with water, aqueous sodium bicarbonate (NaHCO3) and brine, and dried over anhydrous sodium sulfate (Na2SO4). After evaporating the solvent under reduced pressure the title compound (14) was obtained (0.29 g, 58% yield). The absolute configuration was determined by derivatization to a compound having known stereochemistry.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[C:20]([I:22])[C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2].O[Li].O.CO.Cl>O1CCCC1.O>[C:1]([C:4]1[CH:21]=[C:20]([I:22])[C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[C:5]=1[OH:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc(I)c1OCc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(O)c(C(C)=O)cc(I)c1OCc1ccc(C(=O)O)cc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A solution of 245 mg (0.523 mmoles) of methyl 4(-4-acetyl-3-hydroxy-6-iodo-2-propylphenoxy)methylbenzoate in 3 ml of tetrahydrofuran and 0.8 ml of water was treated with 110 mg (2.62 mmoles) of LiOH.H2O and stirred at 22° C. for one hour. The temperature was brought to 55° C. and 3 ml of MeOH was added after 2 hours of reaction. After a total reaction time of 31/2 hours, the mixture was allowed to cool, diluted with water, acidified by addition of concentrated HCl and extracted with dichloromethane. The combined extracts were washed with water, dried over MgSO4 and evaporated to give 217 mg of white powder mp 167°-168.5° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH2:23][C:24]([O:26]CC)=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])[N:17]=2)[CH2:11][C:12]([NH:14][OH:15])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
A solution of ethyl [(5-{(1R)-4-cyclohexyl-1-[2-(hydroxyamino)-2-oxoethyl]butyl)1,2,4-oxadiazol-3-yl)methoxy]acetate (Example 49) (158 mg, 0.40 mmol) in 1,4-dioxan (4 ml) and water (2 ml) was treated with lithium hydroxide monohydrate (2 mg, 0.48 mmol) and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and washed with diethylether (×2). The aqueous layer was acidified to pH 1 with hydrochloric acid (2M) and washed with ethyl acetate (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent was removed under reduced pressure to afford the title compound as a colourless oil (141 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+].Cl>O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][OH:15])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C(=O)C(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=NO)C(C)C)cc1
Reaction time: 4 h

Procedure:
3.2 g of 5A, 7.4 g of hydroxylamine hydrochloride, 40 ml of ethanol and 80 ml of water were mixed. 4.4 g of sodium hydroxide was added to the stirred mixture at room temperature. The mixture was stirred for 4 hours at reflux temperature, cooled, poured into cold dilute hydrochloric acid and extracted with methylene chloride. The extract was dried (MgSO4) and stripped of solvent and the product was chromatographed (silica gel, methylene chloride/ether) to give 1-(4-methylphenyl)-2-methyl-1-propanone oxime (5B), as a liquid, boiling point not determined.
Reaction SMILES: [N:1]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O:12]CC)=[O:11].CO.[Li+:24].[OH-]>C1COCC1>[C:18]([O:17][C:15]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH:2]1[C:10]([O-:12])=[O:11])=[O:16])([CH3:21])([CH3:19])[CH3:20].[Li+:24]
Reactant: CCOC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-tert-butyl 2-ethyl 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (prepared using methods of M Boehringer, et al. U.S. Pat. No. 7,417,144) (200 mg, 684 μmol, Eq: 1.00) in THF (1.2 mL) and MeOH (0.8 mL) was added LiOH (16.4 mg, 684 μmol, Eq: 1.00) in one portion. The reaction mixture was stirred at rt for 72 h. The reaction mixture was concentrated in vacuo and the residue treated with DCM (10 mL) to give lithium 1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate as an off-white solid (200 mg) which was used without further purification.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccc3nsnc3c2)=CC1=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(c2ccc3nsnc3c2)=C(Br)C1=O
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 2.164 mmol) in CHCl3 (15 mL), NBS (0.462 g, 2.590 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 69%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[CH:13]=[N:14][N:15](COCC[Si](C)(C)C)[C:7]=2[CH:6]=1.[I:29]Cl.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10](=[O:11])[N:9]([CH3:12])[C:8]2[C:13]([I:29])=[N:14][NH:15][C:7]=2[CH:6]=1
Reactant: ClI
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2c1cnn2COCC[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1c(=O)c(Oc2ccc(F)cc2F)cc2[nH]nc(I)c21
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.3 %

Procedure:
To a solution of 6-(2,4-difluorophenoxy)-4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1,4-dihydro-pyrazolo[4,3-b]pyridin-5-one (118 mg, 0.289 mmol) in chloroform (25 mL) was added iodine monochloride (141 mg, 3 eq) followed by potassium carbonate (200 mg, 5 eq) and the resulting mixture was heated under reflux with stirring (in the dark) for 24 hours. Additional iodine monochloride (large excess) was added and the resulting solution was stirred under reflux for another 16 hours. The reaction mixture was cooled to room temperature and diluted with dichloromethane, and washed 2× with an aqueous solution of Na2S2O3(aq) followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give the crude product as an oil (97 mg). Purification by Preparative Thin Layer Chromatography eluting with 60% ethyl acetate in hexanes gave the title compound as an off-white powder (12 mg, (M+H)+=462).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.[F:9][C:10]1[C:17]([CH3:18])=[C:16](F)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13].C(=O)([O-])[O-].[Li+].[Li+]>>[F:9][C:10]1[C:17]([CH3:18])=[C:16]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: C[C@@H]1NCC[C@]1(C)O
Reactant: Cc1c(F)ccc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2CC[C@](C)(O)[C@@H]2C)ccc(C#N)c1F

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 2,4-difluoro-3-methylbenzonitrile (321 mg) and lithium carbonate (206 mg), the title compound was obtained as a colorless solid (yield: 194 mg, yield: 56%).