Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:3][CH2:4][OH:5])[NH2:2].Cl[C:7]([O:9][CH3:10])=[O:8].[CH2:11]=O>>[CH3:10][O:9][C:7]([N:1]1[CH2:3][CH2:4][O:5][CH2:11][NH:2]1)=[O:8]
Reactant: COC(=O)Cl
Reactant: C=O
Reactant: NNCCO
Product: COC(=O)N1CCOCN1

Procedure:
The reaction described in the scheme below is an example for the preparation of the compound I where, starting from 2-hydrazinoethanol and methyl chloroformate as acid derivative, firstly N-amino-N-methoxycarbonyl-2-hydrazinoethanol is prepared, which is cyclized in a subsequent reaction with formaldehyde to give tetrahydro-4-methoxycarbonyl-4H-1-oxa-3,4-diazine.
Reaction SMILES: NCCC[Si:5](OCC)(OCC)OCC.[CH:15]1[C:20](N=C=S)=[CH:19][C:18]2[C:24]([O:26][C:27]3([C:37]4[CH:38]=[CH:39][C:40]([OH:42])=[CH:41][C:36]=4[O:35][C:29]4[CH:30]=[C:31]([OH:34])[CH:32]=[CH:33][C:28]3=4)[C:17]=2[CH:16]=1)=[O:25]>C(C(O)C)C>[CH:15]1[CH:20]=[CH:19][C:18]([C:24]([OH:26])=[O:25])=[C:17]([C:27]2[C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:29]=3[O:35][C:36]3[C:37]=2[CH:38]=[CH:39][C:40]([CH:41]=3)=[O:42])[CH:16]=1.[SiH4:5]
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Reactant: CCO[Si](CCCN)(OCC)OCC
Solvent: CCC(C)O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Product: [SiH4]

Procedure:
50 μl APS (γ-amino propyltriethoxyl silane) and 1 ml FITC (fluorescein isothiocyanate, 1 mg/ml ethanol solution) are added into a 4 ml absolute ethyl ethanol under obturation condition to react for 12 hours, so as to obtain a precursor solution upon coupling of fluoresceine and silane coupling agent. The method for preparing the precursor solution is common knowledge in prior art. 3.65 ml ethanol/water mixture (ratio of ethanol to water is 8), 1.2 ml ethanol and 100
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[H-].[Na+].C([O-])([O-])=[O:16].[Cs+].[Cs+].Br[C:22]([CH3:27])([CH3:26])[C:23]([NH2:25])=[O:24]>O1CCOCC1.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[OH:16][C:22]([CH3:27])([CH3:26])[C:23]([NH:25][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2)=[O:24]
Reactant: CC(C)(Br)C(N)=O
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1ccc2cccc(NC(=O)C(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 8-hydroxyquinaldine (722 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil, the rearrangement product, was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain the product as an off-white solid (610 mg, 2.50 mmol, 67.6% yield).: mp 143-144° C.: 1H NMR (300 MHz, CDCl3) δ10.99 (br s, 1 H, N--H), 8.76-8.73 (m, 1 H), 8.03 (d, 1 H, J=8.26), 7.48-7.45 (om's, 2 H), 7.32 (d, 1 H, J=9.21), 2.80 (br s, 1 H, O--H), 2.75 (s, 3 H, Ar--CH3), 1.62 (s, 6 H, C(CH3)2); 13C NMR (75 MHz, CDCl3) δ174.9, 157.4, 138.2, 136.3, 133.5, 126.2, 126.1, 122.4, 121.6, 116.3, 74.2, 28.1, 25.4; MS (CI/NH3) 245; Analysis: Calculated C 68.83, H 6.60, N 11.47; Found C 68.78, H 6.56, N 11.37.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:14])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C1C=CC=CN=1)C>[F:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][N:5]([CH2:4][CH:3]([OH:14])[CH2:2][Cl:1])[C:22](=[O:26])[O:23][CH2:24][CH3:25])=[CH:12][CH:11]=1
Reactant: CCOC(=O)Cl
Reactant: OC(CCl)CNCc1ccc(F)cc1
Agent: CN(C)c1ccccn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(Cc1ccc(F)cc1)CC(O)CCl
Reaction time: 1 h
Yield: 126 %

Procedure:
To a solution of 3-chloro-1-(p-fluorobenzylamino)-2-propanol (20.78 g, 66.50 mmol) in methylene chloride (150 ml) were added in turn triethylamine (10.2 ml, 73.2 mmol), dimethylaminopyridine (812 mg, 6.65 mmol), ethyl chlorocarbonate (5.7 ml, 73 mmol) under ice-cooling and the mixture was stirred for one hour, allowed to rise to room temperature and then stirred for further 19 hours. The reaction mixture was diluted with chloroform (100 ml), washed successively with 10% aqueous hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give crude ethyl N-(p-fluorobenzyl)-N-(3-chloro-2-hydroxypropyl)carbamate (24.28 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH3:17])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:4][CH:3]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[N:36]1([CH2:42][C:43]2[CH:44]=[C:45]([CH:51]=[CH:52][CH:53]=2)[O:46][CH2:47][CH2:48][CH2:49][NH2:50])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(OCC)(=O)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:24]([NH:50][CH2:49][CH2:48][CH2:47][O:46][C:45]2[CH:51]=[CH:52][CH:53]=[C:43]([CH2:42][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:44]=2)=[O:25])[CH3:17])=[CH:6][CH:7]=1
Reactant: CN(CCCCN)CCC(c1ccc(F)cc1)c1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(CCCCNC(=O)NCCCOc1cccc(CN2CCCCC2)c1)CCC(c1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.7 g (2.2 mmol) of N-[3-(4-fluorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,4-butanediamine, an equimolar amount of 1,1'-carbonyldiimidazole and 0.6 g (2.4 mmol) of 3-[3-(piperidinomethyl)phenoxy]propaneamine as starting materials. Working up by chromatography (eluant: ethyl acetate/methanol 95+5) analogously to Example 63 yields the purified title compound in the form of an oil; MS (+FAB method): m/z (rel. int.[%])=590 ([M+H]+ 17), 214 (100); IR (KBr): 1631 cm-1 (C=O).
Reaction SMILES: CC1N=C(C#CC(C2CCNCC2)O)C=CC=1.[F:18][C:19]1[CH:20]=[C:21]([C:26]#[C:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:22]=[C:23]([F:25])[CH:24]=1.Cl[C:36]1[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([CH3:45])[N:37]=1>>[F:18][C:19]1[CH:20]=[C:21]([C:26]#[C:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:36]3[C:41]([N+:42]([O-:44])=[O:43])=[CH:40][CH:39]=[C:38]([CH3:45])[N:37]=3)[CH2:33][CH2:34]2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Fc1cc(F)cc(C#CCC2CCNCC2)c1
Agent: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(CC#Cc3cc(F)cc(F)c3)CC2)n1

Procedure:
The title compound was prepared following the procedure described for the compound of Example 237, but using Compound 248a instead of Compound 237a and 2-chloro-3-nitro-6-picoline instead of 2-bromo-3-nitropyridine. The crude was purified by automated flash liquid chromatography (Horizon™-Biotage) eluting with Petroleum Ether-EtOAc 9:1, affording the title product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[N:13]=[CH:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]([CH3:18])[N:11]=[CH:12][N:13]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CSc2nc[nH]n2)cc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(CSc2ncnn2C)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-p-methoxybenzylthio-1,2,4-triazole (10.0 g : 45.2 mMol.) in methanol (100 ml) is added under ice cooling a solution of diazomethane in ether (prepared from 15 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour. The reaction mixture is concentrated and purified by Lobar column chromatography (toluene : ethyl acetate=1:2 to 1:3) to give 3-p-methoxybenzylthio-2-methyl- 1,2,4-triazole [5.17 g : NMR δ(CDCl3) ppmi 3.63(s, 3H), 3.79(s, 3H), 4.34(s, 2H), 6.80-6.84, 7.19-7.24(A2B2, 4H), 7.88(s, 1H). IR ν(CHCl3) cm-1 : 1611, 1511, 1476, 1464, 1440, 1360, 1302 Yield: 49%]and 3-p- methoxybenzylthio-1-methyl-1,2,4-triazole [3.60 g : NMR δ(CDCl3) ppmi 3.78(s, 3H), 3.87(s, 3H), 4.31(s, 2H), 6.80-6.85, 7.30- 7.34(A2B2, 4H), 7.99(s, 1H). IR ν(CHCl ) cm-1 : 1612, 1512, 1465, 1440, 1421, 1356, 1302. Yield : 34%].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([C:14](=O)[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][O:20][CH:21]([S:29][CH3:30])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11](/[C:14](=[N:19]/[O:20][CH:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:29][CH3:30])/[C:15]([OH:17])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSC(ON)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)ns1
Solvent: CO
Product: CSC(O/N=C(\C(=O)O)c1nsc(NC(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Yield: 49.2 %

Procedure:
2-(5-Tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-oxoacetic acid (3.0 g) was dissolved in methanol (30 ml). To this solution a solution of tert-butyl 2-aminooxy-2-(methylthio)acetate (2.12 g) in methanol (20 ml) was added dropwise. The resultant mixture was stirred for 1 hr. at the room temperature, and then the solvent was evaporated to give (Z)-2-(5-tert-butyloxycarbonylamino-1,2,4-thiadiazol-3-yl)-2-[[(tert-butoxycarbonyl)(methylthio)methoxy]imino]acetic acid (2.42 g).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:45]=[C:44]2[C:40]([C:41]([CH3:53])([CH3:52])[C:42](=[O:51])[N:43]2[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:45]=[C:44]3[C:40]([C:41]([CH3:53])([CH3:52])[C:42](=[O:51])[N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)C(C)(C)c2ccc(CBr)cc21
Product: COCCCN1C(=O)C(C)(C)c2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.853 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.504 g of 6-bromomethyl-1-(3-methoxypropyl)-3,3-dimethyl-1,3-dihydroindol-2-one are reacted. The title compound Is obtained as a slightly yellowish oil. Rf=0.14 (1:1 EtOAc-heptane); Rt=6.13.
Reaction SMILES: [BH3-][C:2]#[N:3].[Na+].N[C@H:6]([C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])=[N:23][CH:24]=[N:25]3)=[CH:20][C:19]=2[O:37][CH3:38])[CH2:13][CH2:12]1)=[O:10])[CH2:7][OH:8].O.O.O.[C:42]([O-])(=O)C.[Na+].C=O.C(O)(=O)C>>[Cl:35][C:31]1[C:30]([F:36])=[C:29]([CH:34]=[CH:33][CH:32]=1)[NH:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([O:17][CH:14]3[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C@@H:6]([N:3]([CH3:2])[CH3:42])[CH2:7][OH:8])[CH2:12][CH2:13]3)=[C:19]([O:37][CH3:38])[CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: CC(=O)[O-]
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)[C@@H](N)CO)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)[C@H](CO)N(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Solid NaCNBH3 (38.3 mg, 0.614 mmol) was added to a stirred solution of (2S)-2-amino-3-[4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidin-1-yl]-3-oxopropan-1-ol (150 mg, 0.307 mmol, Example 15), sodium acetate trihydrate (251 mg, 3.07 mmol), formaldehyde 37% (aq) (2.5 ml) and acetic acid (184 mg, 3.07 mmol) at 0-5° C. The resulting solution was allowed to warm to room temperature and stir for 1 hour. The mixture was then evaporated and the resulting yellow residue was purified by flash chromatography on silica gel eluting with increasingly polar mixtures of dichloromethane/7N ammonia in methanol (100/0-85/15). Fractions containing the desired product were combined and evaporated to give the title compound as a white solid (26%); 1H NMR Spectrum: 1.52-1.69 (m, 2H), 1.94-2.07 (m, 2H), 2.28-2.30 (2 x s, 6H), 3.15-3.22 (m, 2H), 3.53-3.76 (m, 4H), 3.94 (s, 3H), 4.02 (m, 1H), 4.49 (m, 1H), 4.92-4.94 (m, 1H), 7.27(dd, 1H), 7.34 (s, 1H), 7.47 (dd, 1H), 7.51 (dd, 1H), 7.81 (s, 1H), 8.38 (s, 1H), 9.65 (s, 1H); Mass Spectrum: (M+H)+ 518.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:24]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:13][CH:14]([O:24][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1)=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:15][CH3:16]
Reactant: O
Reactant: O=C(Cl)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCC(C)OC(=O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h

Procedure:
Next, S(+)-2-octanol (50 g, 0.38 mol) was dissolved in dry pyridine (150 ml), and to the solution was dropwise added under cooling, a solution of 4'-benzyloxybiphenyl-4-carboxylic chloride (112 g, 0.35 mol) dissolved in dry toluene (150 ml), followed by agitating the mixture at about 50°-60° C. for 2 hours, thereafter adding water (300 ml) and toluene (300 ml), agitating the mixture, washing the separated toluene layer with 6N-HCl, then with 2N-NaOH aqueous solution and further with water until the washing water became neutral, drying the toluene layer with anhydrous sodium sulfate and distilling off toluene to obtain 4'-benzyloxybiphenyl-4-carboxylic acid 1-methylheptyl ester (53 g), dissolving this ester (53 g, 0.13 mol) in ethanol (500 ml) and reducing it in the presence of palladium/carbon (Pd/C) 5 g) to obtain 4'-hydroxy-4-(1-methyl-heptyloxycarbonyl)biphenyl (34 g). (ii) Preparation of 4-octyloxycarbonyloxybenzoic chloride
Reaction SMILES: C(OC(=O)[C@H](O)[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)N)C.[OH-].[Li+].[ClH:18].[CH2:19]([OH:21])C.O>>[CH2:19]([Cl:18])[O:21][CH2:6][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cl
Reactant: CCOC(=O)[C@H](O)[C@@H](N)c1ccccc1
Reactant: CCO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: ClCOCc1ccccc1
Reaction time: 3 h

Procedure:
In either instance, the resulting protected (2R,3S)-3-phenylisoserine ethyl ester compound of formula 8 may simply be converted to the N--CBZ protected C-2' O-BOM-protected (2R,3S) phenylisoserine intermediate hydroxyl by the reaction: ##STR15## Here, the protected (2R,3S)-3-phenylisoserine ethyl ester is dissolved in ethanol/water (ratio 8:1). Lithium hydroxide (or other suitable alkali hydroxide) is added to the solution and the resulting mixture stirred for approximately three hours in order to saponify the compound. The mixture is then acidified (1N HCl) and extracted with ethyl acetate. The resulting organic layer is separated, dried and reduced under vacuum. The residue acid is then isolated for use without further purification. This produces the desired side chain having the general formula: ##STR16## Benzyl itself is another example of a hydrogenatable benzyl protecting group that may be used instead of BOM. The compound of the formula: ##STR17## was therefore produced as above with the substitution of benzyl bromide for BOM-Cl in Reaction V according to the reaction ##STR18## Here, the CBZ protected (2R,3S)-3-phenylisoserine ethyl ester is dissolved in anhydrous THF under a nitrogen atmosphere and cooled to a reduced temperature such as -40° C. or -78° C., for example, in a dry ice/acetone bath followed by the dropwise addition of an alkylithium agent, such as n-butyl lithium, although it is desirable that the alkylithium agent be a straight chain alkyl. The resulting mixture was stirred for about ten minutes. Benzyl bromide (BnBr) was then added dropwise over an interval of about five minutes and the mixture stirred for approximately two to five hours at the reduced temperature. Thereafter, the solution was warmed to -0° C. and quenched with water. The resulting mixture is reduced under vacuum to residue, and this residue is thereafter taken up in ethyl acetate and washed with water and brine. The organic layer may then be dried and reduced under vacuum and the residue recrystallized from ethyl acetate:hexane or chromatographed with ethyl acetate:hexane to give the compound of Formula 10.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:11]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])C(OC(C)(C)C)=O)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[O:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:39]1[CH:43]=[CH:42][C:41]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[S:28]([CH3:31])(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:9]=3)[NH:4][N:3]=2)=[CH:40]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N(c1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccoc3)c2c1
Yield: 35.7 %

Procedure:
N-(3-Furan-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 47 from of 2 g of tert-butyl 3-iodo-5-(N-tert-butoxycarbonyl-2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 660 mg of 3-furanboronic acid, 80 ml of dimethylformamide, 6.4 ml of a saturated aqueous sodium hydrogencarbonate solution and 85.4 mg of tetrakis(triphenylphosphine)palladium[0]. 440 mg of N-(3-furan-3-yl-1H-indazol-5-yl)-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of a white solid melting at 249° C. (analysis —C18H15N3O5S2 % calculated C, 51.79; H, 3.62; N, 10.07; O, 19.16; S, 15.36. % found C, 51.63; H, 3.55; N, 10.00; S, 15.13).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])[N:6]=1)#[N:24]
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)NCCCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 51.6 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.31 mmol) and 5-amino-pentanoic acid (110 mg, 0.94 mmol) (Aldrich) in 0.5 M NaOMe/MeOH (1.25 mL, 0.63 mmol) was microwaved at 120° C. for 1 h. Reaction mixture was diluted with water (60 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. The crude product was triturated with MeOH (2 mL). Solid was collected and dried in vacuo to provide the title compound 65 mg (0.16 mmol) in 52% yield. LC-MS ESI−: 404.03 (M−1)−.
Reaction SMILES: [OH:1][CH:2]([C:5]1([CH2:19][OH:20])[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6]1)[CH2:3]O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.O>ClCCl.C([Sn](=O)CCCC)CCC>[OH:1][CH:2]1[C:5]2([CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:8]2)[CH2:19][O:20][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC(CO)(C(O)CO)C1
Agent: CCCC[Sn](=O)CCCC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CC2(COCC2O)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
Benzyl 3-(1,2-dihydroxyethyl)-3-(hydroxymethyl)azetidine-1-carboxylate (from step (iii); 956 mg, 3.4 mmol) was dissolved in dichloromethane (150 mL) and dibutyltin oxide (17 mg) was added. p-Toluenesulfonyl chloride (686 mg, 3.6 mmol) was added and the solution was cooled to 0° C. Triethylamine (520 μL, 3.75 mmol) was added dropwise and the solution was then allowed to stir at ambient temperature for 16 hrs. Further triethylamine (260 μL, 1.9 mmol) was added and after stirring for 2 hrs, water (250 mL) was added. The mixture was extracted with dichloromethane (2×250 mL), and the extracts dried (MgSO4) then concentrated. The residue was purified by silica chromatography to give the title compound as an oil (456 mg, 1.7 mmol, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Cl)cnc21
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.40 g of 5-{4-(6-chloro-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 65) and 20 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 0.75 g of the title compound, melting at 203°-205° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1.F[C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:24]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][CH2:33][CH2:34][C:35]5[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=5)[C:25]=4[C:26]#[N:27])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)cn2C1CCOC1
Reactant: N#Cc1c(F)cccc1NCCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(NCCc2ccncc2)cccc1Oc1ccc(-c2cn(C3CCOC3)c3ncnc(N)c23)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-[4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-phenol (0.517 g), 2-fluoro-6-(2-(4-pyridinyl)ethylamino)benzonitrile (0.42 g), potassium carbonate (0.48 g) and dimethylformamide (20 ml) were heated at 120° C. under nitrogen for 8 hours. The mixture was allowed to cool, diluted with water then extracted with ethyl acetate to give a solid which was recrystallised from ethyl acetate to give solid which was purified by flash column chromatography on silica using ethyl acetate and then ethyl acetate/methanol (9:1, 8:1, 4:1) to give 2-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]-6-(2-(4-pyridyl)ethylamino)-benzonitrile, m.p 212-213° C.