Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([CH3:20])[CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-:21].[K+]>[Cl-].[Na+]>[F:21][CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)c2ccccc2)cc1
Reactant: [F-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: C[C@H](CF)c1ccccc1
Temperature: 62.5 °C
Reaction time: 48 h
Yield: 62.3 %

Procedure:
9.62 g of toluene-4-sulfonic acid (S)-2-phenyl-propyl ester (33.13 mmol) were dissolved in 80 ml of polyethylenglycol 400. 9.62 g of potassium fluoride (165.6 mmol) were added and the reaction mixture was stirred at 50° C. for 3 days and another 2 days at 55-70° C. The reaction was treated with 150 ml of saturated aqueous sodium chloride solution, extracted three times with diethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified via silica gel chromatography using cyclohexyane/ethyl acetate 15% as eluent. 2.85 g of the desired product were isolated, containing ˜25% of the elimination side product.
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CNCCCCCCCCNC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)(C(C)(C)C)(C)C.[NH2:67][CH2:68][C@@H:69]([C:71]1[CH:76]=[CH:75][C:74]([OH:77])=[C:73]([CH2:78][O:79][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])[CH:72]=1)[OH:70].[CH3:87][O:88][C:89]1[CH:90]=[C:91]([NH:95][C:96]2[C:105]3[C:100](=[C:101]([CH3:130])[CH:102]=[C:103]([S:106]([C:109]4[CH:114]=[CH:113][CH:112]=[C:111]([C:115](=[O:129])[NH:116][C:117]5[CH:122]=[CH:121][C:120]([CH2:123][CH2:124][CH2:125][CH2:126][CH:127]=O)=[CH:119][CH:118]=5)[CH:110]=4)(=[O:108])=[O:107])[CH:104]=3)[N:99]=[CH:98][C:97]=2[C:131]([NH2:133])=[O:132])[CH:92]=[CH:93][CH:94]=1>>[Si:80]([O:79][CH2:78][C:73]1[CH:72]=[C:71]([C@@H:69]([OH:70])[CH2:68][NH:67][CH2:127][CH2:126][CH2:125][CH2:124][CH2:123][C:120]2[CH:121]=[CH:122][C:117]([NH:116][C:115]([C:111]3[CH:110]=[C:109]([S:106]([C:103]4[CH:104]=[C:105]5[C:100](=[C:101]([CH3:130])[CH:102]=4)[N:99]=[CH:98][C:97]([C:131]([NH2:133])=[O:132])=[C:96]5[NH:95][C:91]4[CH:92]=[CH:93][CH:94]=[C:89]([O:88][CH3:87])[CH:90]=4)(=[O:107])=[O:108])[CH:114]=[CH:113][CH:112]=3)=[O:129])=[CH:118][CH:119]=2)[CH:76]=[CH:75][C:74]=1[OH:77])([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:81])[CH3:82]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCC=O)cc5)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CN)ccc1O
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCCCCNC[C@H](O)c6ccc(O)c(CO[Si](C)(C)C(C)(C)C)c6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 148, using Intermediate 9 in place of Intermediate 2 and Intermediate 120 in place of Intermediate 112. ES/MS calcd. for C51H62N5O8SSi+ 932.40. Found m/z=932.4 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:23])=[O:2])=[O:22])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
N-tert-butoxycarbonyl L-prolyl L-proline methyl ester 1 (1.10 g, 3.37 mmol) was dissolved in THF (23 mL) and the solution cooled to 0° C. (icebath). LiOH monohydrate (0.156 g, 3.72 mmol) was dissolved in de-ionized H2O (11.5 mL) and the solution cooled to 0° C. before being added dropwise to the solution of 1 over 5 min. The icebath was removed and stirring continued for an additional 3 h 30 min before solid NaHCO3 (0.566 g, 6.74 mmol) was added. Stirring was continued for 20 minutes and the THF evaporated. The solution was diluted with H2O (11.5 mL), washed with Et2O (2×11.5 mL) and acidified to pH 2 by addition of 2M aqueous H2SO4. The resulting solution was extracted with CH2Cl2 (70 mL+4×23 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (0.933 g, 89%) with spectral characteristics in accordance with literature data1; δH(300 MHz; d6-DMSO) 12.41 (1H, br s, COOH), 4.45-4.21 (2H, m, CαH(Pro1)/CαH(Pro2)), 3.73-3.13 (4H, m, CδH2(Pro1)/CδH2(Pro2)), 2.29-1.61 (8H, m, CH2), 1.37/1.30/1.16 (9H, s, (CH3)3, all rotomers); δC (75 MHz; CDCl3) 173.8, 173.5, 173.3, 173.0, 154.6, 153.6, 79.9, 59.6, 59.5, 57.7, 57.6, 47.1, 47.0, 46.9, 46.7, 30.0, 29.2, 28.4, 28.3, 27.7, 27.5, 25.0, 24.2, 23.6; m/z (ESI) 335.1595 ([M+Na]+; C15H24N2O5Na requires 335.1582)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:26]([C:27]#[N:28])[C:25]=1[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: CC1(C)OB(c2c(F)cccc2C#N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cccc(F)c1-c1cc(-c2cnnc(-c3ccc(F)cc3F)n2)ccc1F
Temperature: 80 °C
Yield: 6.3 %

Procedure:
To a degassed mixture of 5-(3-bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine (0.2 g, 0.55 mmol) and 3-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile (0.270 g, 1.1 mmol) in 1,4-dioxane (6 ml) and sodium carbonate (2 ml, 2N solution) was added tetrakis(triphenylphosphine)palladium(0), and the mixture heated at 80° C. Fog 24 h. The mixture was cooled to ambient temperature and partitioned between water (30 ml) and dichloromethane (40 ml). The aqueous layer was extracted with dichloromethane (2×40 ml) and the combined organics dried over Mg2SO4, filtered and the solvent removed at reduced pressure. The crude product was chromatographed on silica gel, eluent 5% ethyl acetate in dichloromethane, to give the product as a pale yellow solid (0.014 g): δH (400 MHz, CDCl3) 6.99-7.10 (2H, m), 7.49 (4H, m), 8.30-8.44 (3H, m), 9.69 (1H, dd, J 0.8, 2.0 Hz); m/z (ES+) 407.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14])(=[O:32])=[O:31]
Reactant: COC(=O)c1ccccc1CSc1ccc(C)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1CSc1ccc(C)cc1NS(=O)(=O)c1cc2ccccc2o1
Yield: 74.3 %

Procedure:
Following General Procedure B, the title compound (688 mg, 75%) was prepared from methyl 2-(((2-amino-4-methylphenyl)thio)methyl)benzoate (567 mg, 1.98 mmol) and benzofuran-2-sulfonyl chloride (854 mg, 3.96 mmol) in pyridine (10 ml).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:28]([C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33])#[CH:29].Cl.ClC1C=C(NC2C3C(=CC(OC4CCNCC4)=C(OC)C=3)N=CN=2)C=CC=1F>>[ClH:1].[C:28]([C:30]1[CH:31]=[C:32]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:34]=[CH:35][CH:36]=1)#[CH:29]
Reactant: C#Cc1cccc(N)c1
Reactant: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: COc1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OC1CCNCC1
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3cc(OC4CCNCC4)c(OC)cc23)c1

Procedure:
tert-butyl 4-[(4-chloro-6-methoxyquinazolin-7-yl)oxy]piperidine-1-carboxylate was coupled with 3-ethynylaniline using an analogous process to that described in Example 22 (preparation of starting materials) for the preparation of N-(3-chloro-4-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride, to give N-(3-ethynylphenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine hydrochloride 1H NMR Spectrum: (DMSO d6) 1.85-2.1 (m, 2H), 2.1-2.3 (m, 2H), 3.0-3.35 (m, 4H), 4.05 (s, 3H), 4.25 (s, 1H), 4.8-4.95 (m, 1H), 7.39 (d, 1H), 7.47 (dd, 1H), 7.6 (s, 1H), 7.8 (d, 1H), 7.89 (s, 1H), 8.5 (s, 1H), 8.83(s, 1H), 9.22 (bs, 2H), 11.68 (s, 1H); Mass Spectrum: (M+H)+ 375.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:8]([CH:9]=[O:10])[C:7]([OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>C1COCC1>[CH2:18]([O:17][C:15]([CH2:14][O:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH:9]=[O:10])=[O:16])[CH3:19]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1C=O
Yield: 79 %

Procedure:
A solution of 5-nitrosalicylaldehyde (Aldrich) (0.167 g, 1.0 mmol), ethyl bromoacetate (0.166 g, 1.0 mmol), K2CO3 (0.276 g, 2.0 mmol) and NaI (0.015 g, 0.1 mmol) in THF (10 mL) is heated to 80° C. for 24 h. The solution is concentrated and the residue is purified by chromatography (silica gel, gradient, 5-20% CH3OH in CH2Cl2) to afford the title compound (0.20 g, 87%).
Reaction SMILES: [F:1][CH:2]([F:23])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:10](=[O:21])[NH:9][C:8]2=[O:22].[CH:24]([O-])=[O:25].[NH4+].O>C(#N)C.O1CCOCC1>[F:23][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:16][CH2:17][N:18]([CH:24]=[O:25])[CH2:19][CH2:20]1)[C:10](=[O:21])[NH:9][C:8]2=[O:22]
Reactant: O=C[O-]
Reactant: O=c1[nH]c(=O)n(C2CCNCC2)c2ccc(OCC(F)F)cc12
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: O=CN1CCC(n2c(=O)[nH]c(=O)c3cc(OCC(F)F)ccc32)CC1
Yield: 67.1 %

Procedure:
A mixture of 6.13 g of 6-(2,2-difluoroethoxy)-1-(piperidin-4-yl)quinazoline-2,4(1H,3H)-dione obtained in stage 3.6 and 3.12 g of ammonium formate in 28 ml of ACN and 28 ml of dioxane is irradiated under a microwave field at 140° C. for 1 h 00. The reaction mixture is run into water. The mixture is filtered and the precipitate is washed with water and then with ether to give 4.47 g of the expected product.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].OS([O-])(=O)=O.[K+].[O-]S([O-])(=O)=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(S(=O)(=O)c3ccc(O)cc3)cc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
t-Butyldimethylchlorosilane (116.55 mg, 0.773 mmol), TEA (0.1336 mL, 0.975 mmol) and DMAP (9 mg, 0.0736 mmol) were added to a solution of (S)-3-[4-(4-hydroxy-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (297 mg, 0.736 mmol) in DCM (5 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 3 hours. and then a solution of 10% KHSO4/Na2SO4 was added. The mixture was extracted with DCM, and the combined organic extracts were washed with NaHCO3 (10% aqueous solution), dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting crude material was purified via flash chromatography (hexane/EtOAc, 783/17) to give 370.6 mg (97% yield) of (S)-3-{4-[4-(tert-butyl-dimethyl-silanyloxy)-benzenesulfonyl]-phenyl}-pyrrolidine-1-carboxylic acid tert-butyl ester as a foam.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][N:3]=1.[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20][NH2:21]>>[CH:14]([S:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH:21][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])=[N:3][CH:4]=1)(=[O:13])=[O:12])([CH3:16])[CH3:15]
Reactant: CN(C)CCN
Reactant: CC(C)S(=O)(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: CC(C)S(=O)(=O)c1cnc(NCCN(C)C)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 2-chloro-5-(isopropylsulfonyl)-3-nitropyridine (Step D of Example 22) and N,N-dimethylethylenediamine.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccccc1
Yield: 96.8 %

Procedure:
To a suspension of 44 g (0.318 mol) of K2CO3 in 300 ml of acetone, 15 g (0.159 mol) of phenol and 18.9 ml (0.191 mol) of 1-bromo-3-chloropropane are added successively at r.t. under N2 atmosphere. The mixture is refluxed for 6 h and concentrated under reduced pressure. The crude mixture is diluted with cold 1 N aqueous NaOH and extracted with AcOEt. The combined extracts are washed with H2O, dried over MgSO4 and concentrated under reduced pressure to give 26.25 g of (3-chloro-propoxy)benzene (yield 83%); NMR (CDCl3): 2.20–2.27 (m, 2H), 3.75 (t, 2H, J=6.04 Hz), 4.11 (t, 2H, J=6.04 Hz), 6.9–6.97 (m, 3H), 7.25–7.31 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([CH:13]([OH:34])[CH2:14][N:15]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:16]([CH3:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:11][C:10]=1[N+:37]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd]>[NH2:37][C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:13]([OH:34])[CH2:14][N:15]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:16]([CH3:26])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1ccc(CC(C)N(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(N)c2)cc1
Temperature: 40 °C

Procedure:
To a solution of 4-benzyloxy-3-nitro-α-[N-benzyl-N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl alcohol (100 gms, 0.19 M) in SPDS (1.0 lit) was added 10% Pd/C. The resulting mass was heated to 40° C. and ammonium formate (36 gms, 0.57 M) was added in lots in 1 hour. The reaction mass was heated slowly to 70° C. for 1 hour, and then cooled to 50° C. The catalyst was removed by filtration and the clear filtrate evaporated. The residue was stirred in water (500 ml) and basified with liq. Ammonia. The reaction mass was extracted in 1.0-lit toluene, washed organic extract with water, dried on sodium sulfate and evaporated to obtain title compound. (78 gms, 83%)
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47]CC5C=CC=CC=5)=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:55]([OH:58])([CH3:57])[CH3:56])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:55]([OH:58])([CH3:57])[CH3:56])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([OH:47])=[CH:45][CH:46]=1
Reactant: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCc5ccccc5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CC(C)(O)[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](O)[C@@H](O)[C@@H]2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.5 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[3-[(4-benzyloxyphenyl)methyl]-4-chloro-phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 25o (100 mg, 0.12 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.07 mL, 0.63 mmol) and 10% Pd/C (20 mg, 0.02 mmol) at room temperature. The mixture was stirred under H2 at room temperature for 4 hours and filtered. The filtrate was concentrated in vacuo to give the title compound 25p as a white solid (54.8 mg, 100%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 481.0[M+HCOO]−.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:15]([O:17][CH3:18])=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>CO>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4]/[C:10](=[CH:9]/[C:15]([O:17][CH3:18])=[O:16])/[C:11]([O:13][CH3:14])=[O:12]
Reactant: Nc1ccccc1F
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)/C=C(/Nc1ccccc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a solution 2-fluoroaniline (P1) (1.00 g, 9.00 mmol) in MeOH (11.1 mL) at 0° C. was added dimethyl acetylenedicarboxylate (P2) (DMAD, 1.34 mL, 10.8 mmol). The reaction was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel flash chromatography (gradient 0-25% EtOAc in Hex) to give dimethyl (2E)-2-[(2-fluorophenyl)amino]but-2-enedioate (P3) (1.9 g, 83%). ES-MS [M+1]+=254.4. The above compound (1.90 g, 7.50 mmol) was dissolved in Eaton's reagent (8.00 mL, 50.4 mmol) and heated at 55° C. for 1 h. The LC-MS showed clean conversion. The reaction mixture was cooled to room temperature and slowly poured into a cold saturated solution of NaHCO3. The light-yellow precipitate formed was collected by filtration, washed with H2O and dried in vacuum to provide methyl 8-fluoro-4-hydroxyquinoline-2-carboxylate (P4) that gave a mass ion of 222.4 for M+H+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=3)[C:12]2=[O:22])[CH:10]=1.O.[NH2:25][NH2:26]>C(O)C>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:22])[N:11]([C:9]1[CH:10]=[C:5]([CH2:4][C:3]([NH:25][NH2:26])=[O:2])[CH:6]=[N:7][CH:8]=1)[CH2:20][CH2:19]2
Reactant: COC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1cncc(N2CCc3cc(Cl)ccc3C2=O)c1
Temperature: 90 °C

Procedure:
[5-(6-Chloro-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-acetic acid methyl ester (100 mg, 0.30 mmol) and hydrazine monohydrate (0.75 mL) were dissolved in ethanol (8.0 mL) and the reaction mixture was heated at 90° C. for 3 h before it was cooled and concentrated in vacuo to give a crude product (100 mg, quant.) as light yellow oil. MS: 331.1 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12](Cl)(=[O:14])=[O:13].O>O1CCOCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:5]=1[S:12]([NH:2][CH3:1])(=[O:14])=[O:13]
Reactant: CN
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1c(Cl)cc(Cl)cc1Cl

Procedure:
40% strength aq. methylamine soln. (36.0 g, 464 mmol) was added dropwise to a soln. of 2,4,6-trichorobenzenesulfonic acid chloride (10.0 g, 35.7 mmol) in 1,4-dioxane (60 ml) and the mixture was stirred at RT for 30 min. Water (500 ml) was then added, with vigorous stirring, whereupon a white precipitate formed, which was filtered out and dried over potassium hydroxide in a desiccator.
Reaction SMILES: [C:1]1([C:7]([OH:12])([CH3:11])[C:8](=[O:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C[O:14][C:15](=[O:23])[C:16](OC)(OC)OC.[H-].[Na+]>C1COCC1>[C:1]1([C:7]2([CH3:11])[O:12][C:16]([C:15]([OH:23])=[O:14])=[CH:9][C:8]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(=O)C(C)(O)C1=CCCCC1
Reactant: COC(=O)C(OC)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C2=CCCCC2)OC(C(=O)O)=CC1=O
Temperature: 65 °C

Procedure:
To an oven-dried 10 mL vial was added 3-cyclohex-1-enyl-3-hydroxy-butan-2-one (0.80 g, 4.80 mmol), THF (4 mL) and trimethoxy-acetic acid methyl ester (0.94 g, 5.76 mmol). The vial was capped with a septum and flushed with Ar. In a dried round-bottom flask with stirring bar was added sodium hydride (60% dispersion in mineral oil, 0.57 g, 14.4 mmol) and THF (20 mL). The flask was capped with a septum and flushed with Ar. The contents of the vial were added dropwise via syringe to the round-bottom flask. The round-bottom flask was equipped with a condenser and septum and heated to 65° C. under Ar for 12 h. The reaction was quenched with sat'd NH4Cl (20 mL) and the layers were separated. The organic extract was concentrated and dissolved in 1,4-dioxane (4 mL). The solution was mixed with conc. HCl (0.5 mL) and stirred overnight at rt. Saturated NaHCO3 solution (20 mL) was added and the reaction was extracted with EtOAc (3×50 mL). The extracts were dried (Na2SO4), filtered and concentrated. The crude product was purified with a Biotage 25+M silica gel column using a gradient of 0-10% EtOAc in hexanes providing 0.37 g (32%) of racemic 5-cyclohex-1-enyl-5-methyl-4-oxo-4,5-dihydro-furan-2-carboxylic acid methyl ester: LC-MS) m/z 235 (M−1); 1H NMR (400 MHz, CDCl3) 6.20 (s, 1H), 5.90-5.88 (m, 1H), 3.96 (s, 3H), 2.14-2.04 (m, 3H), 1.87-1.78 (m, 1H), 1.63-1.52 (m, 4H), 1.54 (s, 3H).