Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.N1C=CC=CC=1.[C:22]([C:25]1[S:29][C:28]2[C:30]3[C:35]([CH2:36][CH2:37][C:27]=2[CH:26]=1)=[CH:34][C:33](O)=[CH:32][CH:31]=3)(=[O:24])[CH3:23].O>C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C>[C:22]([C:25]1[S:29][C:28]2[C:30]3[C:35]([CH2:36][CH2:37][C:27]=2[CH:26]=1)=[CH:34][C:33]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])=[CH:32][CH:31]=3)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cc2c(s1)-c1ccc(O)cc1CC2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)c1cc2c(s1)-c1ccc(OS(=O)(=O)C(F)(F)F)cc1CC2
Reaction time: 2 h

Procedure:
5 mL of trifluoromethanesulfonic anhydride was added under ice cooling to a 50 mL pyridine solution of 5 g of the compound obtained in Example 39, and the system was stirred for 2 hours at the same temperature. After the reaction, water was added at the same temperature, and extraction was performed with ethyl acetate. The extracted organic layer was washed with saturated brine, dried with magnesium sulfate, and then subjected to reduced-pressure solvent distillation. The residue thus obtained was refined by silica gel column chromatography (25% ethyl acetate/hexane) to obtain 6.24 g of 2-acetyl-4,5-dihydro-7-(trifluoromethanesulfonyloxy)naphtho[1,2-b]thiophene in the form of a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([N:14]=[N+]=[N-])=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH3:13])=[CH:8][CH:7]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[NH:14][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)=[O:17]
Reactant: COC(=O)C(=Cc1ccc(SC)cc1)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: COC(=O)c1cc2ccc(SC)cc2[nH]1
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of methyl-2-azido-3-(4-methylthiophenyl)-propenoate (20.6 g, 83 mmol) in xylene (200 ml) was added dropwise to boiling xylene (250 ml) over a period of 2 hours. The reaction mixture was allowed to heat at reflux temperature for an additional 2 hours, then cooled slowly and placed in a freezer overnight. The solids were filtered, washed with a small amount of CH2Cl2/hexane (1:3) and dried to give 11.2 g (61.0%) of methyl-6-methylsulfanyl-1H-indole-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[H-].[Na+]>>[CH2:2]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH3:1])=[CH:3][C:4]1=[O:12])[C:11]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Cc1cc(=O)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(=O)n(Cc2ccccc2)c2ccccc12
Reaction time: 1 h

Procedure:
4-Methylquinol-2-one (24.0g.) was added in portions to a stirred suspension of sodium hydride [6.5g.; weighed as a 60% w/w dispersion in oil, but subsequently washed by decantation with petroleum ether (b.p. 40°-60° C.)] in dimethylformamide (150ml.), at 20°-25° C. After the addition was complete the mixture was stirred at 20°-25° C. for a further 1 hour. Benzyl chloride (23.0g.) was then added and the subsequent mixture was heated at 95°-100° C. for 20 hours. The mixture, which contained some solid, was then added to water (1 liter) and the resultant mixture was stirred for 1 hour. The solid which formed was separated by filtration, washed with water, and then was resuspended in a mixture of water (300ml.) and 2N hydrochloric acid (50ml.). This mixture was stirred for 15 minutes and then the solid separated by filtration to give 1-benzyl-4-methylquinol-2-one, as a white crystalline solid, 20.0g., m.p. 109°-111° C. after recrystallisation from cyclohexane.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[F:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[F:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:22][CH2:21]1
Reactant: FC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(F)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-Fluoropyperidine (Flrochem) (95.7 mg; 0.92 mmol; 1.40 eq.) and triethylamine (0.37 ml; 2.65 mmol; 4 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (48) as a white-off powder (36 mg; 13%). 1H NMR (DMSO-d6, 300 MHz) δ 1.71-2.12 (m, 4H), 2.16 (s, 3H), 2.50 (s, 3H), 3.75 (m, 2H), 4.33 (m, 2H), 4.97 (ttd, J=3, 6, 51 Hz, 1H, —CFH), 8.02 (s, 1H), 12.19 (s, 1H). M− (ESI): 367.13; M+ (ESI): 369.12. HPLC (method A), Rt: 3.04 min (purity: 95.8%).
Reaction SMILES: I[CH:2]([O:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:3].[NH2:11][C:12]1[S:13][CH:14]=[C:15](/[C:17](=[N:38]/[O:39][CH3:40])/[C:18]([NH:20][C@@H:21]2[C:36](=[O:37])[N:23]3[C:24]([C:33]([O-:35])=[O:34])=[C:25]([C@@H:28]4[CH2:32][CH2:31][CH2:30][O:29]4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:11][C:12]1[S:13][CH:14]=[C:15](/[C:17](=[N:38]/[O:39][CH3:40])/[C:18]([NH:20][C@@H:21]2[C:36](=[O:37])[N:23]3[C:24]([C:33]([O:35][CH:2]([O:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])[CH3:3])=[O:34])=[C:25]([C@@H:28]4[CH2:32][CH2:31][CH2:30][O:29]4)[CH2:26][S:27][C@H:22]23)=[O:19])[N:16]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)OC(=O)OC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)OC(=O)OC(C)C)=C([C@@H]3CCCO3)CS[C@H]12)c1csc(N)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 19.9 %

Procedure:
A solution of (RS)-1-iodo-1-(propan-2-yl)oxycarbonyloxyethane (516mg) in 1-methyl-2-pyrrolidinone (2ml) was added dropwise over 45 mins to an ice-cold mixture of sodium (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-[(S) -tetrahydrofuran-2-yl]ceph-3-em-4-carboxylate (237mg) and finely powdered potassium carbonate (276mg) in 1-methyl-2-pyrrolidinone (5ml). The mixture was stirred for an additional 15 mins, diluted with ethyl acetate, washed with water, brine, dried (magnesium sulphate), concentrated and flash chromatographed on silica gel eluting with 50, 60, 70, 80% ethyl acetate in hexane to give the title compound as a foam (58mg); vmax (CHCl3) 2960, 1787, 1760, 1682, 1633, 1519 and 1377cm-1 ; δ(CDCl3, 250MHz) 1.20-2.50 (13H, m), 3.35-3.80 (2H, m), 3.80-4.20 (2H, m), 4.22 (3H, s), 4.83-5.10 (2H, m), 5.85-6.00 (1H, m), 6.85-7.08 (1H, m), 7.27 (1H, s) and 7.76 (1H, br, m). [Mass spectrum: +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (606)].
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=1)=[S:7])[CH2:2][CH2:3][CH3:4].Cl[CH2:18][C:19](OCC)=[O:20].N1C=CC=CC=1>CCO>[CH2:1]([N:5]1[C:19](=[O:20])[CH2:18][S:7][C:6]1=[N:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:15]#[N:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)CCl
Reactant: CCCCNC(=S)Nc1cccc(C#N)c1
Solvent: CCO
Solvent: c1ccncc1
Product: CCCCN1C(=O)CSC1=Nc1cccc(C#N)c1
Yield: 67.9 %

Procedure:
To a 100 mL flask was added anhydrous EtOH (25 mL), 1-butyl-3-(3-cyanophenyl)thiourea (0.99 g, 4.2 mmol), ethyl chloroacetate (0.51 mL, 5.0 mmol), and anhydrous pyridine (0.5 mL, 5 mmol). After heating under reflux 16 h, the product mixture was concentrated under reduced pressure and chromatographed (silica gel, 2:98 MeOH/DCM) to afford the title product (0.78 g, 67%) as a colorless oil. 1H-NMR (CDCl3): δ 7.40–7.47 (2H, m), 7.25 (1H, m), 7.19 (1H, m), 3.84 (2H, t), 3.84 (2H, s), 1.69 (2H, m), 1.39 (2H, m), 0.97 (3H, t); MS(ESI): 274 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[OH:15])[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:37])([F:36])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH2:30][CH2:29][CH2:28][C:27]#[C:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:18]([F:17])([F:36])[F:37])=[CH:21][CH:22]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2cccc(OCCCC#Cc3ccc(OC(F)(F)F)cc3)c21
Yield: 16 %

Procedure:
A suspension of (7-hydroxy-indol-1-yl)-acetic acid ethyl ester (50 mg, 0.23 mmol), methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (74 mg, 0.23 mmol; example 9 a]), cesium carbonate (82 mg, 0.25 mmol) and a trace of potassium iodide in acetonitrile (2.5 ml) was stirred for 14 h at ambient temperature and for 4 h at 50° C. The reaction mixture was poured onto 1 N HCl/ice water 1/1 and extracted two times with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica gel, heptane/AcOEt) to give 16 mg (0.04 mmol, 16%) of the title compound as colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][C@@H:43]2[O:45][CH2:44]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][C@H:43]1[CH2:44][O:45]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (300 mg, 0.93 mmol), (prepared as described in Example 49), potassium carbonate (385 mg, 2.79 mmol) and (2R)-(−)-glycidyl tosylate (426 mg, 2.79 mmol) in DMF (15 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate exaporated in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate solution. The organic layer was then dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow solid. This was triturated with ether, filtered off and dried to give (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline as a yellow solid (185 mg, 53%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:14]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[C@@H:13]([CH3:20])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[NH:27][C:28]([C:30]2[C:39]([NH:40]C(=O)OCC3C=CC=CC=3)=[CH:38][C:37]3[C:32](=[CH:33][C:34]([N:51]4[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]4)=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>CO.C1COCC1.[Pd]>[NH2:40][C:39]1[C:30]([C:28]([NH:27][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][C:21]=2[N:11]2[CH2:12][C@H:13]([CH3:20])[C@H:14]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[C@H:9]([NH2:8])[CH2:10]2)=[O:29])=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[C:34]([N:51]1[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]1)[CH:33]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1n1ccnn1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCN(C)CC4)ccc3cc2N)C[C@@H](N)[C@H]1n1ccnn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To a solution of benzyl [2-[({4-[(3R,4S,5S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-4-(1H-1,2,3-triazol-1-yl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(4-methylpiperazin-1-yl)quinolin-3-yl]carbamate (8.0 mg, 0.01 mmol) in MeOH (0.4 mL) and THF (0.4 mL), 10% Pd on carbon (4 mg) was added. The reaction mixture was deoxygenated under reduced pressure and hydrogen was introduced via a balloon. The reaction mixture was stirred at room temperature under hydrogen for 1 h. The mixture was filtered and concentrated under reduced pressure to give an intermediate. The intermediate was treated with 4.0 M HCl in dioxane (0.1 mL, 0.4 mmol) with stirring at room temperature for 30 min., then concentrated under reduced pressure. The residue was diluted with MeOH and NH4OH, filtered and purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the title compound as a yellow powder (3.0 mg, 54%). LCMS calc. for C28H36N11O (M+H)+: m/z=542.3. Found: 542.3.
Reaction SMILES: [CH:1]1([N:6]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1>CC(O)=O.[Zn]>[CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1c2ccc(O)cc2C(=O)N1C1CCCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1c2ccc(O)cc2CN1C1CCCC1
Yield: 43.5 %

Procedure:
To a solution of 2-cyclopentyl-5-hydroxyisoindoline-1,3-dione (4.1 g, 18.0 mmol), in CH3CO2H (129 mL), Zn dust (11.6 g, 180 mmol) was added and the mixture heated at reflux for 5 min. The volatiles were removed in vacuo and the residue was dissolved in water and extracted with ethyl acetate. The crude residue was purified using automated prep-HPLC to yield the desired compound (1.7 g, 44%) as a white solid. 1HNMR (400 MHz, DMSO-d6): 10.10 (bs, 1H), 7.44 (d, J=8.5 Hz, 1H), 6.89 (s, 1H), 6.83 (d, J=7.9 Hz, 1H), 4.52-4.48 (m, 1H), 4.31 (s, 2H), 1.83-1.57 (m, 8H). LCMS calcd for C13H15NO2 [M+H]+ 218 found: 218.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][CH:23]=2)([OH:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:37][C:38]([F:49])([F:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>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>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:21])([C:22]2[CH:27]=[CH:26][C:25]([C:42]3[CH:43]=[CH:44][C:39]([C:38]([F:49])([F:48])[F:37])=[CH:40][CH:41]=3)=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1
Reactant: CCCCCCC(O)(c1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: [K+]
Product: CCCCCCC(O)(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 54.9 %

Procedure:
3-{4-[1-(4-Bromo-phenyl)-1-hydroxy-heptyl]-benzoylamino}-propionic acid methyl ester (350 mg, 0.74 mmol), potassium carbonate (304 mg, 2.2 mmol), 4-trifluoromethylphenyl boronic acid (279 mg, 1.5 mmol) and tetrakis(triphenylphosphine)palladium (86 mg, 0.074 mmol) are place in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 mL/5 mL) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[1-Hydroxy-1-(4′-trifluoromethyl-biphenyl-4-yl)-heptyl]-benzoylamino}-propionic acid methyl ester (220 mg) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])=[CH:6][C:5]=1[O:16][CH2:17][CH2:18][CH3:19])[CH3:2].[OH-].[K+].O>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[O:16][CH2:17][CH2:18][CH3:19])[CH3:2]
Reactant: CCCOc1cc(/C=C/C(=O)OC)ccc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCOc1cc(/C=C/C(=O)O)ccc1OCC
Temperature: 70 °C

Procedure:
1.0 g (3.78 mmol) of methyl 3(E)-[4-ethoxy-3-propoxyphenyl]acrylate are suspended in 50 ml of a 10% solution of potassium hydroxide in methanol. 2 ml of water are then added and the mixture is heated to 70° C. for 3 hours and then cooled. Thereafter, the reaction mixture is partitioned between diethyl ether and water, the organic phase is washed several times with saturated sodium chloride solution and the combined aqueous phases are adjusted to pH 4 with a 25% hydrochloric acid solution and extracted several times with methylene chloride. The methylene chloride phases are then combined, dried over magnesium sulfate, filtered and evaporated down. This gives 3(E)-[4-ethoxy-3-propoxyphenyl]acrylic acid.
Reaction SMILES: C([C:3]1[C:4](=[O:17])[N:5]([CH3:16])[C:6](=[O:15])[N:7]([CH3:14])[C:8]=1[CH:9]=[CH:10][N:11](C)[CH3:12])=O.N>C(O)C>[CH3:14][N:7]1[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:3]=2[C:4](=[O:17])[N:5]([CH3:16])[C:6]1=[O:15]
Reactant: CN(C)C=Cc1c(C=O)c(=O)n(C)c(=O)n1C
Agent: N
Solvent: CCO
Product: Cn1c(=O)c2cnccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
0.47 g of 5-formyl-1,3-dimethyl-6-(2-dimethylaminovinyl)uracil was dissolved in ethanol, and ammonia was added thereto. The solution was stirred for 30 min at room temperature. The precipitated crystals were separated from the solution by filtration and recrystallized from ethanol to give 0.32 g of 1,3-dimethylpyrido[4,3-d]pyrimidine-2,4-dione (Compound 1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH3:8])=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.Cl>O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH3:8])=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 83.2 %

Procedure:
A mixture of methyl 4-(1-(4-fluorophenoxy)ethyl)benzoate (0.49 g, 1.8 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), tetrahydrofuran (15 mL), methanol (5 mL) and water (5 mL) was stirred at 20° C. for 4 hours. The mixture was neutralized to pH=1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 4-(1-(4-fluorophenoxy)ethyl)benzoic acid (0.39 g, 83%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[CH2:17][CH3:18]>C(O)C>[CH2:17]([C:16]1[N:12]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[S:13][CH:15]=1)[CH3:18]
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCc1csc(Cc2ccc([N+](=O)[O-])cc2)n1

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (1.50 g), 1-bromo-2-butanone (1.27 g) and ethanol (50 mL) was heated under reflux for 30 min. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-ethyl-2-(4-nitrobenzyl)-1,3-thiazole was obtained as a brown oil (1.59 g, yield 84%) from a fraction eluted with hexane-ethyl acetate (7:1-4:1, v/v).
Reaction SMILES: [Cl:1][CH:2]([CH3:27])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][C:21]([F:26])([CH2:23][CH2:24][CH3:25])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:28]1[O:30][CH2:29]1>CO>[Cl:1][CH:2]([CH3:27])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][C:21]([F:26])([CH2:23][CH2:24][CH3:25])[CH2:20][N:19]1[CH2:28][CH2:29][OH:30])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCC1(F)CNC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)C1
Reactant: C1CO1
Solvent: CO
Product: CCCC1(F)CC(C(=O)NC(C(C)Cl)C2OC(SC)C(O)C(O)C2O)N(CCO)C1

Procedure:
4-Fluoro-4-propyl-pyrrolidine-2-carboxylic acid [2-chloro-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide 18a (Example 32) was treated with ethylene oxide in methanol as detailed in scheme 19 to furnish the title compound. MS (ESPOS): 473.3 [M+H]+.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[N:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:32]([C:38]1[S:42][C:41]([C:43](Cl)=[O:44])=[CH:40][CH:39]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>O>[CH2:32]([C:38]1[S:42][C:41]([C:43]([O:31][C:28]2[CH:27]=[CH:26][C:25]([C:22]3[N:23]=[CH:24][C:19]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][N:21]=3)=[CH:30][CH:29]=2)=[O:44])=[CH:40][CH:39]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCc1ccc(C(=O)Cl)s1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCc1cnc(-c2ccc(OC(=O)c3ccc(CCCCCC)s3)cc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.1 %

Procedure:
15 ml of pyridine was added to 0.80 g (2.36×10-3 mol) of 4-(5-dodecyl-2-pyrimidinyl)phenol, followed by cooling on an iced water bath. To the mixture, 0.54 g (2.36×10-3 mol) of 5-hexylthiophene-2-carboxylic chloride was added, followed by stirring for 5 hours at room temperature. After the reaction, the reaction mixture was poured into 100 ml of water and acidified with conc. hydrochloric acid, followed by three times of extraction with 50 ml of isopropyl ether. The organic layer was washed with water repeatedly until the washing liquid reacted neutrality, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of a hexane/ethyl acetate =10/1 mixture solvent and recrystallized from ethanol to obtain 0.38 g of a pure product (yield: 30.2%). ##STR29##
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[Na+].Br[CH2:11][C:12]1([CH2:20]Br)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1.[Cl-].[NH4+]>C1COCC1.CN(C=O)C>[CH2:3]([O:2][P:1]([CH2:11][C:12]1([CH2:20][P:1]([O:5][CH2:6][CH3:7])([O:2][CH2:3][CH3:4])=[O:8])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: CCOP([O-])OCC
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOP(=O)(CC1(CP(=O)(OCC)OCC)COC(C)(C)OC1)OCC
Temperature: 68 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
Sodium diethyl phosphite (63.6 g, 400 mmol, 6.0 eq.) was added to a solution of 5,5-di(bromomethyl)-2,2-dimethyl-1,3-dioxane (20.0 g, 66 mmol) in an anhydrous mixture of THF/DMF (9:1, 600 ml). The reaction mixture was stirred for 15 h at 68° C. and subsequently mixed with a saturated aqueous solution of ammonium chloride (20.0 ml) and the volatile constituents were removed in vacuo. The residue was diluted with deionized water (200 ml) and the solution formed was extracted with methylene chloride (3×200 ml). The combined organic phases were dried with anhydrous sodium sulphate and the solvent was then removed under reduced pressure. The obtained crude product was purified by flash column chromatography (eluent: ethyl acetate/methanol 9:1). 19.6 g (71% yield) of the product was obtained as a colorless oil.