Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.Cl[CH2:9][C:10](=O)[CH3:11].C([O-])(O)=O.[Na+]>O>[Br:1][C:2]1[S:6][C:5]2=[N:7][C:10]([CH3:11])=[CH:9][N:4]2[N:3]=1
Reactant: CC(=O)CCl
Reactant: Nc1nnc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cn2nc(Br)sc2n1
Temperature: 25 °C
Yield: 50.6 %

Procedure:
5-bromo-1,3,4-thiadiazol-2-amine (1 g, 5.55 mmol, 1 eq) and chloroacetone (1.327 mL, 16.665 mmol, 3 eq) in water (24 mL) was stirred at reflux temperature overnight. More chloroacetone (1.106 mL, 13.887 mmol, 2.5 eq) was added, and heating was continued over the weekend. The reaction mixture was cooled to RT, poured into NaHCO3 (sat. sol., 43 mL) and extracted with DCM. The organic extracts were dried (MgSO4), filtered and concentrated to give a dark brown residue that was purified by flash chromatography (SiO2, DCM) affording the desired product (white solid, 0.613 g, 50%). HPLC-MS (10-95% B in 4 min at 0.5 mL+2 min 100% B, flow 0.7 mL/min): tR=4.81 min, [M+H]+ m/z 217.9; 1H NMR (300 MHz, CDCl3) δ 7.47 (s, 1H), 2.32 (s, 3H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][NH2:15].[OH-].[K+].[C:18](OC(=O)C)(=O)[CH3:19]>>[ClH:1].[CH2:18]([NH:15][CH2:14][CH:9]1[C:10]2[C:5](=[C:4]([O:3][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)[CH3:19]
Reactant: COc1cccc2c1CCCC2CN
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCNCC1CCCc2c(OC)cccc21

Procedure:
The product from Example 14 was treated with KOH to qive the free base, then reacted with acetic anhydride affording the amide. Anal. calcd. for C14H19NO2 : C, 72.07; H, 8.21; N, 6.00. Found: C, 72.03; H, 8.25; N, 6.01. This amide was reduced using the procedure of Example 5 to give the desired compound. Anal. calcd. for C14H22C1NO C, 65.74; H, 8.67; N, 5.48. Found: C, 65.71; H, 8.61; N, 5.47.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=[N:28][C:29]1([CH2:44][C:45]#[CH:46])[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:30]1=[O:43])(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[NH2:28][C:29]1([CH2:44][C:45]#[CH:46])[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:41])([CH3:40])[CH3:42])[C:30]1=[O:43]
Reactant: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCCN(COCC[Si](C)(C)C)C1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C#CCC1(N)CCCN(COCC[Si](C)(C)C)C1=O
Reaction time: 120 h
Yield: 77.7 %

Procedure:
Citric acid monohydrate (1.58 g, 7.5 mmol) was added to a solution of 3-(benzhydrylideneamino)-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)piperidin-2-one (which may be prepared as described in Description 23) (1.34 g, 3 mmol) in THF (30 mL) at 20° C. and the reaction was stirred for 5 days. The solution was evaporated and loaded onto an SCX cartridge (10 g) then eluted with MeOH, followed by 2M NH3 in MeOH. The fractions containing the desired product were collected and evaporated to afford 3-amino-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)piperidin-2-one (658 mg, 2.3296 mmol, 77.7% yield) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][CH:20]=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[C:31]1(=[N:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:34][CH2:33][CH2:32]1>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][C:20]([C:31]5([NH:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:32][CH2:33][CH2:34]5)=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cncs2)c1
Reactant: CC(C)(C)S(=O)N=C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC3)s2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added LDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](=[N:12][O:13][CH2:14][C:15]([OH:17])=O)[CH2:7][CH:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:5][C:4]=2[N:3]=1.S(Cl)(Cl)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C(Cl)Cl>[N:29]1([C:15](=[O:17])[CH2:14][O:13][N:12]=[C:8]2[CH2:7][CH:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:5][C:4]3[N:3]=[C:2]([NH2:1])[N:11]=[CH:10][C:9]2=3)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: Nc1ncc2c(n1)CC(c1ccc(F)cc1)CC2=NOCC(=O)O
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1ncc2c(n1)CC(c1ccc(F)cc1)CC2=NOCC(=O)N1CCOCC1

Procedure:
The title compound was prepared from [2-amino-7-(4-fluoro-phenyl)-7,8-dihydro-6H-quinazolin-5-ylideneaminooxy]-acetic acid, compound 9, and thionyl chloride forming the acid chloride followed by amidation using morpholine and triethylamine in DCM.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16].O1CCCC1.CO.O.[OH-].[Li+]>Cl.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:20]2[C@@H:21]([CH3:23])[CH2:22][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:7]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=3[O:5][CH2:4][C:3]([OH:33])=[O:2])[C@H:18]([CH3:32])[CH2:19]2)=[CH:30][CH:29]=1
Reactant: COC(=O)COc1cc(C)ccc1CCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-oxo-propyl}-5-methyl-phenoxy)-acetic acid methyl ester (0.18 g, 0.40 mmol) in 2:2:1 tetrahydrofuran:methanol:water (5 mL) was added lithium hydroxide hydrate (0.026 g, 0.62 mmol) and the reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with 0.2 M hydrochloric acid, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration in methylene chloride/diethyl ether to give the title compound (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]O.S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(Cl)c1
Yield: 86.7 %

Procedure:
A solution of 187 g (0.974 mole) of 2,6-dichloroisonicotinic acid, 1650 ml of methanol and 5 ml of concentrated sulfuric acid was heated at reflux for 24 hours. Most of the solvent was removed in vacuo, leaving crude product which was dissolved in 750 ml of methylene chloride and washed with water and 1N sodium hydroxide. The organic layer was dried (Na2SO4) and solvent removed in vacuo affording 174 g (86.7% yield) of methyl 2,6-dichloroisonicotinate, m.p. 79°-81° C.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH3:34])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][C:30]([CH3:31])([CH3:32])[CH3:33])[NH:9][C:8]2([CH3:34])[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C)(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C)(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 33b (1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-2-methyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 98%).
Reaction SMILES: [F:1][CH:2]([CH3:35])[CH2:3][N:4]([S:26]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)(=[O:28])=[O:27])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1.[OH-].[Na+:37]>C1COCC1.CO>[F:1][CH:2]([CH3:35])[CH2:3][N:4]([S:26]([C:29]1[S:30][CH:31]=[C:32]([CH3:34])[N:33]=1)(=[O:28])=[O:27])[C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O-:22])=[O:21])=[CH:24][CH:25]=1.[Na+:37]
Reactant: COC(=O)c1ccc(COc2cc3c(cc2N(CC(C)F)S(=O)(=O)c2nc(C)cs2)CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1csc(S(=O)(=O)N(CC(C)F)c2cc3c(cc2OCc2ccc(C(=O)[O-])cc2)CCC3)n1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
351 mg of methyl 4-{[(6-{(2-fluoropropyl)[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate was dissolved in 5.00 mL of THF and 5.00 mL of methanol, and 2.03 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at 50° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, to the obtained residue were added a 5% w/v aqueous citric acid solution and chloroform, and the organic layer was separated using a Phase Separate-filter manufactured by Isotute, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was dissolved in 5.00 mL of ethanol, and 0.765 mL of an aqueous sodium hydroxide solution was added thereto, followed by concentration under reduced pressure. The obtained crude product was crystallized by the addition of isopropanol/ethanol, collected by filtration, and dried under reduced pressure to obtain 268 mg of sodium 4-{[(6-{(2-fluoropropyl)[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate.
Reaction SMILES: [C:1]([CH2:3][N:4]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[CH:14][CH:13]=1)C(=O)OC(C)(C)C)#[N:2].C(O)(C(F)(F)F)=O>ClCCl>[C:17]1([N:16]2[C:12]([NH:4][CH2:3][C:1]#[N:2])=[CH:13][CH:14]=[N:15]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N(CC#N)c1ccnn1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCNc1ccnn1-c1ccccc1
Reaction time: 5 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl (cyanomethyl)(1-phenyl-1H-pyrazol-5-yl)carbamate (4.38 g) in dichloromethane was added TFA (16.7 g) at room temperature, and the mixture was stirred for 5 hr. The reaction mixture was concentrated under reduced pressure, and adjusted to pH 9-10 with 1N aqueous sodium hydroxide solution. The reaction mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (1.90 g).
Reaction SMILES: [C:1]([C@H:5]1[C:34](=[O:35])[N:33]2[CH2:36][C@@H:30]([CH2:31][C@H:32]2[C:37]([O:39][CH3:40])=[O:38])[O:29][C:17]2=[N:18][C:19]3[C:20]([O:27][CH3:28])=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([OH:26])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:41][C@H:9]2[O:8][C:7](=[O:42])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:43][CH2:44][CH2:45][CH2:46]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:43][CH2:44][CH2:45][CH2:46][O:26][C:25]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:27][CH3:28])[C:19]=2[N:18]=[C:17]2[O:29][C@H:30]3[CH2:36][N:33]([C:34](=[O:35])[C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[NH:6][C:7](=[O:42])[O:8][C@@H:9]4[CH2:41][C@H:10]4[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]=12)[C@H:32]([C:37]([O:39][CH3:40])=[O:38])[CH2:31]3
Reactant: BrCCCBr
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3c(OC)cccc3c1O)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3c(OC)cccc3c1OCCCBr)O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-17-hydroxy-13-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-8-carboxylate (253 mg) (prepared by the same method as Example 113, Steps 1-5 with intermediates B10 and C8) and 1,3-dibromopropane (500 μl) in DMF (5 ml) was added cesium carbonate (700 mg). After 90 minutes of stirring at room temperature, the reaction mixture was partitioned between water/brine 1:1 and ethyl acetate. The product was extracted twice with ethyl acetate and the combined organic phases were washed with water and brine, dried over sodium sulfate and evaporated. The crude residue was purified by flash chromatography (ISCO 10%-50% ethyl acetate in hexanes) to afford a white solid (231 mg). LRMS (ES+) m/z 704.30 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])[CH2:3]1.O.[OH-].[Na+]>CO>[O:1]=[C:2]1[CH2:5][CH:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:3]1
Reactant: CCOC(=O)CCC1CC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCC1CC(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A solution of ethyl 3-(3-oxocyclobutyl)propanoate (200 mg, 1.18 mmol) in methanol (4 mL) was treated with water (0.75 mL) and a 2N solution of sodium hydroxide (0.75 mL, 1.41 mmol) and the solution was heated at 55° C. till the starting material was consumed by TLC (25% EA/hept). After 1 h the starting material was found to be consumed. The reaction mixture was cooled to room temperature and concentrated to remove the MeOH. The aqueous phase was diluted with 2 mL H2O and made acidic to pH˜2 with 1N HCl. The solution was saturated with NaCl and extracted with three 10 mL portions of ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated to yield the title compound (157 mg, 94%) as a light orange viscous oil that was used as is in the next step: GC purity 63.2% (ret. time, 4.27 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH3:15])[C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[O:6].CC(=CC)C.Cl([O-])=[O:22].O.P([O-])(O)(O)=O.[Na+].[OH-].[Na+]>O.C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH3:15])[C:9]=1[O:10][CH:11]([CH3:12])[CH3:13])[C:5]([OH:22])=[O:6]
Reactant: [O-][Cl+][O-]
Reactant: COc1cc(C=O)cc(F)c1OC(C)C
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cc(C(=O)O)cc(F)c1OC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (250 mg, 1.5 mmol) in DMF (2.5 mL) was treated with potassium carbonate (812 mg, 5.9 mmol) and stirred for 30 minutes. 2-Iodopropane (500 mg, 2.9 mmol) was added over 10 minutes and reaction mixture was stirred for 20 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium chloride solution. The organic layer was washed with saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate, filtered and concentrated in vacuo to give 3-fluoro-4-isopropoxy-5-methoxybenzaldehyde. To the aldehyde was added tert-butanol (6.7 mL) and 2-methylbut-2-ene (4 mL, 38.2 mmol) and the reaction mixture was cooled to 0° C. A solution of chlorite (345 mg, 3.8 mmol) and sodium dihydrogen phosphate hydrate (527 mg, 3.8 mmol) in water (6.7 mL) was added dropwise over 5 minutes, and the reaction mixture was stirred 30 minutes. The reaction mixture was warmed to room temperature and stirred for 12 hours. The reaction mixture was basified with 1 N NaOH solution and extracted with ethyl acetate (2×50 mL). The aqueous layer was acidified with 1 N HCl solution and extracted with EtOAc (4×50 mL). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo to afford 3-fluoro-4-isopropoxy-5-methoxy-benzoic acid (190 mg, 56%) as a white solid. ESI-MS m/z calc. 228.0. found 229.3 (M−1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I.CS[C:17]1[NH:18][CH2:19][CH2:20][N:21]=1.CO>C(OCC)C>[NH:21]1[CH2:20][CH2:19][N:18]=[C:17]1[N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1
Reactant: CSC1=NCCN1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: I
Solvent: CO
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CN(C1=NCCN1)CC2

Procedure:
A mixture of 10 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline, 13.7 g of 2-methylsulphanyl-4,5-dihydro-1H-imidazole hydriodide and 100 ml of methanol is heated at reflux for 12 hours. The addition of diethyl ether causes the separation of a precipitate, which is taken up in water, neutralised using sodium hydroxide and extracted with dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][CH:23]=1>>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=3[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:15])=[CH:23][CH:24]=1)(=[O:30])[CH3:29]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: CC(=O)c1ccc(N)cc1
Product: CC(=O)c1ccc(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carbonyl chloride (0.25 mg, 0.59 mmol) and 1-(4-aminophenyl)ethanone (88 mg, 0.65 mmol). The title compound was obtained as a solid (27.0 mg, 10% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.78 (1H, s), 9.01 (2H, s), 8.75 (1H, m), 8.01 (2H, m), 7.82 (2H, m), 2.51 (3H, s). MS m/z: 466.03, 468.03 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][O:6][C:5]([CH3:8])=[N:4]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][F:31].C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:3]2([CH2:2][OH:1])[CH2:7][O:6][C:5]([CH3:8])=[N:4]2)=[CH:16][CH:15]=1
Reactant: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Reactant: FCCCCCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=NC(CO)(CCc2ccc(OCCCCCCF)cc2)CO1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of (R/S)-4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (500 mg, 0.2.12 mmol) in dry DMF (8 ml) is added under inert atmosphere Cs2CO3 (901 mg, 2.76 mmol, 1.3 eq.) and 1-bromo-6-fluoro-hexane (464.1 mg, 2.55 mmol, 1.2 eq.). The reaction mixture is stirred under inert atmosphere at 85° C. overnight. A saturated solution of NaHCO3 (20 ml) and ethyl acetate (40 ml) are then added. The organic layer is separated and the aqueous phase is extracted with ethyl acetate (3×40 ml). The combined organic extracts are washed with brine and 1M HCl, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (cy Hexane/ethyl acetate(9/1) to (1/1) and (0/1)) affords (R/S)-(4-{2-[4-(6-fluoro-hexyloxy)-phenyl]-ethyl}-2-methyl-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[O:16][CH3:17])[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.O.[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[O:16][CH3:17])[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of (S)-4-[3-(4-chloro-phenyl)-3-methoxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.50 g) in ethyl acetate (100 ml) at room temperature was added platinum(IV) oxide monohydrate (484 mg). The mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to yield (S)-4-[3-(4-chloro-phenyl)-3-methoxy-propyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a light yellow oil (1.57 g, 62%); MS (ISP): 386.2 ([{37Cl}M+H]+), 384.2 ([{35Cl}M+H]+).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[Cl:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][C:26]=1O)[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.CCCCCC>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:26]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:17]([Cl:16])[CH:18]=1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add dropwise triflic anhydride (6.7 ml, 39.8 mmol) to a solution of methyl 3-chloro-4-hydroxybenzoate (5.42 g, 29.0 mmol), DMAP (490 mg, 4.0 mmol) and triethylamine (5.6 ml, 40.1 mmol) in anhydrous dichloromethane (200 ml). Stir the mixture at room temperature overnight under nitrogen atmosphere. Quench the mixture by addition of a saturated aq. solution of ammonium chloride. Separate the organic layer and extract the aqueous layer with dichloromethane (×3). Wash the combined organic layers with saturated aq. sodium chloride, dry over anhydrous sodium sulfate, filter and concentrate to yield a crude brown oil. Take up this crude oil in hexane and wash the organic layer with water (×3), dry over anhydrous sodium sulfate, filter and concentrate to. yield the title compound.