Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:6]([O:8]C)=O.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:6]([N:18]([O:19][CH3:20])[CH3:17])=[O:8]
Reactant: COC(=O)c1cc(OC)cc(C(F)(F)F)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)OC)cc(C(F)(F)F)c1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
Methyl 3-methoxy-5-trifluoromethylbenzoate (O4.014, 1 g) and N,O-dimethylhydroxylamine (416 mg) were initially charged in THF (30 ml). Thereafter, the mixture was cooled to −15° C., and isopropylmagnesium chloride (3.2 ml; 2 M in THF) was added dropwise within 10 min. The mixture was stirred at −15° C. for another 20 min before the cooling bath was removed. After 3 h, the mixture was cooled again to −15° C. and further isopropylmagnesium chloride (3.2 ml) was added. After the cooling bath had been removed, the mixture was stirred at RT for another hour, then admixed with 20% ammonium chloride solution and extracted three times with EA. The combined EA phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (50 g cartridge, DCM as eluent). 465 mg of the title compound were obtained, as well as 427 mg of reactant.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH2:14][CH:7]1C[C:9](=O)[CH2:10]2)=[O:5])[CH3:2].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH:7]2[CH2:9][CH2:10][CH:11]1[CH2:12][C:13]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:14]2)=[O:5])[CH3:2]
Reactant: C1CCNC1
Reactant: CCOC(=O)N1C2CCCC1CC(=O)C2
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CCOC(=O)N1C2C=C(N3CCCC3)CC1CC2
Reaction time: 110 h
Yield: 98.7 %

Procedure:
36.6 g of 8-azabicyclo[3,2,1]octan-3-one-8-carboxylic acid ethyl ester (e) are dissolved in 500 ml of absolute petroleum ether, and 52.8 g of pyrrolidine are added. A solution of 19.4 g of titanium tetrachloride in 100 ml of petroleum ether is added dropwise within 70 minutes, with vigorous stirring. With slight warming of the solution, a light-yellow precipitate is immediately precipitated. After 110 hours' stirring at roomtemperature, the precipitate is allowed to settle and the yellow petroleum ether solution is decanted. The precipitate is suspended in 250 ml of anhydrous benzene, suction filtered, and washed with benzene. The united organic phases are concentrated in a vacuum; the oil which remains behind is purified by vacuum distillation to obtain 42.8 g (92.2 percent) of (d) as a light-yellow, viscous oil (b.p. 125° to 128° C. at 8 Pa.).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=1)#[N:2].[CH3:21][NH2:22]>>[C:1]([NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[O:11][C:12]([CH2:15][N:16]([CH3:18])[CH3:17])=[CH:13][CH:14]=1)=[N:22][CH3:21])#[N:2]
Reactant: CN
Reactant: CSC(=NC#N)NCCSCc1ccc(CN(C)C)o1
Product: CN=C(NC#N)NCCSCc1ccc(CN(C)C)o1

Procedure:
A solution of N'-cyano-N-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]carbamimidothioic acid, methyl ester (1.06 g) in ethanolic methylamine 33% (10 ml) was stirred at room temperature for 4 hr. The solution was evaporated to dryness and the oily residue crystallised from ethyl acetate-light petroleum (b.p. 80°-100°) to give the title compound m.p. 77°-80°.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]>>[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=3)=[O:12])=[CH:29][CH:28]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Product: CC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3ccc(OC(F)(F)F)cc3)cc2)c1C(N)=O

Procedure:
2-Acetylamino-4-{4-[(3-(4-trifluoromethoxyphenyl)ureido]phenyl}-1H-pyrrole-3-carboxamide may be prepared as described in Example 12 from 4-(trifluoromethoxy)phenyl isocyanate and 2-acetylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide.
Reaction SMILES: BrCC1C(CBr)=CC=CC=1.[C:11]1(=O)[NH:15][C:14](=O)[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].Cl.C[N:25](C)C=O>>[NH2:15][CH2:11][C:12]1[C:13]([CH2:14][NH2:25])=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C=O
Agent: BrCc1ccccc1CBr
Agent: Cl
Agent: [K]
Product: NCc1ccccc1CN

Procedure:
12.3 g of α,α'-dibromoxylene and 17.3 g of potassium phthalimide are stirred in 390 ml of N,N-dimethylformamide at a bath temperature of 150° C. for 2.4 hours. After cooling the resulting intermediate is filtered off under suction, washed with ethyl acetate, dried and then reacted in 200 ml of ethanol with 4.6 ml of hydrazine hydrate under reflux. After cooling the resulting suspension is treated with 50 ml of 25% hydrochloric acid, filtered and concentrated to 1/3 of its volume. After repeated filtration the mixture is adjusted to pH 14 by the addition of concentrated sodium hydroxide solution and evaporated. The product is dissolved out from the residue with 300 ml of methylene chloride. After evaporation of the solvent the residue as is taken up in 25 ml of isopropanol and the dihydrochloride of the product is crystallized with 20 ml of 3.26N isopropanolic hydrochloric acid. There are obtained 2.64 g, colourless crystals; m.p.:>250° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+].C(Cl)(Cl)Cl>C(O)C>[CH3:12][C:11]1[C:3]([CH2:2][S:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Cc1cc2c(cc1CCl)OCO2
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1CSCC(=O)O)OCO2
Yield: 20.5 %

Procedure:
A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 g of mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of 50% hydrous ethanol was heated under reflux for 1 h. The reaction mixture was concentrated. Water was added thereto and the mixture was washed with ethyl acetate. The aqueous layer was acidified with 1Nhydrochloric acid. After extraction with chloroform, the extract was dried over magnesium sulfate. The solvent was distilled off and the product was isolated according to silica gel column chromatography (chloroform). The crystals thus obtained were recrystallized from diisopropyl ether to obtain 1.6 g of the intended compound in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:24])=O>CN(C=O)C>[Cl:24][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COCCNCCOc1cc2nc[nH]c(=O)c2cc1OC
Solvent: CN(C)C=O
Product: COCCNCCOc1cc2ncnc(Cl)c2cc1OC
Yield: 38 %

Procedure:
A mixture of 6-methoxy-7-(2-(2-methoxyethylamino)ethoxy)-3,4-dihydroquinazolin-4-one (300 mg, 1 mmol), thionyl chloride (5 ml) and DMF (0.1 ml) was heated at reflux for 45 minutes. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The resulting gum was partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic layer was separated and the aqueous layer extracted with methylene chloride (4×40 ml). The combined extracts were passed through phase separating paper and the solvent removed by evaporation to give 4-chloro-6-methoxy-7-(2-(2-methoxyethylamino)ethoxy)quinazoline (120 mg, 38%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:9][C:8](N)=[C:7]2[C:2]=1[CH:3]=[C:4](S(O)(=O)=O)[CH:5]=[C:6]2O.C1C2C(=CC=CC=2)C=CC=1.O.[S:32](=[O:36])(=[O:35])([OH:34])O.[OH:37][S:38](O)(=[O:40])=[O:39].O=S(=O)=O>>[C:8]1([S:38]([OH:40])(=[O:39])=[O:37])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:1]=[C:10]([S:11]([OH:14])(=[O:13])=[O:12])[C:9]=1[S:32]([OH:34])(=[O:36])=[O:35]
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: c1ccc2ccccc2c1
Solvent: O
Product: O=S(=O)(O)c1cc2ccccc2c(S(=O)(=O)O)c1S(=O)(=O)O

Procedure:
It is known from FIAT Final Report No. 1,016, page 32 to 39, that H-acid can be prepared as follows: naphthalene is reacted with sulphuric acid monohydrate (=100% strength H2SO4) and 65% strength oleum, a particular temperature programme being maintained and sulphuric acid monohydrate and oleum being added stepwise, to give a naphthalene-trisulphonic acid isomer mixture, which is nitrated with mixed acid. After diluting with water, driving off the nitrous gases and separating off the sulphuric acid in the form of calcium sulphate, the isomer mixture of nitronaphthalene-trisulphonic acids is reduced with iron, and dissolved iron salts are then precipitated with magnesium oxide and separated off. The acid calcium sodium salt of T-acid (1-naphthylamine-3,6,8-trisulphonic acid) is precipitated by adding rock salt and hydrochloric acid and is filtered off and washed several times. This salt of T-acid is introduced into the wash water and sodium carbonate is added. The chalk which has precipitated is then pressed out and the salt solution is concentrated. The concentrated solution of the trisodium salt of T-acid is reacted with 50% strength sodium hydroxide solution under pressure. Thereafter, first sulphuric acid and then water are added and the H-acid is finally isolated, as the monosodium salt, by filtration, washing and drying.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(O)(=O)C>[Br:27][CH:1]([C:3]1[N:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:21])[N:4]=1)[CH3:2]
Reactant: BrBr
Reactant: CCc1nc2cccc(C)c2c(=O)n1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2nc(C(C)Br)n(-c3ccc(F)cc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a mixture of 1.969 g 2-ethyl-3-(4-fluoro-phenyl)-5-methyl-3H-quinazolin-4-one (IX) (6.974 mmol, 1.000 equiv) and 0.687 g sodium acetate (8.37 mmol, 1.20 equiv) in 28 mL glacial acetic acid at 40° C. (external temperature, oil bath) was added a solution of 0.372 mL bromine (7.32 mmol, 1.05 equiv) dissolved in 5 mL glacial acetic acid dropwise by addition funnel over 30 min. After 2 h the reaction solution was poured into 250 mL water. The resulting mixture was stirred vigorously at room temperature for 1 h, after which time the precipitate was collected by vacuum filtration, rinsing with warm (ca. 40° C.) water (3×50 mL). The solid was dried in vacuo over phosphorous pentoxide overnight, affording 2.19 g of a white solid. m.p. decomposes upon heating. 1H NMR (CDCl3)δ2.04 (d, 3H, J=6.8 Hz), 2.82 (s, 3H), 4.51 (q, 1H, J=6.8 Hz), 7.15 (ddd, 1H, J1=2.4 Hz, J2=4.4 Hz, J3=8.4 Hz), 7.23 (dd, 1H, J1=2.8 Hz, J2=10.8 Hz), 7.25-7.31 (m, 2H), 7.56 (ddd, J1=2.8 Hz, J2 4.8 Hz, J3 8.8 Hz), 7.64 (2×d, 2×1H, J=5.2 Hz) ppm. MS (ESI+) 361.1 [MH]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@H:2]1[C:11]([N:13]1[CH2:20][CH2:19][C@:18]2([CH3:23])[C@@H:21]([CH3:22])[C@H:14]1[CH2:15][C:16]1[CH:27]=[CH:26][C:25](OS(C(F)(F)F)(=O)=O)=[CH:24][C:17]=12)=[O:12]>CO.C(OCC)(=O)C.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@H:2]1[C:11]([N:13]1[CH2:20][CH2:19][C@:18]2([CH3:23])[C@@H:21]([CH3:22])[C@H:14]1[CH2:15][C:16]1[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=12)=[O:12]
Reactant: C[C@H]1[C@H]2Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3[C@]1(C)CCN2C(=O)[C@@H]1COc2ccccc2O1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@H]1[C@H]2Cc3ccccc3[C@]1(C)CCN2C(=O)[C@@H]1COc2ccccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Pd/C (0.10 g) is added to a solution of (2R,6R,11R)-trifluoro-methanesulfonic acid 3-[(S)-2,3-dihydro-benzo[1,4]dioxine-2-carbonyl]-6,11-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-yl ester (0.50 g) in methanol (15 mL) and ethyl acetate (25 mL). The resulting mixture is shaken under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst is separated by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by HPLC on reversed phase (MeCN/H2O) to give the product as a colorless gum-like solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:15])[CH:4]=1)#[N:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20].[Cl-].[Li+]>CCOC(C)=O>[C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[CH:18][N:19]([CH3:21])[CH3:20])[C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH3:15])[CH:4]=1)#[N:2]
Reactant: COC(=O)Cc1cc(F)c(C#N)cc1C
Reactant: COC(OC)N(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COC(=O)C(=CN(C)C)c1cc(F)c(C#N)cc1C
Yield: 96.4 %

Procedure:
Combined methyl 2-(4-cyano-5-fluoro-2-methylphenyl)acetate (5.00 g, 24.13 mmol), 1,1-dimethoxy-N,N-dimethylmethanamine (32.2 mL, 241 mmol), and lithium chloride (0.102 g, 2.413 mmol) and heated to 105° C. After 2 hours the reaction mixture was concentrated in vacuo and repeatedly diluted with EtOAc (30 mL) and concentrated to give an oil. The oil was dissolved in EtOAc (50 mL) and washed with water, 10% aqueous sodium chloride, and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to afford a thick red oil, which was crystallized to give the title compound as a yellow solid (6.1 g, 23.26 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 3H) 2.34 (s, 1H) 2.54-2.81 (m, 6H) 3.50 (s, 3H) 7.20 (d, J=10.11 Hz, 1H) 7.58 (s, 1H) 7.72 (d, J=7.07 Hz, 1H). ESI-MS m/z [M+H]+ 263.2.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:21]([CH3:33])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:34][O:35][CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][CH:36]([O:35][CH3:34])[CH2:37][CH2:38]4)[C:17]=23)=[CH:20][C:21]=1[CH3:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccc1
Reactant: COC1CCNCC1
Product: COC1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccc5)c(C)c4)c23)CC1
Yield: 37 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[4-(benzyloxy)-3-methylphenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 110) and 4-methoxypiperidine (prepared as described in Example 118, starting material) to give the title compound in 37% yield; NMR Spectrum: 1.37-1.43 (m, 2H), 1.78-1.81 (m, 2H), 2.18-2.22 (m, 2H), 2.22 (s, 3H), 2.75-2.78 (m, 4H), 3.12-3.16 (m, 1H), 3.20 (s, 3H), 4.40 (t, 2H), 5.13 (s, 2H), 7.01 (d, 1H), 7.31-7.48 (m, 7H), 8.23 (s, 1H), 8.32 (s, 1H); Mass Spectrum: 489 (MH+).
Reaction SMILES: C(N(CC)CC)C.[I-].[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20](N2C=C[N+](C)=C2)=[O:21])[CH2:16][C@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10].[CH2:28]([N:34]([CH3:43])[C:35]([C@@H:37]1[CH2:41][C@@H:40]([OH:42])[CH2:39][NH:38]1)=[O:36])[CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33]>C(Cl)Cl>[CH2:9]([O:11][C:12]([C@@:14]1([NH:19][C:20]([N:38]2[CH2:39][C@H:40]([OH:42])[CH2:41][C@H:37]2[C:35](=[O:36])[N:34]([CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[CH3:43])=[O:21])[CH2:16][C@@H:15]1[CH:17]=[CH2:18])=[O:13])[CH3:10]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)n1cc[n+](C)c1)C(=O)OCC
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Triethylamine (1.3 mL, 3 eq.) was added at room temperature under nitrogen to a mixture of 1-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropyl-carbamoyl)-3-methyl-1H-imidazol-3-ium iodide 34 (0.7 g, 1 eq.) and compound 49 (1.2 g, 1 eq.) in DCM (15 mL). The reaction mixture was stirred overnight at room temperature and then quenched with 1M aqueous hydrochloric acid. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 50 as a white solid in 70% yield. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.10-1.14 (td, J=7.07 and 2.01 Hz, 3H), 1.15-1.17 (m, 1H), 1.22-1.30 (m, 1H), 1.33-1.41 (m, 2H), 1.42-1.50 (m, 1H), 1.54-1.57 (m, 1H), 1.71-1.79 (m, 1H), 1.97-2.07 (m, 4H), 2.74 (s, 1H), 2.97 (s, 2H), 3.11 (d, J=10.24 Hz, 1H), 3.15-3.21 (m, 1H), 3.43-3.48 (m, 1H), 3.91-4.07 (m, 2H), 4.29-4.30 (m, 1H), 4.65-4.69 (d, J=6.50 Hz, 1H), 4.90-4.96 (m, 3H), 5.00-5.06 (m, 2H), 5.19-5.25 (dd, J=17.04 and 6.50 Hz, 1H), 5.51-5.61 (m, 1H), 5.71-5.83 (m, 1H), 7.08 (s, 1H); MS (ESI−): m/z=406 (MH−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].CCN(C(C)C)C(C)C.[CH2:23]([S:27](Cl)(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][C:7](=[O:12])[CH:6]=[C:5]([O:13][S:27]([CH2:23][CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[C:4]=2[CH:3]=1
Reactant: CCCCS(=O)(=O)Cl
Reactant: O=c1cc(O)c2cc(Cl)ccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCS(=O)(=O)Oc1cc(=O)oc2ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 25.1 %

Procedure:
6-Chloro-4-hydroxycoumarin (0.455 mmol, 0.090 g) is suspended in 5 mL DCM. DIEA (1.37 mmol, 0.237 mL) is added and the reaction is cooled to 0° C. 1-Butanesulfonyl chloride (0.5 mmol, 64.8 μL) is dissolved in DCM is added and and the reaction is stirred at ambient temperature for 2 hrs. The DCM is removed under reduced pressure and the residue is redissolved in MeOH/H2O then is purified by HPLC to afford the title compound (36.2 mg, 25%) 1H NMR (DMSO-d6, 300 MHz) δ 7.81 (2H, m), 7.56 (1H, d, J=8.75 Hz), 6.59 (1H, s), 3.99 (2H, m), 1.83 (2H, m), 1.46 (2H, m), 0.92 (3H, t, J=7.25 Hz); MS (ESI, Pos.) calcd for C13H13ClO5S m/z [M+H]=317.0, found 317.1.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:5].CC(C)([O-:19])C.[K+].O>CCOCC>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C@@H:7]1[CH2:8][C@H:6]1[C:4]([OH:19])=[O:5]
Reactant: CC(C)(C)[O-]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1ccccn1
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (±)-(trans)-2-pyridin-2-yl-cyclopropanecarboxylic acid methoxy-methyl-amide (950 mg, 4.61 mmol, 1 eq) in Et2O (30 mL), potassium tert-butoxide (569 mg, 5.07 mmol, 1.1 eq) and H2O (0.4 mL) were added. The mixture was stirred at r.t. for 18 hours. Potassium tert-butoxide (1.86 g, 16.6 mmol, 3.6 eq.) was added again. The mixture was stirred at r.t. for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in water (5 mL) and formic acid (3 mL). The solution was directly purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions, extremely polar method) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN1CCOCC1.[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24](Cl)=[O:25]>ClCCl>[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][C:24]([NH:11][NH:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:25]
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A suspension of 4-nitrobenzohydrazide (0.500 g, 2.76 mmol), and 4-methylmorpholine (0.455 ml, 4.14 mmol) were stirred in dichloromethane (20 ml). 3,3-Dimethylbutanoyl chloride (0.422 ml, 3.04 mmol) was added and the reaction mixture was stirred for 2 hours. Normal phase chromatography of the crude reaction mixture gave the title compound.
Reaction SMILES: [C:1]1([CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7]Cl)[CH:2]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+:15].[Na+]>C1(C)C=CC=CC=1.O>[C:1]1([CH2:9][S:11]([O-:14])(=[O:13])=[O:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][S:11]([O-:14])(=[O:13])=[O:12])[CH:2]=1.[Na+:15].[Na+:15]
Reactant: ClCc1cccc(CCl)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)([O-])Cc1cccc(CS(=O)(=O)[O-])c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
In a 300-ml egg-plant type flask provided with cooling pipe for reflux, 17.5 g (0.1 mol) of m-xylylene dichloride was dissolved in 40 ml of toluene, and a solution of 28.0 g (0.22 mol) of sodium sulfite in 40 ml of distilled water was put into the flask. The mixture in the flask was heated in an oil bath kept at 130° C. under refluxing for 24 h, while the mixture was vigorously stirred with a magnetic stirrer using teflon-coated stirring pieces. After that the reaction mixture was cooled to room temperature, and a white precipitate was collected by filtration. The precipitate was dried under reduced pressure and purified by well washing with diethyl ether and then recrystallizing in a 2:1 mixture of water and methanol. The purified product was 16.5 g of sodium m-xylylenedisulfonate (53% yield). The sodium salt was dissolved in distilled water and passed through a column of an ion-exchange resin (Duolite C-20 of Wako Junyaku Co.) to obtain the aimed disulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[Cl:1][C:2]1[N:7]=[C:6]([O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccnc(Cl)n1
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of 2,4-dichloropyrimidine (32.4 g) in methanol (200 ml) was added dropwise a solution of sodium methoxide (11.7 g) in methanol (120 ml) over 40 min and the mixture was stirred for 30 min. The reaction mixture was poured into water (500 ml) and extracted with chloroform (300 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was recrystallized from hexane to give the title compound (21.5 g) as white crystals, m.p.=50-52° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(OC([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([O-])=[O:26])=[N:23][CH:24]=1)=O)(C)(C)C.[Li+].CCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:25]([C:22]2[CH:21]=[CH:20][C:19]([CH2:18][NH2:17])=[CH:24][N:23]=2)=[O:26])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)[O-])nc1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccc(C(=O)NCc2ccc(F)cc2)nc1
Yield: 26.3 %

Procedure:
Use the General Procedure 6-2, using 4-fluoro-benzylamine (551 mg, 4.4 mmol), lithium 5-(tert-butoxycarbonylamino-methyl)-pyridine-2-carboxylate (740 mg, 2.93 mmol) and DIEA (2.6 mL) as cosolvent, to give the title compound as a white solid (200 mg, 26%). MS (ES+) m/z: 260 (M+H)+.
Reaction SMILES: [ClH:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10]O)=[CH:5][CH:4]=1>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][Cl:1])=[CH:5][CH:4]=1
Reactant: Cl
Reactant: OCCc1ccc(O)cc1
Product: Oc1ccc(CCCl)cc1

Procedure:
In a similar process using 12N HCl, 2-(4-hydroxyphenyl) ethanol gave 70% isolated yield of the (2-[4-hydroxyphenyl]ethyl) chloride. 1H NMR (CDCl3) δ 2.96 (2H, t, J=7.8 Hz), 3.67 (2H, t, J=7.2 Hz), 6.79 (2H, d, J=8.4 Hz), 6.94 (2H, d, J=8.1 Hz)