Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH3:8][NH:9][S:10]([C:13]1[CH:14]=[C:15]([C:23]([OH:25])=[O:24])[C:16]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:22]=1)(=[O:12])=[O:11].[C:26](=O)([O-])[O-].[Na+].[Na+]>O>[CH3:26][O:24][C:23]([C:15]1[C:16]2[O:21][CH2:20][CH2:19][O:18][C:17]=2[CH:22]=[C:13]([S:10](=[O:11])(=[O:12])[NH:9][CH3:8])[CH:14]=1)=[O:25]
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)c1cc2c(c(C(=O)OC)c1)OCCO2
Yield: 85 %

Procedure:
750 ml of methanol were introduced into a balloon flask provided with a condenser. Then, under cooling, 273 g of concentrated sulfuric acid and 160 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux, cooled and poured into water and sodium carbonate. The precipitate was dried off, washed and dried. 143 g of methyl-7-methylsulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 159°-160° C.; yield: 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(F)cc(Cl)c2)cc1
Reactant: C#CCCCCC
Solvent: CCCCCCC
Product: CCCCCC#Cc1cc(F)cc(Cl)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-chloro-5-fluoro-phenyl ester and 1-heptyne following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (110 mg, 98%); 1H NMR δ (CDCl3): 7.16 (s, 1H), 7.02-6.94 (m, 2H), 2.43 (t, J=7.13 Hz, 2H), 1.62 (p, J=7.12 Hz, 2H), 1.45-1.29 (m, 4H), 0.92 (t, J=7.22 Hz, 3H); LCMS m/z: 224.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccccn1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.50 g), 2-hydroxypyridine (407 mg), and potassium carbonate (987 mg) in DMF (15 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was diluted with hexane and the resultant crystals were collected by filtration. The crystals were recrystallized from hexane-ethyl acetate to obtain 2-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]pyridine (830 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:17]([NH2:31])[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>O>[NH2:30][CH2:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][CH2:17][NH:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCCOCCOCCOCCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: O
Solvent: c1ccncc1
Product: NCCCOCCOCCOCCCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 52.7 %

Procedure:
1.41 g (0.01 mol) of 1-fluoro-4-nitrobenzene and 1.62 ml (0.02 mol) of pyridine were introduced into a three-necked flask under nitrogen. 8.75 ml (0.04 mol) of 4,7,10-trioxatridecane-1,13-diamine were added dropwise with stirring. The mixture was heated to 70° C. After reaction for 24 hours, the reaction mixture was cooled and 40 ml of distilled water were then added with vigorous stirring. Next, the reaction mixture was extracted with dichloromethane, washed twice with water, dried over MgSO4 and then evaporated under vacuum. The crude product, isolated in the form of a yellow oil comprising about 90% of expected mono-nitro derivative, was purified on a column of silica, eluting with ethyl acetate (to separate out the dinitro derivative), and then with methanol (to recover the expected mono-nitro derivative). 1.8 g of expected product (19) were obtained in the form of a dark yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9]C.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([OH:9])[CH:4]=[CH:5][C:6]=1[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[C:12]([F:11])[CH:13]=1)=[O:16]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl

Procedure:
The Friedel-Crafts reaction described in the foregoing examples is repeated with 2,3-dichloroanisole, 3--fluorobenzoyl chloride and AlCl3 to yield 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1>CN(C=O)C.O>[O:7]([CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:17]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)nc1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenol (489 mg, 5.21 mmol) and K2CO3 (1.44 g, 10.4 mmol) in DMF (15 mL) was added methyl 6-(bromomethyl)nicotinate (1.1a) (1.20 g, 5.21 mmol). The reaction was stirred at room temperature for 30 min and then diluted with water to give 1.2a after isolation by vacuum filtration and further drying in vacuo (810 mg): 1H-NMR (400 MHz, CDCl3) δ 9.21 (d, J=2.0 Hz, 1H), 8.34 (dd, J=8.0, 2.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.37-7.26 (m, 2H), 7.05-6.96 (m, 3H), 5.34 (s, 2H), 3.99 (s, 3H); LC-MS (220 nm) >98%, 244.2 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40]Br)([CH3:34])([CH3:33])[CH3:32].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:42])[O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCNC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol (511 mg, 1.55 mmol, 1.0 eq.) and potassium carbonate (428 mg, 3.1 mmol, 2.0 eq.) in dry DMF (10 mL) was added tert-butyl(3-bromopropyl)carbamate (480 mg, 2.01 mmol, 1.3 eq.). The mixture was stirred for 3 h at 90° C. and then cooled to RT. EtOAc was added and the organic phase was washed three times with water. The organic phase was dried over MgSO4 and solvents were removed in vacuo. The desired product R1 was obtained as brown oil and was used without further purification in the next step. MS (ES) C24H26FN3O7 requires: 487. Found: 488 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=O)=[CH:10][N:9]2[CH3:17])=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([O:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([CH:30]=[C:31]([NH:33][C:34]([CH:36]4[CH2:38][CH2:37]4)=[O:35])[N:32]=3)[CH:29]=2)=[C:21]([F:41])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:36]1([C:34]([NH:33][C:31]2[N:32]=[C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]4[CH:39]=[CH:40][C:19]([NH:18][C:14]([C:11]5[C:12](=[O:13])[N:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[N:9]([CH3:17])[CH:10]=5)=[O:16])=[CH:20][C:21]=4[F:41])=[CH:29][N:28]3[CH:30]=2)=[O:35])[CH2:37][CH2:38]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1
Yield: 80.3 %

Procedure:
In the same manner as in Example 46 and using 2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid (280 mg, 1.2 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (260 mg, 0.80 mmol), HATU (460 mg, 1.2 mmol), N,N-diisopropylethylamine (310 mg, 2.4 mmol) and N,N-dimethylformamide (6 mL) as starting materials, the title compound (350 mg, 81%) was obtained as a white solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][PH:15](=[O:20])[O:16]C(C)C)[CH2:10]1)=O)(C)(C)C>Cl>[NH2:8][C@@H:9]1[CH2:13][CH2:12][C@H:11]([CH2:14][PH:15](=[O:16])[OH:20])[CH2:10]1
Reactant: CC(C)O[PH](=O)C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Product: N[C@@H]1CC[C@H](C[PH](=O)O)C1

Procedure:
(±)-cis-Isopropyl [3-(t-butyloxyamino)cyclopentanyl]methylphosphinate (10) (2.1 g, 9.6 mmol) was dissolved in aqueous HCl (6M, 40 cm3) and the solution heated at reflux for 30 h. After cooling, the solution was evaporated to dryness under reduced pressure. The residue was dissolved in water (10 cm3) and applied to an ion exchange column (Dowex 50, H+ form). The column was eluted with water until the eluate was colourless and pH neutral and then eluted with aqueous pyridine (1M). Ninhydrin positive fractions were combined and evaporated to dryness under reduced pressure. Residual traces of pyridine were removed by repeatedly redissolving the compound in water (20 cm3) and re-evaporating (3 times). Recrystallisation from ethanol/acetone and drying gave the title compound (11) as an off white solid (1 g, 46%): 1H NMR (300 MHz, D2O) δ 1.27 (3H, d, J=12.9 Hz, PCH3), 1.56-2.27 (7H, m, C(1)—H, C(2)—H, C(2)—H′, C(4)—H, C(4)—H′, C(5)—H and C(5)—H), 3.59 (1H, m, C(3)—H), 13C NMR (75.46 MHz, D2O) 13.02 (PCH3, d, JPC=92.0 Hz), 23.9 (C(5)), 30.50 (C(4), d, 3JPC=7.5 Hz), 31.55 (C(2)), 37.20 (C(1), d, JPC=97.3 Hz), 52.29 (C(3), d, 3JPC=9.3 Hz), 31P NMR (121 MHz, D2O) δ 45.9, MS (CI, CH4) m/z 164 (38%) (MH+), 147 (30), 105 (100). (ESI) 164.0822 (MH+-C6H15NO2P requires 164.0840).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.S(Cl)([Cl:12])=O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Cl:12])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ClCc1cncc(Br)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of (5-bromopyridin-3-yl)methanol (3 g, 16.0 mmol) in DCM (15 mL) cooled to 0° C. was added thionylchloride (7.59 g, 63.8 mmol) dropwise and the reaction mixture was stirred at room temperature over night. The mixture was poured onto ice/water (20 mL), basified with NaOH conc. (8 mL) and extracted with EtOAc (2×50 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc-Heptane gradient to give the title compound (3.08 g, 93%) as a white solid. MS: 206.0, 207.9 (M+H+).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[OH:8][C:9]([CH3:17])([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][SH:11].C(NC(C)C)(C)C>C(Cl)Cl>[CH2:12]([C:9]1([CH3:17])[O:8][C:4](=[O:5])[CH:3]([CH2:2][C:1]([OH:6])=[O:7])[S:11][CH2:10]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(C)(O)CS
Reactant: O=C1C=CC(=O)O1
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Reaction time: 0.25 h

Procedure:
Into a mixture consisting of 10 g of maleic acid anhydride, 8.5 g of 2-hydroxy-2-methylheptane-1-thiol and 105 ml of methylene chloride, 1 ml of diisopropylamine, dissolved in 5 ml of methylene chloride is dropped. During this step the temperature is maintained at equal to or less than 30°. An additional 8.5 g of 2-hydroxy-2-methylheptane-1-thiol, dissolved in 5 ml of methylene chloride is added. After 15 minutes the usual work-up is performed. (Usual working up refers to the following procedure throughout the examples: washing of the organic phase with 1% aqueous sulphuric acid and with water; drying of the organic phase over MgSO4 ; distilling off the solvent; and chromatographic purification of the residue on silica gel with chloroform or ether:petroleum ether = 2:8 as elution agent.) 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid is obtained: NMR: 3.88 (q), 1.54 (s), 0.9 (t).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1)(C(C)(C)C)(C)C.[F:15][C:16]([F:43])([F:42])[C:17]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[N:30]=[CH:29]2)(C1N=C(CO)SC=1)[OH:18]>>[F:43][C:16]([F:15])([F:42])[C:17]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[N:30]=[CH:29]2)([C:12]1[S:11][C:10]([CH2:9][OH:8])=[N:14][CH:13]=1)[OH:18]
Reactant: CC(C)(C)[Si](C)(C)OCc1nccs1
Reactant: OCc1nc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cs1
Product: OCc1ncc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)s1
Yield: 17 %

Procedure:
The title compound (73.1 mg, 17% overall yield) was prepared from 2-(tert-butyldimethylsilanyloxymethyl)thiazole (242 mg, 1.06 mmol) according to methods described for the synthesis of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(2-hydroxymethyl-thiazol-4-yl)ethanol (Example 84). MS m/z 424.48 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C([O-])CCCO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCCO)OCc1ccccc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
Sodium 4-hydroxybutyrate (25 g, 0.2 mol) and benzyl bromide (37 g, 0.22 mol) were dissolved in a mixed solvent of DMF (40 ml) and ethyl acetate (50 ml), and the reaction mixture was heated and refluxed for 4 hours. Then, the reaction mixture was allowed to cool to room temperature, diluted with a proper amount of ethyl acetate, washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product. The resulted product was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=4/1) to give 34.9 g of benzyl 4-hydroxybutyrate. Yield: 90%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][C:13]2[C:8](=[C:9]([O:19][CH3:20])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:15]([NH2:16])=[CH:14][C:13]2[C:8](=[C:9]([O:19][CH3:20])[CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OC)cccc2cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(OC)cccc2cc1N

Procedure:
Palladium-on-carbon (10%, 1.281 g, 1.204 mol, 0.1 equiv) was added under an atmosphere of argon to a solution of 8-methoxy-3-nitro-naphthalene-2-carboxylic acid ethyl ester (3.313 g, 12.04 mmol) in EtOH (50 ml). The atmosphere was replaced by hydrogen gas, and the mixture was stirred at room temperature for 3 hours (hydrogen balloon). The atmosphere was changed back to argon, the catalyst was filtered off and the filtrate was concentrated in vacuo to afford the title compound (2.820 g, 96%, inseparable 1:1.15 mixture of regioisomers A:B) of adequate purity for direct use in the next transformation. 1H NMR (400 MHz, CDCl3): δ=8.88 (s, 1H isomer B), 8.44 (s, 1H isomer A), 7.36 (s, 1H isomer A), 7.32-7.26 (m, 1H isomer A+1H isomer B), 6.91 (s, 1H isomer B), 6.73 (d, J=7.4 Hz, 1H isomer A), 6.50 (d, J=7.6 Hz, 1H isomer B), 4.41 (q, J=7.0 Hz, 2H isomer B), 4.40 (q, J=7.1 Hz, 2H isomer A), 3.97 (s, 3H isomer B), 3.96 (s, 3H isomer A), 1.44 (t, J=7.1 Hz, 3H isomer B), 1.44 (t, J=7.0 Hz, 3H isomer A). MS (ES+): 246 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].[O:19]1[CH:24]=[CH:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl.C(OCC)(=O)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1>[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
tert-Butyl [(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamate (Method 15, 7.0 g, 28.1 mmol) and 3,4-dihydro-2H-pyran (4.7 g, 56.2 mmol) dissolved in DCM (50 mL). 4-Toluene sulphonic acid pyridinium salt (100 mg) was added and the reaction stirred for 4 hours at ambient temperature. The reaction was diluted with ethyl acetate (100 mL), washed with water (2×50 mL), brine (50 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (8.9 g, 95%) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=S)=[N:7]1.[NH3:21]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:21])=[N:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7]1
Reactant: N
Reactant: OCCCCn1ccc(NC(=S)Nc2ccccc2)n1
Product: NC(=Nc1ccccc1)Nc1ccn(CCCCO)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
Yellow mercuric oxide (0.295 g.) was added to a solution of 1-(4-hydroxybutyl)-3-(3-phenylthioureido)pyrazole (100 mg.) in ethanolic ammonia (6 M; 10 ml.). The mixture was stirred at room temperature for 48 hours, centrifuged to remove the precipitated mercuric sulphide, and the supernatant evaporated to dryness in vacuo to give 1-(4-hydroxybutyl)-3-(2-phenylguanidino)pyrazole (98 mg; 100%) having the following n.m.r. spectrum in d6DMSO: 7.3 (br m, 9H); 5.7 (d, 1H); 4.2 (br m, 1H); 3.9 (t, 2H); 3.3 (t, 2H); 1.5 (br m, 4H).
Reaction SMILES: [N:1]1[C:10]2[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH3:19])([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:12]([O:16][C:17](=[O:25])[N:18]([CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1CCCc2cccnc21
Reactant: CN(CCCCN)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C

Procedure:
Using General Procedure B: Reaction of 6,7-dihydro-5H-quinolin-8-one, (4-amino-butyl)-methyl-carbamic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2 gave methyl-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-carbamic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.50-1.60 (m, 4H), 1.72-1.81 (m, 2H), 1.95-2.20 (m, 4H), 2.67-2.78 (m, 4H), 2.83 (s, 3H), 3.17-3.24 (m, 2H), 3.75-3.79 (m, 1H), 7.06 (dd, 1H, J=7.6, 4.7 Hz), 7.36 (d, 1H, J=7.7 Hz), 8.38 (d, 1H, J=4.5 Hz).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[I:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([CH:21]=O)=[CH:18][CH:19]=2)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:13]=1.N1CCCCC1>C(O)C>[I:11][C:12]1[C:20]2[C:15](=[CH:16][C:17](/[CH:21]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:18][CH:19]=2)[N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[N:13]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Oxindole (665 mg, 5 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (2 g, 5 mmol) were dissolved into ethanol (25 mL). Piperidine (0.1 mL) was added and the solution was heated to 70° C. for 2 h, cooled to rt and stirred overnight. The solvent was removed in vacuo to give an orange solid which was triturated with ethanol to give the title compound in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.86 (s, 1H), 7.62-7.55 (m, 3H), 7.24 (d, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.8 Hz), 6.86 (t, 1H, J=7.6 Hz), 5.75 (s, 2H), 3.62-3.58 (m, 2H), 0.93-0.89 (m, 2H), −0.04 (s, 9H); MS ESI 518.0 [M+H]+, calcd for [C22H24IN3O2Sii+H]+ 518.4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Br:23])C(=O)C1>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[Br:23])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cn(C)c(=O)c(C)c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent) in DMF is added NBS (1.20 equivalents) at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].F[C:21]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[C:23]([F:29])[C:22]=1[N+:30]([O-:32])=[O:31].C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]1[C:22]([N+:30]([O-:32])=[O:31])=[C:23]([F:29])[CH:24]=[C:25]([F:28])[C:26]=1[F:27]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1F
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: -78 °C
Reaction time: 16 h
Yield: 59.24 %

Procedure:
A stirred solution of 2-fluoro-4-iodoaniline (3.64 gm, 15.37 mmol) in dry THF (100 ml) under nitrogen was cooled to −78° C. and a solution of 1.0 M lithium hexa methyl disilazide (LiN(SiMe3)2) “LHMDS” (15.37 ml, 15.37 mmol) was added slowly. This reaction mixture was kept stirring at −78° C. for another hour and then 2,3,4,6-tetrafluoronitrobenzene was added. The reaction mixture was allowed to warm to room temperature and stirring continued for another 16 hours. Ethyl acetate (200 ml) was added to the reaction mixture and was washed with water. Organic layer was dried over sodium sulfate and further purified by column chromatography to provide yellow solid (3.75 gm, yield: 59.24%). M−H+: 410.9. 1H NMR (DMSO, 300 MHz): 6.85 (t, 1H); 7.38 (d, 1H); 7.62 (m, 2H); 8.78 (s, 1H).