Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH:10]2[CH:6]([CH2:7][N:8]([C:11](=[O:22])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH3:13])[CH2:9]2)[C:5](=[O:23])[CH2:4][CH2:3]1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Mg]Br>>[CH3:24][C:2]1([CH3:1])[C@H:10]2[C@H:6]([CH2:7][N:8]([C:11](=[O:22])[C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[CH3:13])[CH2:9]2)[C@:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])([OH:23])[CH2:4][CH2:3]1
Reactant: COc1ccccc1[Mg]Br
Reactant: COc1ccccc1[C@H](C)C(=O)N1CC2C(=O)CCC(C)(C)C2C1
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2[C@H](C1)[C@@](O)(c1ccccc1OC)CCC2(C)C
Yield: 26.1 %

Procedure:
By working according to the experimental procedure of Example 9, from 0.78 g of 7,7-dimethyl-2-[2-(S)-(2-methoxyphenyl)propionyl]-4-perhydroisoindolone (mixture of (3aR,7aR) and (3aS,7aS) diastereoisomers) and 1.5 g of 2-methoxyphenylmagnesium bromide, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 21 cm), 0.27 g of (3aR*,4R*,7aR*)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[2-(S)-(2-methoxyphenyl)propionyl]-4-perhydroisoindolol is obtained, in the form of a white foam.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:26]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:8]([NH2:28])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:30][CH2:31][CH3:32]>>[NH2:28][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:26])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:30][CH2:31][CH3:32])[CH2:22][CH2:21]1
Reactant: CCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCC3CCN(CCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[5-(4-piperidinyl)pentyl]-9H-purin-6-amine and 1-iodopropane.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:6][C:5]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[NH:21][C:20]2=[O:30])=[C:4]([F:31])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:38](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:38][N:21]1[C:22]([C:26]([F:28])([F:29])[F:27])=[CH:23][C:24](=[O:25])[N:19]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([F:16])([F:17])[F:18])[C:2]([Cl:1])=[CH:3][C:4]=2[F:31])[C:20]1=[O:30]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2C(F)(F)F)c(Cl)cc1F
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3C(F)(F)F)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 3-[4-chloro-2-fluoro-5-(2-trifluoromethylphenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4,-dione (0.7 g), potassium carbonate (0.27 g) and 2,4-dinitrophenoxyamine (0.39 g) in anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 72 hours. The solution was processed and the resulting oil chromatographed on silica gel eluting with hexane:ethyl acetate, 4:1, containing 0.1% of triethylamine. The product (Compound 9-24) was isolated as a pale yellow amorphous solid (0.6 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]=[CH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[C:24](I)[CH:23]=[CH:22][C:21]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH3:11])[CH:23]=[CH:22][C:21]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=Cc1c(C)cc(C)cc1C
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)c(C(C)c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c(C)c1
Temperature: 120 °C

Procedure:
A mixture of 1,3,5-trimethyl-2-vinylbenzene (0.058 mL, 0.36 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), Pd(OAc)2 (5 mg, 0.09 mmol) and triethylamine (0.13 mL, 0.9 mmol) in acetonitrile (1.5 mL) is heated in a microwave apparatus at 120° C. for 1 h. The mixture is filtered over Celite and the filtrate is evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].[OH-].[NH4+]>>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Clc1ccc(Cc2ccccn2)cc1
Reactant: O=[N+]([O-])O
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Cc2ccccn2)ccc1Cl
Reaction time: 8 h

Procedure:
99 G. (0.487 mol) of 2-(p-chlorobenzyl)pyridine was added to 500 ml. of fuming nitric acid cooled to 10 ° while maintaining the temperature at <10° for 2 hours. The resulting mixture was poured into 800 ml. of ice, neutralized with ammonium hydroxide and allowed to stand overnight at room temperature. The resulting solid was collected, washed with water and air dried to give 2-(4-chloro-3-nitrobenzyl)pyridine as off-white prisms, m. 58°-60° C. (aq. ethanol).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1.CC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11](=[N:21][C:17]3[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccnc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(=Nc3cccnc3)CC2)cc1

Procedure:
A mixture of 19 parts of 1-(phenylmethyl)-4-piperidinone, 11.8 parts of 3-pyridinamine, 120 parts of methylbenzene and a small volume of 4-methylbenzenesulfonic acid is stirred and refluxed for 5 hours. (The reaction vessel is provided with reflux-condensor and water-separator). After the calculated amount of water is separated, the solvent is evaporated. The oily residue is dissolved in 800 parts of 2,2'-oxybispropane and evaporated again, yielding 27 parts of N-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine as a yellow-brown oil.
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18](=[N:20]O)[NH2:19]>N1C=CC=CC=1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]1[N:20]=[C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:9][N:19]=1
Reactant: NC(=NO)c1cc(F)ccc1F
Reactant: CCOC(=O)CC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Cc1nc(-c2cc(F)ccc2F)no1
Yield: 770.5 %

Procedure:
Ethyl 3-chloro-3-oxopropanoate (1.7 mL; 13.2 mmol) was added to 2,5-difluoro-N′-hydroxybenzenecarboximidamide (JRD-Fluorochemical, 1.13 g; 0.6 mmol) in pyridine (30 mL). The mixture was heated to reflux for 4 hours and the solvent removed in vacuo. The residue was taken up into DCM (20 mL) and washed with water (10 mL). The organic phase was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified on a Biotage 25+M column, eluting with petrol containing increasing amounts of EtOAc to give ethyl 2-(3-(2,5-difluorophenyl)-1,2,4-oxadiazol-5-yl)acetate (1.24 g, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-])=O.O1CCCC1.C([O-])=O.[NH4+]>CO.[Pd]>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
5-nitroindole (1.0 g, 6.17 mmol) was dissolved in methanol (10 ml) and anhydrous tetrahydrofuran (10 ml) at room temperature and then, palladium/carbon (10%) of a catalystic amount and ammonium formate (2.0 g, 31.7 mmol) were added to be stirred slowly at room temperature for 30 minutes. After completing the reaction, the reacting solution was filtered through celite, washed with methanol, concentrated under reduced pressure and then, dropped a silica gel short column. Afterward, the residue was concentrated again under reduced pressure and triturated with isooctane. As a result, the present compound (0.45 g, productive yield 55%) was obtained as a solid phase.
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[CH:25]=[C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH:23]=[CH:22][C:8]=1[O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19]([OH:21])=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45](O)[O:44]1)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CC#N>[CH2:33]([O:40][C:41]([C@H:43]1[C@H:48]([OH:49])[C@@H:47]([OH:50])[C@H:46]([OH:51])[C@H:45]([O:20][C:19](=[O:21])[CH2:18][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][C:8]3[CH:22]=[CH:23][C:24]([NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][C:7]=3[CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=2)[O:44]1)=[O:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COc1ccc(CC(=O)O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Reactant: O=C(OCc1ccccc1)[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CC#N
Product: COc1ccc(CC(=O)O[C@@H]2O[C@@H](C(=O)OCc3ccccc3)[C@H](O)[C@@H](O)[C@@H]2O)cc1Oc1ccc(NC(=O)C(C)(C)C)cc1CSC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid (0.200 g, 0.44 mmol), (2R,3R,4R,5S,6R)-3,4,5,6-tetrahydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.200 g, 0.7 mmol; prepared according to the procedure described in Tetrahedron 2007, 63, 7596), HATU (0.266 g, 0.7 mmol), and N-methylmorpholine (0.1 mL, 0.7 mmol) were combined in MeCN, and the reaction was stirred overnight at room temperature. The mixture was concentrated, and the residue was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid benzyl ester, which was subsequently treated with palladium hydroxide on carbon and stirred under an atmosphere of H2 overnight. The crude material was purified by preparative HPLC to give (2R,3R,4R,5S,6S)-6-(2-{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-phenoxy]-4-methoxy-phenyl}-acetoxy)-3,4,5-trihydroxy-tetrahydro-pyran-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].[N+:23]([C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br)([O-:25])=[O:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:20]([C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:3]2[CH:4]=[C:5]([O:8][CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][C:2]=2[NH:1][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[O:13])=[CH:19][CH:18]=1)([CH3:22])[CH3:21]
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCOc1ccc(NCc2cccc([N+](=O)[O-])c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A mixture of 30 g (102 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone, 23.8 g (110 mmol) 3-nitrobenzylbromide and 21 ml (120 mmol) Hünig's base in 160 ml methylene chloride is stirred overnight at 45° C. The resulting dark solution is washed twice with 200 ml water and with brine. Purification of the crude product by chromatography (CH2Cl2/petroleum ether 1:1) affords 34.4 g (79%) of a viscous red oil.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(O)C>[C:18]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:9][OH:10])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ethanol solution (300 ml) of 3,3,3-triphenylpropionic acid (15 g) was added dropwise, under ice-cooling, thionyl chloride (5 ml). The mixture was refluxed for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, which was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution. The organic layer was dried, which was then concentrated under reduced pressure. The concentrate was dissolved in ether (50 ml), which was added dropwise, under ice-cooling, to an ether suspension (250 ml) of lithium aluminum hydride (1.89 g). The mixture was stirred for one hour at room temperature, which was processed with 10% HCl, followed by addition of ether. The organic layer was washed with water, dried and concentrated under reduced pressure (14.2 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1)=O.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:3]([C:5]2([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]2)=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
To a mixture of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (4.2 g) and 4-fluoroaniline (3.3 g) in DCM (40 ml) was added EDC (7.4 g) and HOBt (4 g), the reaction was stirred at RT for 4 hours and washed with 1N HCl, NaHCO3 solution, water, brine and dried over Na2SO4. The solution was evaporated and the residue was mixed with NaOH (3.2 g) and MeOH/H2O (60 ml/6 ml). The mixture was refluxed for 30 minutes then was evaporated. The residue was acidified with 4N HCl and the precipitate was filtered. The filter cake was washed with water followed by cold EtOH to give the product as 1-(4-fluorophenylcarbamoyl)-cyclopropanecarboxylic acid 2.8 g. This product (1.8 g) was mixed with DCM (30 ml) and two drops of DMF. Oxalyl chloride (1.2 ml) was added into the solution and the reaction was refluxed for one hour. The solvent was removed followed by adding DCM (20 ml) and DIPEA (1.3 ml). To the above solution was added 4-methoxybenzyl 1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropylcarbamate (1.5 g), the reaction was stirred at RT for 4 hours. Saturated NaHCO3 (30 ml) and DCM (80 ml) were added into the reaction, the solution was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified with silica gel column to give the titled compound 2.1 gram. Mass: (M+1), 739
Reaction SMILES: [CH2:1]([O:7][C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:11])[CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[S:25](Cl)([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[S:25]([O:27][CH2:28][CH3:29])([O:10][CH2:9][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:11])=[O:26]
Reactant: CCCCCCOC(C)(CO)OCCCCCC
Reactant: CCOS(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCOC(C)(COS(=O)OCC)OCCCCCC
Temperature: 23 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
To a solution of alcohol 4 (20.6 g, 79.1 mmol) in CH2Cl2 (200 mL) is added pyridine (8.12 g, 102.8 mmol) and ethyl chlorosulfite (12.2 g, 94.9 mmol). The reaction mixture is stirred at 23° C. for 10 hours. The reaction is quenched with water (100 mL) and extracted with CH2Cl2 (2×100 mL). The combined organic layers are washed with HCl (1N, 100 mL), saturated NaHCO3 (100 mL), brine (100 mL) and dried over anhydrous sodium sulfate. The solvent is removed and the residue is purified by silica gel chromatography (1→10% ethyl acetate/hexane) to give 2,2-bis(hexyloxy)propanyl ethyl sulfite 6 (24.5 g, 88%) as a colorless oil: Rf(15% EtOAc/hexane)=0.44; IR (thin film, cm−1) 2932, 2872, 1467, 1379, 1213, 1194, 1176, 1001, 888; 1H NMR (600 MHz, CDCl3) δ 4.11-4.00 (m, 2H), 3.93 (d, J=10.8 Hz, 1H), 3.77 (d, J=10.8 Hz, 1H), 3.42-3.37 (m, 4H), 1.51-1.48 (m, 4H), 1.33 (s, 3H), 1.31-1.24 (m, 15H), 0.85 (t, J=7.2 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 99.0, 62.9, 60.8, 58.5, 58.3, 31.6, 29.8, 25.9, 22.6, 20.9, 15.3, 14.0.
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:18].[OH-].[Na+].CCOCC>O1CCCC1>[ClH:18].[N:1]1([C:10]2[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(N2CCc3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCc1ccc(N2CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.06 g (54.8 mmole) of 4-(1-indolinyl)benzonitrile of Example 2a in 62 ml tetrahydrofuran (THF) was added dropwise to a rapidly stirred ice cold solution of BH3 in THF (181 ml of 0.93 M solution, 3.07 equiv. 168.4 mmole) under nitrogen. After heating at reflux for 1.5 hours, the solution was permitted to cool to room temperature and stand overnight. The ice cold reaction mixture was then treated dropwise with 6 M aq. HCl (100 ml), heated at reflux for 40 minutes, cooled to 0° C., and made basic using solid NaOH. The resulting aqueous phase was extracted with ether and the combined organic portions (100 ml total) were washed with water (300 ml), twice with brine (300 ml portions) dried (Na2SO4) and concentrated to afford 13.2 g of crude free base. A solution of 7.5 g (33.4 mmole) of crude free base in 200 ml 1:1 ethanol-ether was treated with 50 ml of ethanolic HCl. 200 ml dry ether was added and the resulting solid was filtered, washed with dry ether, and dried thus giving 5.9 g (67.7%) of crude product. Recrystallization from hot ethanol-ether (charcoal) afforded 2.98 g of pure 4-(1-indolinyl)benzenemethanamine hydrochloride, m.p. 251.5°-252.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(#N)C>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:5]2[S:1][C:2]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[CH:19][CH:20]=3)=[N:3][CH:4]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2nccs2)cc1
Reactant: Clc1ccc(I)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)COc1ccc(-c2ncc(-c3ccc(Cl)cc3)s2)cc1
Temperature: 60 °C
Yield: 65.2 %

Procedure:
To a solution of tert-butyl 2-(4-(thiazol-2-yl)phenoxy)acetate (360 mg, 1.23 mmol) and 1-chloro-4-iodobenzene (412.5 mg, 1.73 mmol) in anhydrous acetonitrile (ACN) (5.2 mL) was added PPh3 (32.74 mg, 124 μmol) and Ag2CO3 (685.2 mg, 2.46 mmol). The flask was evacuated and re-filled with nitrogen three times and then PdCl2dppf was added (50.5 mg, 0.062 mmol). The reaction mixture was heated under Ar atmosphere for 72 h at 60° C. When the reaction was completed, the reaction mixture was filtered through Celite® (inorganic solids were removed) and the precipitate was washed with several portions of dichloromethane(3×20 mL). The filtrate was evaporated, and the residue was absorbed onto silica then subjected to flash chromatography (SiO2, hexane: ethyl acetate (AcOEt), 9:1) to afford 322.5 mg of tert-butyl 2-(4-(5-(4-chlorophenyl)thiazol-2-yl)phenoxy)acetate as a yellow solid (76% yield). RMN1H (CDCl3, 400 MHz): δ 7.94; (s, 1H), 7.92-7.87; (m, 2H), 7.56-7.46; (m, 2H), 7.42-7.35; (m, 2H), 7.01-6.93; (m, 2H), 4.57; (d, J=3.6 Hz, 2H), 1.50; (s, 9H) ppm.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH2:2]([N:9]([CH2:21][CH:22]([OH:20])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1ccccc1OCC1CO1
Reactant: Oc1ccc(OCCNCc2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Oc1ccc(OCCN(Cc2ccccc2)CC(O)COc2ccccc2F)cc1

Procedure:
A mixture of N-benzyl-2-(p-hydroxyphenoxy)ethylamine hydrochloride (see Example 1) (5.6 g), 1,2-epoxy-3-o-fluorophenoxypropane (3.6 g) and anhydrous potassium carbonate (2.7 g) was heated under reflux in propan-2-ol (100 ml) for 24 hours. The reaction mixture was cooled, the solid removed by filtration and the solvent evaporated from the filtrate. The residual oil was purified by chromatography on silica eluting with 1% v/v methanol in dichloromethane to give N-benzyl-N-(2-p-hydroxyphenoxyethyl)-3-o-fluorophenoxy-2-hydroxypropylamine as a colourless oil; NMR: 2.27-3.15 (m, 4H, CH2NCH2), 3.8 (dd,2H, NCH2Ph), 3.9-4.2 (m,5H, OCH2.CHOH, o--F-Ph.OCH2), 6.7 (s, 4 aromatic H), 6.8-7.1 (m, 4 aromatic H), 7.3 (m,5H, CH2Ph).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:15])[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7]2.[OH-:16].[Na+]>CC#N.O>[CH3:15][N:4]1[C:3]([CH2:2][OH:16])=[C:11]2[C:6]([CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:10]2)=[N:5]1
Reactant: [OH-]
Reactant: Cn1nc2cc([N+](=O)[O-])ccc2c1CBr
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cn1nc2cc([N+](=O)[O-])ccc2c1CO
Temperature: 25 °C
Reaction time: 48 h
Yield: 33 %

Procedure:
3-(Bromomethyl)-2-methyl-6-nitro-2H-indazole (4.20 g, ˜14.9 mmol) in CH3CN (500 ml) and water (200 ml) was treated with NaOH to give pH˜11. The solution was stirred at rt for 2 days then conc. in vacuo and repeatedly extracted with dichloromethane and chloroform. The combined organic extracts were evaporated, and the crude product was purified by silica gel column chromatography to give (2-methyl-6-nitro-2H-indazol-3-yl)methanol (1.03 g, 33% TY). MS (ES+, m/z) 208.