Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([F:23])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[F:23][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH:8]=[O:9])=[CH:14][CH:15]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: FC1(c2ccc(Br)cc2)CCC1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2(F)CCC2)cc1

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S1-A) using 1.64 g of 1-bromo-4-(1-fluoro-cyclobutyl)-benzene (7.16 mmol), 4.92 ml of a 1.6 molar solution of n-BuLi in hexane (7.87 mmol) and 1.1 ml of DMF (14.32 mmol). 4-(1-Fluoro-cyclobutyl)-benzaldehyde was isolated as crude product as a light yellow liquid (1.23 g, 96%). 1H NMR (CDCl3, 300 MHz): δ 1.84 (m, 1H), 2.15 (m, 1H), 2.49-2.81 (m, 5H), 7.63 (d, J=8 Hz, 2H), 7.92 (d, J=8 Hz, 2H), 10.03 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[CH:9].I[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[C:9][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCNCc1ccc(OC)cc1OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNCC#Cc2ccc([N+](=O)[O-])cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 23A (12.47 g, 60.83 mmol) in a mixture of N,N-dimethylformamide (150 mL) and triethylamine (150 mL) was added 1-iodo-4-nitrobenzene (18.18 g, 73 mmol), CuI (2.33 g, 12.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.51 g, 3.04 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The crude material was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 2.36 (br s, 1H), 3.59 (s, 2H), 3.72 (s, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 6.48 (dd, J=6.0, 2.4 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 8.22 (d, J=8.8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH3:10])=[C:4]([F:14])[CH:3]=1.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16].C1COCC1>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:10])=[CH:16][NH:15][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([F:14])[CH:3]=1
Reactant: C/C(=C\c1ccc(Cl)cc1F)[N+](=O)[O-]
Reactant: [C-]#[N+]CC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.2 %

Procedure:
To a suspension of (E)-4-chloro-2-fluoro-1-(2-nitroprop-1-enyl)benzene (5 g, 23.2 mmol) and ethyl 2-isocyanoacetate (2.65 mL, 24.4 mmol) in a mixture of dry THF (20 mL) and i-PrOH (20 mL) was added 2.6 mmol TBD/g polymer (9.8 g, 25.5 mmol). The suspension was stirred at room temperature for 5 d. The reaction mixture was filtered off and the residue was washed with i-PrOH/THF (1:1, 30 mL). The filtrate was concentrated to give the desired product (5.7 g, 87%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](N)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1.ClC(Cl)C>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([N:8]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)CNc2cccc(Cl)c2C)cc1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(O)cc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 22.8 %

Procedure:
200 mg of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)glycinamide was dissolved in 2.0 mL of pyridine, and a solution (2.0 mL) of 200 mg of 4-hydroxybenzenesulfonamide in dichloroethane was added thereto, followed by stirring at 80° C. overnight. The reaction liquid was concentrated under reduced pressure, to the residue was added water, followed by extraction with ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70), and further purified by silica gel column chromatography (chloroform:methanol=100:0 to 97:3), and the obtained residue was crystallized from diisopropyl ether to obtain 68 mg of N2-(3-chloro-2-methylphenyl)-N2-[(4-hydroxyphenyl)sulfonyl]-N-(4-methoxybenzyl)glycinamide.
Reaction SMILES: C1(=O)[NH:5][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18]C2C=CC(CBr)=CC=2)=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:13][C:14]1[CH:28]=[CH:27][C:17]([S:18][C:9]2[CH:10]=[CH:2][C:3]([CH2:4][NH2:5])=[CH:7][CH:8]=2)=[CH:16][CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(Sc2ccc(CBr)cc2)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccc(CN)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
To a stirred mixture of potassium phthalimide (3.60 g, 19.4 mM) and dry N,N-dimethylformamide (200 ml) was added dropwise a solution of 4-(4-methylthiophenoxy)benzylbromide (5.00 g, 16.2 mM) in dry N,N-dimethylformamide at room temperature, the mixture was stirred for 5 h at the same temperature. The mixture was poured into water, and the mixture was extracted with toluene. The extract was washed with 5N NaOH, water and brine, dried with magnesium sulfate, and concentrated in vacuo. The residue was diluted with methanol (200 ml), and to the mixture was added dropwise hydrazine monohydrate (1.10 g, 21.1 mM). The mixture was stirred for 6 h under reflux, and this was cooled to the room temperature and concentrated in vacuo. The residue was diluted with chloroform and the mixture was filtered through celite. The filtrate was washed with 5N NaOH(x3) and brine(x2), dried with potassium carbonate, and concentrated in vacuo to give 4-(4-methylthiophenoxy)benzylamine (3.02 g, 76%) as colorless crystals, m.p. 61.8° C.
Reaction SMILES: [OH:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.[I-].[Na+]>CCOC(C)=O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:1][C@@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:11][CH:12]=1
Reactant: COC(=O)[C@H](C)O
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C)OCc1ccc(OC)cc1
Temperature: 150 °C
Yield: 61.9 %

Procedure:
A mixture of (S)-methyl 2-hydroxypropanoate (1.5 g, 14.41 mmol), 1-(chloromethyl)-4-methoxybenzene (3.38 g, 21.61 mmol), DIPEA (4.03 ml, 23.05 mmol) and sodium iodide (0.150 g, 1.001 mmol) was heated to 150° C. for 2 h. Reaction mixture then was cooled to room temperature diluted with EtOAc (100 mL) and washed with saturated NaHCO3 solution (2×50 mL) and brine. Combined organic extracts were dried over anhydrous Na2SO4 and concentrated. The crude mixture was purified by flash chromatography on silica gel using an ISCO system (eluted with 9:1 Hexanes and EtOAc) to give (S)-methyl 2-((4-methoxybenzyl)oxy)propanoate (2 g) as a gummy liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:4][CH:3]=1.[S:41](Cl)(=[O:44])(=[O:43])[NH2:42].O>CN(C)C(=O)C>[S:41]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[C:19]4[C:24]([CH:25]=3)=[CH:23][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=4)=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:40])=[CH:6][CH:7]=1)(=[O:44])(=[O:43])[NH2:42]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: NS(=O)(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2ccc(-c3ccc(OS(N)(=O)=O)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.9 %

Procedure:
4-(4-Hydroxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (56.2 mg, 0.105 mmol) was dissolved in N,N-dimethylacetoamide (3.9 mL), and the solution was added with sulfamoyl chloride (61 mg, 0.53 mmol), followed by stirring at room temperature for 17 hours. The reaction mixture was added with water and extracted with ethyl acetate and chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=5/1) to obtain 4-(4-sulfamoyloxyphenyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (36.2 mg, yield 56%).
Reaction SMILES: CO[C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]([CH:9]=[C:10](OC)[C:11]=1[O:12][CH3:13])[C:6](O)=O.C1C[O:22][CH2:21]C1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:21][OH:22])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC
Reactant: C1CCOC1
Product: COc1ccc(CCO)c([N+](=O)[O-])c1

Procedure:
To a stirred solution of the 3,4,5-Trimethoxy-2-nitrobenzoic acid (2 g, 7.77 mmol) and BH3 (1.0 M in THF, 13.2 ml) in THF (10 ml) was stirred and refluxed for 3 hours. After cooling, the reaction mixture was extracted with water and CH2Cl2. The combined organic layers were dried over MgSO4, and then evaporated to afford 4-methoxy-2-nitrobenzyl methanol. The crude 4-methoxy-2-nitrobenzyl methanol was dissolved in anhydrous CH2Cl2 (20 mL) and was subjected to pyridinium dichromate, PDC oxidation (5.84 g, 15.55 mmol)/molecular sieves (powder, 6 g) at room temperature for 16 h. The reaction mixture was filtrated by Celite and extracted with water and CH2Cl2. The organic layers were combined and evaporated. The residue was purified by flash chromatography (EtOAc:n-hexane=1:1) to afford compound A1 as a yellow solid, yield 69%. mp 73.8-75.1° C., 1H NMR (500 MHz, CDCl3) δ 3.97 (s, 3H), 3.99 (s, 6H), 7.21 (s, 1H), 9.86 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1.[H-].[Na+].I[CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C=O>[CH2:23]([O:19][C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:9][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:11]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCI
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2F)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCOC1(c2ccccc2F)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
135 mg (0.4 mmol) of 3-(2-fluorophenyl)-3-hydroxy-1-(tert-butoxycarbonyl)azetidine at 80% in 2 ml of dimethylformamide are added to a suspension of 65 mg (1.6 mmol) of sodium hydride at 60% in 1.5 ml of dimethylformamide, under nitrogen, at 0° C. After stirring for 20 minutes at 0° C., 0.2 ml (1.5 mmol) of iodobutane are added. The reaction medium is stirred at ambient temperature for 1 h 30 and is then hydrolysed with water and with a saturated aqueous solution of ammonium chloride and extracted with a 1/2 heptane/ethyl acetate mixture. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated. The crude product is purified by silica gel chromatography, elution being carried out with an 8/2 heptane/ethyl acetate mixture. 104 mg of 3-butoxy-3-(2-fluorophenyl)-1-(tert-butoxycarbonyl)azetidine are obtained in the form of a yellow oil with a yield of 79%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:21]1[O:24][CH:22]1[CH3:23]>>[OH:24][CH:22]([CH3:23])[CH2:21][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1ccc(CCN2CCNCC2)cc1
Reactant: CC1CO1
Product: CCOC(=O)Cc1ccc(CCN2CCN(CC(C)O)CC2)cc1
Yield: 92 %

Procedure:
This is prepared analogously to Example 11 by the reaction of ethyl 4-[2-(piperazin-1-yl)-ethyl]-phenylacetate with propylene oxide. Yield 92% of theory; colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH2:22][C:21]1[C:16]([NH:15][C:10](=[O:12])[C:9]([O:8][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)([CH3:14])[CH3:13])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccnc1N
Reactant: CC(C)(Oc1cccc(Cl)n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(C)(Oc1cccc(Cl)n1)C(=O)Nc1ncccc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
2-(6-Chloro-pyridin-2-yloxy)-2-methyl-propionic acid (0.53 g, 2.4 mmol) and 2,3-diaminopyridine (0.268 g, 2.4 mmol) were dissolved in DMF (5 ml) cooled to 0° C. and added EDCI (0.62 g, 3.2 mmol) and stirred for 4 h. The reaction mixture was extracted in EtOAc (30 ml) and washed with brine (2×10 ml) dried over Na2SO4 and concentrated under reduced pressure to obtain crude product. The product was purified on silica gel to yield N-(3-Amino-pyridin-2-yl)-2-(6-chloro-pyridin-2-yloxy)-2-methyl-propionamide (0.54 g, 72%). 1H NMR (400 MHz, CDCl3): 4.84 (brs, 2H), 6.67 (dd, J=4.8 and 7.6 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 7.02 (d, J=8. Hz, 1H), 7.40 (d, J=8. Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.996 (dd, J=4.8 Hz and 7.6 Hz, 1H). MS (EI) m/z: 307 (M+1).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[C:10]([O:15][CH2:16][CH3:17])(=[O:14])/[CH:11]=[CH:12]/[CH3:13].NC1C(F)=CC(/C(/C)=C/C(OCC)=O)=C(F)C=1>>[NH2:6][C:5]1[CH:7]=[CH:8][C:2](/[C:12](/[CH3:13])=[CH:11]/[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[C:3]([Cl:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(Cl)c1
Reactant: C/C=C/C(=O)OCC
Agent: CCOC(=O)/C=C(\C)c1cc(F)c(N)cc1F
Product: CCOC(=O)/C=C(\C)c1ccc(N)cc1Cl
Yield: 31 %

Procedure:
Using 4-bromo-3-chloroaniline (10.0 g) and ethyl crotonate (10.0 ml), Compound 12a (3.56 g, 31%) was obtained as a brown solid in the same manner as Compound 10a was synthesized.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:22][Si:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][S:26]([NH2:29])(=[O:28])=[O:27]>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:8]2=[N:29][S:26]([CH2:25][CH2:24][Si:23]([CH3:31])([CH3:30])[CH3:22])(=[O:28])=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=O)C1
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=NS(=O)(=O)CC[Si](C)(C)C)C1
Temperature: 110 °C
Yield: 97.7 %

Procedure:
A mixture of tert-butyl 6′-bromo-1′-oxo-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate (0.2863 g, 0.8 mmol), 2-(trimethylsilyl)ethanesulfonamide (0.2000 g, 1.1 mmol), and Ti(OEt)4 (0.6900 g, 3.0 mmol) in 1,2-dichloroethane (3 mL) was heated at 110° C. for 20 h. The reaction mixture was then quenched with ice, extracted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.4031 g (96%) of tert-butyl 6′-bromo-1′-(((2-(trimethylsilyl)ethyl)sulfonyl)imino)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate. LC-MS tR=2.31 min in 3 min chromatography, m/z 515, 517 (MH), 459, 461 (MH+-56).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:52]([N:51]([CH3:50])[C:10]([C@@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH2:53][CH2:54][CH2:55][CH:56]=[CH2:57]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Reactant: C=CCCCCNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a cold solution of cis-N-Boc-4-hydroxy-L-proline (10 g. 1 eq.), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU 15.5 g, 1.12 eq.) and N-methylhex-5-en-1-amine tosylate salt 32a (13.6 g, 1.1 eq.), which was prepared according to Scheme 13 as described herein, in DMF (80 mL) containing DIPEA (29.4 mL, 3.9 eq.) was added dropwise under nitrogen at 0° C. The reaction mixture was stirred overnight at room temperature, and then quenched with water and extracted with diethyl ether. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to yield compound 48 as a rose powder in 95% yield. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 1.29-1.3 (m, 9H), 1.33-1.55 (m, 4H), 1.70-1.80 (m, 1H), 1.97-2.12 (m, 3H), 2.77-2.97 (m, 3H), 3.15-3.40 (m, 4H), 4.22 (br s, 1H), 4.50-4.62 (m, 1H), 4.90-5.04 (m, 3H), 5.71-5.83 (m, 1H); MS (ESI+): m/z=327 (MH+).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:37]=[N:36][N:35]=2)=[CH:24][CH:23]=1.O>CS(C)=O>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:38]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:37]=[N:36][N:35]=3)=[CH:26][CH:27]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
0.87 g (5 mmol) of 2-n-butyl-benzimidazole is dissolved in 20 ml of dimethylsulphoxide and 0.61 g (5.5 mmol) of potassium tert.butoxide is added with stirring. After 1/2 hour, 4'-bromomethyl-2-(1-triphenylmethyl-1H-tetrazol-5-yl)-biphenyl is added and the mixture is stirred for 3 hours at ambient temperature. It is poured into about 50 ml of iced water and extracted by shaking 3 times using 30 ml of ethyl acetate each time. The ethyl acetate phase is extracted by shaking using 30 ml of water, dried over sodium sulphate and evaporated to dryness. The crude product is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol=100:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]([F:27])([F:26])[F:25])=[CH:4][C:5]([N+:21]([O-])=O)=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:7]=1.O.NN>C(O)C.[Ni]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:13][CH2:14]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:24]([F:26])([F:25])[F:27]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c(Cl)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
N-(5-Chloro-4-trifluoromethyl-2-nitrophenyl)-1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (D51) (0.64 g, 1.57 mmole) was dissolved in ethanol (25 ml) and Raney nickel (50% aqueous suspension, 100 mg) was added at room temperature; the mixture was heated to 60° C. and hydrazine monohydrate (0.8 ml) was added over 30 min. After 2 hr more, the reaction mixture was cooled to room temperature, filtered through Celite and the solvent was evaporated to dryness. The residue was purified by silica gel chromatography eluting with 2 to 20% methanol in dichloromethane to yield the title compound as a cream solid, 0.34 g, 58%. MH+=378 and 380.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:3][CH:2]=1.[I-:15].[Na+]>CC(C)=O>[C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][I:15])=[CH:3][CH:2]=1
Reactant: Cc1ccc(CCCCCCBr)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1ccc(CCCCCCI)cc1

Procedure:
6-(p-Tolyl)hexyl iodide [VIa; Ar is 4-CH3C6H4, R is H] was prepared from 6-(p-tolyl)hexyl bromide (Preparation C14) and sodium iodide in acetone according to the procedure of Preparation D2 above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][C:7]([CH3:14])=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)(=O)C.C(Cl)(Cl)Cl.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=C(C)Nc1ccc(OC)c(OC)c1
Agent: O=[Pt]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CC(C)Nc1ccc(OC)c(OC)c1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 30.0 g of the product of Example 1 (m.p. 59°-60°), and 2.0 g of platinum oxide in 250 ml of acetic acid was hydrogenated in a Paar shaker at 50 p.s.i.; reduction was complete in 1 hr. The mixture was filtered and concentrated under reduced pressure, to give an amber oil which was dissolved in chloroform and washed with sodium bicarbonate solution followed by saturated sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 30.0 g of an amber oil which was used in the next step without further purification. A sample of oil was converted to the hydrochloride salt, m.p. 137.5°-139°. An equivalent sample of the hydrochloride salt (m.p. 138°-139.5°) was analyzed.