Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([N+:17]([O-])=O)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[PH2]([O-])=O.[Na+]>C1COCC1>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([NH2:17])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1Oc1ccc(F)cc1F
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(N)c2ncccc2c1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
To a solution of 5-(2,4-difluoro-phenoxy)-6-methoxy-8-nitro-quinoline (1.36 g, 4.1 mmol) in 30 mL of THF was added an aqueous solution of sodium hypophosphite (2.7 g, 31 mmol in 10 mL H2O). The reaction mixture was degassed under N2, treated with Pd/C (˜1 g), and stirred at room temperature under N2 for 1 hour. The reaction mixture was filtered through Celite®, and washed with 1N NaOH solution followed by water. The organic layer was dried over MgSO4, and the solvent removed to give 0.9 g (75%) of 5-(2,4-difluoro-phenoxy)-6-methoxy-quinolin-8-ylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]([S:18]([NH2:20])=[O:19])([CH3:17])[CH3:16].[B-].[Na+]>C1COCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)S(N)=O
Reactant: CC(=O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [B-]
Solvent: C1CCOC1
Product: CC(NS(=O)C(C)(C)C)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
A mixture of 1-(4-amino-3-nitrophenyl)ethanone (500 mg, 2.78 mmol, J. Med. Chem. 1998, 41, 1777-1788), 2-methylpropane-2-sulfinamide (674 mg, 5.56 mmol) in THF (25 mL) was added titanium(IV) ethoxide (1.75 ml, 8.34 mmol) at room temperature. The mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, sodium borohydrate (316 mg, 8.34 mmol) was added to the mixture at room temperature. The mixture was stirred at room temperature for 14 hours. The mixture was quenched with MeOH (6 ml), poured into saturated sodium hydrogencarbonate aqueous solution (20 mL), extracted with EtOAc (150 mL×2). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated. The residue was chromatgraphed on a column of silica gel with hexane-EtOAc (1:2) as an eluent to afford 675 mg (85%) of title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 1.11 (9H, s), 1.37 (3H, d, J=6.6 Hz), 4.33-4.24 (1H, m), 5.64 (1H, d, J=6.6 Hz), 6.99 (1H, d, J=8.8 Hz), 7.40 (2H, s), 7.45 (1H, d, J=8.8 Hz), 7.97 (1H, s). MS (ESI) m/z 286 (M+H)+, 284 (M−H)−.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C@@H:4]([CH3:9])[NH:3]1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:3]2[C@H:4]([CH3:9])[CH2:5][C:6](=[O:8])[CH2:7][C@@H:2]2[CH3:1])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C[C@@H]1CC(=O)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(=O)C[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
The crude cis-2,6-dimethylpiperidin-4-one 91 from previous experiment (1.1 g, 8.6 mmol) was dissolved in CH2Cl2 (50 mL) and triethylamine (5 mL, 35 mmol) was added. Stirred solution was treated with 4-chlorobenzenesulfonyl chloride (2.2 g, 9.5 mmol). The mixture was stirred for 24 hr then was divided between water (100 mL) and CH2Cl2 (100 mL). Organic layer was washed with 0.2 N citric acid, water, brine and dried over anhydrous Na2SO4. The solution was filtered and evaporated. The residue was purified by flash chromatography, eluting with EtOAc-hexane (1:3) mixture. Yield 60 mg (2% after two steps).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][S:7][CH:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NS(=O)(=O)c1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1csc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of the product of Example 2 in 5.0 mL of acetic acid-chloroform (1:1) at room temperature was added 0.299 g (1.682 mmol) of N-bromosuccinimide. The reaction was stirred for 18 h and then diluted with ether, washed with water and saturated sodium bicarbonate solution, dried over MgSO4, filtered and concentrated in vacuo. The tan solid residue was washed with ether-hexanes (1:1) to provide 0.504 g (81%) of the desired product as a tan solid. Electrospray Mass Spec: 406.1 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH3:20][CH:21]1[CH2:26][C:25](=O)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>ClCCl>[CH3:20][CH:21]1[CH2:26][C:25]2([O:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:8]3[CH:9]=[CH:10][CH:11]=[C:12]23)[CH2:24][CH2:23][N:22]1[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1-n1cccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC2(CCN1C(=O)OC(C)(C)C)Oc1ccccc1-n1cccc12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (443 pt, 5.75 mmol) was added to a solution of 2-pyrrol-1-ylphenol (457 mg, 2.87 mmol) and tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate (613 mg, 2.87 mmol) in dichloromethane (19 mL) and the solution was vigorously stirred for 16 h. The reaction mixture was quenched with saturated aqueous NaHCO3, and the organics were extracted with EtOAc (3×200 mL). The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (silica gel: 0-10% EtOAc in dichloromethane) to give tert-butyl 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate as a brown oil. The crude residue was dissolved in a solution of HCl in dioxane (1.4 mL of 4.0 M, 5.6 mmol) and stirred for 30 min at room temperature. The volatiles were removed in vacuo and the residue was dissolved in diethylether. The solids were collected by filtration to provide 2′-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] hydrochloride (386 mg, 46%) as a reddish brown solid. ESI-MS m/z calc. 254.1, found 255.5 (M+1)+; Retention time: 1.12 minutes (3 min run).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([N+:8]2[N-:9][O:10][C:11](=[NH:13])[CH:12]=2)[CH2:4][CH2:3]1.[OH-:14].[Na+]>O>[O:2]1[CH2:7][CH2:6][N:5]([N:8]([CH2:12][C:11]([NH2:13])=[O:10])[N:9]=[O:14])[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: N=c1c[n+](N2CCOCC2)[n-]o1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)CN(N=O)N1CCOCC1
Reaction time: 1 h

Procedure:
To 4.1 g of 3-morpholino-sydnonimine hydrochloride dissolved in 10 ml of water is added with stirring 1.440 g of 40% aqueous sodium hydroxide. The reaction mixture is stirred for 1 hour. The aqueous solution is concentrated and cooled. Two crops of crystals are collected, combined and recrystallized from a 2 to 1 solution of chloroform and methanol. Two crops of the purified product, α-(N-morpholino-N-nitrosoamino)acetamide, m.p. 134° - 136° C., are collected.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].F[C:10]1[CH:11]=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[C:14]([NH2:16])[CH:15]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:10]2[CH:11]=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[C:14]([NH2:16])[CH:15]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: CCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
A mixture of 1-ethyl-piperazine (1.2 mL, 9.6 mmol), 5-fluoro-2-nitro-phenylamine (1 g, 6.4 mmol), DIPEA (1.24 g, 9.6 mmol) in DMF (15 mL) was heated at 80° C. overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The combined extract was washed with brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by flash chromatography on silica to afford the title compound (1 g, yield: 63%). ESI-MS: 251 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32]([C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32]([C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Product: Cc1cccc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccccc2)c1

Procedure:
0.251 g (0.460 mmol) of (2R*,4S*)-2-benzyl-1-(3-toluoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.070 g (1.84 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR71## is obtained (0.172 g, 83%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.27, FD-MS: M+ =449.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:18]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:19]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH3:20].CN1CCOCC1>CN(C=O)C>[NH:18]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C@H:19]([C:21]([NH:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:22])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O

Procedure:
H-Glu(OBzl)-OH (7.0 g, 29.5 mmol) was finely ground in a mortar and pestle and then stirred with 8.88 g (32.3 mmol) of Boc-Ala-OSu for 48 hours in 250 ml DMF in the presence of 6 ml N-methylmorpholine (NMM). Some more NMM was added to maintain the reaction slightly basic during the reaction. The solvent was evaporated and the residue partitioned between 30 ml ethyl acetate and 500 ml H2O containing 2 ml of 10% H2SO4. The organic layer was then washed three times with water, dried(Na2SO4) and evaporated to dryness. The product was taken up in a small volume of ether and treated with a large volume of petroleum ether. A white amorphous solid was obtained which was homogeneous on tlc: Yield, 11.0 g (91.5%); mp 84°-88°; [α]D25 = -8.08° (c l, DMF).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C(#N)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCCCCC>C1COCC1.O1CCOCC1.[Zn+2].[Br-].[Br-]>[C:1]1([C:7]#[C:8][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccccc1
Reactant: C#Cc1ccccc1
Agent: CCCCCCCCCCCCC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 44 %

Procedure:
A solution of phenylacetylene (0.439 ml; 0.409 g; 4.00 mmol) in THF (2 ml) was treated at 0° C. with n-butyllithium (1.6 ml; 4.0 mmol; 2.5 M in hexanes) and the resulting solution was allowed to warm to room temperature for 10 min. The solution was cooled to 0° C., then treated with a solution of ZnBr2 (0.923 g; 4.10 mmol) in THF (2 ml) and allowed to warm to room temperature for 30 min. Solvent was removed in vacuo, then 1,4-dioxane (2 ml) was added. This solution was then added to a room temperature solution of benzonitrile (0.204 ml; 0.206 g; 2.00 mmol), dichlorobis(trimethylphosphine)nickel (0.0564 g; 10 mol %), and tridecane (0.244 ml; 0.184 g; 1.00 mmol) in 1,4-dioxane (2 ml). The reaction mixture was then heated to 65° C. and stirred for 42 h; then a sample was withdrawn and quenched in a mixture of 1 M sodium citrate (aq) and MTBE. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 0.88 mmol (44% yield) of diphenylacetylene and 0.51 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:16]=[O:17]>CO.C(Cl)Cl>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[NH:14][C:13]([CH3:15])=[N:12][C:11]=2[CH2:16][OH:17])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(Sc2cnc(C)[nH]2)c1
Reactant: C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)cc(Sc2[nH]c(C)nc2CO)c1
Yield: 21 %

Procedure:
Heated was a solution of 7.0 g (3.2 mmol) of 5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazole (5b) in 37% aqueous formaline (20 ml) at 120° C. for 15 hours in a sealed tube. The reaction mixture was dissolved in methanol/methylene chloride, and the aqueous layer was separated off. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methanol:ethyl acetate=2:98), and the crude product was washed with isopropyl ether to obtain 1.7 g of [5-(3,5-dimethylphenylthio)-2-methyl-1H-imidazol-4-yl]methanol (41d) (yield 21%). mp 199-201° C.
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.[CH3:8][Si:9]([CH3:31])([C:27]([CH3:30])([CH3:29])[CH3:28])[O:10][C@H:11]1[CH2:16][C@H:15]([O:17][Si:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][C:13](=[O:25])[CH:12]1[CH3:26]>C1COCC1>[CH3:31][Si:9]([CH3:8])([C:27]([CH3:30])([CH3:29])[CH3:28])[O:10][C@H:11]1[CH2:16][C@H:15]([O:17][Si:18]([CH3:24])([CH3:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][C:13]([C:3]#[CH:4])([OH:25])[CH:12]1[CH3:26]
Reactant: CC1C(=O)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [Li]CCCC
Agent: C#C
Solvent: C1CCOC1
Product: C#CC1(O)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1C
Yield: 70.7 %

Procedure:
At 0° C., acetylene is introduced into 50 ml of THF for 20 minutes. 1.25 ml n-Butyllithium solution (1.6M in hexane, 2 mmol) is added in drops and stirred for 20 more minutes at this temperature. Then, 215 mg (0.58 mmol) of 9 in 2 ml of THF is added in drops and stirred for 2 hours. Then, it is quenched with saturated ammonium chloride solution, diluted with ethyl acetate, and the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate and the solvent is removed. The residue is purified on silica gel by column chromatography (mobile solvent: EE:H=4:6, Rf =0.6), whereby 163 mg (0.41 mmol) of title compound 10 is obtained as a white crystalline substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH2:10].C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28])([O-:20])=[O:19]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N+:18]([O-:20])=[O:19])(=[O:28])=[O:29]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
1 mL of 2-(2-chlorophenyl)ethylamine and 1.2 mL of triethylamine were dissolved in 50 mL of dichloromethane. To the solution, 1.6 g of 2-nitrobenzenesulfonyl chloride was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with saturated saline, and the organic layer was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2.3 g of the title compound as a pale yellow crystalline solid (92%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:12]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([NH2:26])=[C:24]([CH3:25])[C:11]2=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>CO>[Cl:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:26][C:23]2[C:22]([CH3:27])=[C:21]([CH3:28])[C:12]3[O:13][C:14]4([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=4)[C:11]=3[C:24]=2[CH3:25])=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(Cl)cc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Yield: 58 %

Procedure:
By using 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-amine and 4-chlorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 58%. Melting point: 293-295° C. (Methanol).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[CH3:12])=[O:4].[CH2:13]([OH:17])[CH2:14]CC.CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O.C(O)CO>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=2[CH3:12])[O:17][CH2:13][CH2:14][O:4]1
Reactant: CCCCO
Reactant: Cc1cc(Br)ccc1C(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: OCCO
Product: Cc1cc(Br)ccc1C1(CBr)OCCO1
Reaction time: 8 h

Procedure:
To a stirred mixture of 78.8 parts of 2-bromo-1-(4-bromo-2-methylphenyl)-1-ethanone and 200 parts of butanol are added 3 parts of 4-methylbenzenesulfonic acid and 225 parts of benzene. Then there are added dropwise 33.5 parts of 1,2-ethanediol. Upon completion, stirring is continued overnight at reflux temperature with water-separator. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is stirred with 15 parts of a concentrated sodium hydroxide solution. The layers are separated and the aqueous phase is extracted with 2,2'-oxybispropane. The combined organic layers are washed with water (till neutralization), dried, filtered and evaporated. The solid residue is crystallized from methanol, yielding 30.5 parts of 2-(bromomethyl)-2-(4-bromo-2-methylphenyl)-1,3-dioxolane; mp. 86° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH:10]([C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[OH:11])[CH2:9][CH2:8]2)OCC[O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl-].[Na+]>C(Cl)Cl.CO>[OH:11][CH:10]([C:7]1([C:2](=[O:3])[CH3:1])[CH2:9][CH2:8]1)[C:12]([F:23])([F:24])[C:13]([F:21])([F:22])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC1(C2(C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)C1(C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
3.2 g of 98 in 50 ml of methylene chloride/methanol 1:1 is dissolved, and 750 mg of p-toluenesulfonic acid is added. It is stirred under argon for 2 hours at room temperature. Sodium chloride solution is added, extracted with methylene chloride, the organic phase is washed with sodium bicarbonate solution and sodium chloride-solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 2.7 g of 1-[1-(1-hydroxy-2,2,3,3,4,4,5,5,5-nonafluoropentyl)cyclopropyl]ethanone 99 is obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=O)=[C:10]([O:22][CH3:23])[CH:9]=2)=[CH:4][C:3]=1[C:24]1[N:25]=[N:26][N:27]([CH:29]([CH3:31])[CH3:30])[CH:28]=1.B(F)(F)F.CCOCC.[BH4-].[Na+]>C1COCC1>[CH:29]([N:27]1[CH:28]=[C:24]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][N:16]4[CH2:17][CH2:18][O:19][CH2:20][CH2:21]4)=[C:10]([O:22][CH3:23])[CH:9]=3)[CH:4]=2)[N:25]=[N:26]1)([CH3:31])[CH3:30]
Reactant: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1C(=O)N1CCOCC1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(-c2cnc(N)c(-c3cn(C(C)C)nn3)c2)ccc1CN1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of [4-[6-amino-5-(1-isopropyltriazol-4-yl)-3-pyridyl]-2-methoxy-phenyl]-morpholino-methanone (200 mg, 0.473 mmol) in THF (10.0 mL) was added BF3.Et2O (0.3 mL, 2.36 mmol) at 0° C. and stirred for 30 min. After 30 min, NaBH4 (89 mg, 2.36 mmol) was added at 0° C. and stirred at room temperature for 18 h. After cooling to 0° C., quenched with MeOH (2 mL) and heated to reflux for 6 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (30 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 100% EtOAc to afford 100 mg (yield: 51.81%) of the title compound as white solid.
Reaction SMILES: N([O-])=O.[Na+].Cl.N[C:7]1[C:8]([Cl:18])=[C:9]([C:13]([Cl:17])=[CH:14][C:15]=1[Br:16])[C:10]([OH:12])=[O:11].[PH2](O)=O>>[Br:16][C:15]1[CH:7]=[C:8]([Cl:18])[C:9]([C:10]([OH:12])=[O:11])=[C:13]([Cl:17])[CH:14]=1
Reactant: Nc1c(Br)cc(Cl)c(C(=O)O)c1Cl
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Product: O=C(O)c1c(Cl)cc(Br)cc1Cl
Temperature: -7.5 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
An aqueous solution of sodium nitrite (3.64 g dissolved in 4 mL of water, 52 mmol) was added drop wise to the concentrated hydrochloric acid (15 mL) cooled to −10 to −5° C. 3-Amino-4-bromo-2,6-dichlorobenzoic acid (5 g, 17 mmol, Step c) was added to the above solution portion-wise while maintaining the temperature around −5° C. The reaction mixture was stirred at this temperature for about 2 hours. Then hypophosphorous acid (9 mL, 170 moles) was added very slowly over a period of 1 hour at the same temperature. The reaction mixture was stirred at the same temperature for about 3 hours and then kept in refrigerator overnight. A precipitate was observed at this stage. The reaction mixture was allowed to warm to room temperature and kept for another 2 hours at room temperature. The reaction mixture was filtered, the residue was washed with cold water and dried to obtain 4-bromo-2,6-dichloro benzoic acid as a yellowish solid (2 g, 42%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:22])[CH:16]=[CH:17][CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH3:13].[N+:23]([CH3:26])([O-:25])=[O:24]>CC#N>[CH2:12]([O:14][C:15](=[O:22])[CH2:16][CH:17]([CH2:26][N+:23]([O-:25])=[O:24])[CH2:18][CH:19]1[CH2:20][CH2:21]1)[CH3:13]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=CCC1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CC(CC1CC1)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
DBU (4.1 g, 26.9 mmol) is added to a solution of 4-cyclopropyl-2-butenoic acid ethyl ester (3.4 g, 26.9 mmol) and nitromethane (9.13 g, 135 mmol) in 20 mL of CH3CN. The solution is warmed to 60° C. under Ar for 4 hours, then stirred at room temperature overnight. The CH3CN is evaporated, and the residue is taken up in 50 mL of EtOAc. The solution is washed with saturated KH2PO4 (3×50 mL) followed by 50 mL of brine. The organic layer is dried over Na2SO4 and evaporated to give an oil which is chromatographed (MPLC) over silica gel with 25% EtOAc/hexane to give 2.4 g of 4-cyclopropyl-3-nitromethyl-butanoic acid ethyl ester 3.