Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[C:43]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=1.O>CN(C=O)C.C(OCC)(=O)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:31]([NH:49][C:46]4[CH:47]=[CH:48][C:43]([C:39]5[NH:38][CH:42]=[CH:41][N:40]=5)=[CH:44][CH:45]=4)=[O:32])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Nc1ccc(-c2ncc[nH]2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(-c5ncc[nH]5)cc4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.7 %

Procedure:
A mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.40 g, 1.1 mmol) and CDI (0.19 g, 1.2 mmol) in DMF (5 mL) was stirred at room temperature for 18 hours. To the mixture was added 4-(1H-imidazol-2-yl)-phenylamine (0.17 g, 1.1 mmol) at room temperature, and the mixture was stirred at 60° C. for 1 d. To the mixture was added water (25 mL) and ethyl acetate (20 mL). The mixture was stirred at room temperature for 2 h. The suspension was filtered and the solid was washed with water (20 mL), ethyl acetate (20 mL) and water (20 mL) to give a solid. The solid was purified with Prep HPLC to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-[4-(1H-imidazol-2-yl)-phenyl]-urea as a white solid (150 mg, 30% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 5/95 grad 95/5 in 5 min CH3CN/0.1% H3PO4, 4.41 min (95.9%); mp: 190-192° C.; 1H NMR (DMSO-d6) δ 1.91-2.08 (m, 1H, CHH), 2.27-2.47 (m, 1H, CHH), 2.54-2.66 (m, 1H, CHH), 2.81-3.01 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.38-4.52 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, NCH), 6.78 (t, J=6.0 Hz, 1H, NH), 7.33-7.76 (m, 9H, Ar), 8.17 (s, 1H, HCOOH), 8.67 (s, 1H, NH), 10.99 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.41, 31.10, 42.69, 47.02, 51.49, 114.17 (br), 117.80, 121.79, 122.84, 124.55, 126.81, 126.98, 130.19, 135.46, 138.55, 142.31, 144.83, 155.14, 163.19 (HCOOH), 167.88, 170.92, 172.77; LCMS MH=459; Anal. Calcd for C24H22N6O4+2 H2O+0.7 HCOOH+0.3 DMF: C, 56.04; H, 5.42; N, 16.08; Found: C, 55.84; H, 5.34; N, 16.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CS(O[CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=1)(=O)=[O:28].[I-].[K+].[C:48](=[O:51])([O-:50])[O-].[K+].[K+]>C(#N)C.O>[C:8]([OH:9])(=[O:28])/[CH:7]=[CH:6]\[C:48]([OH:50])=[O:51].[C:38]([OH:40])(=[O:2])/[CH:39]=[CH:34]\[C:48]([OH:50])=[O:51].[CH3:45][O:44][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][CH2:31][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:17]3[CH:16]=[CH:15][N:14]=[C:13]([C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:18]=3)[CH2:21][CH2:22]2)[CH:39]=[C:38]([O:40][CH3:41])[C:37]=1[O:42][CH3:43]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C([O-])[O-]
Reactant: COc1cc(CCCOS(C)(=O)=O)cc(OC)c1OC
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CCCN2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc(OC)c1OC
Product: O=C(O)/C=C\C(=O)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]-methyl]piperazine (57 mg) was dissolved in acetonitrile (4 mL), and to the solution 3-(3,4,5-trimethoxyphenyl)propyl methanesulfonate (50 mg), potassium iodide (35 mg) and potassium carbonate (46 mg) were added, and the mixture was stirred at 70° C. for 2 hours. Water was added to the reaction mixture to conduct extraction with chloroform. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1). Maleic acid was added to the resultant oil to produce a salt, thereby obtaining the title compound.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[N:11]=[CH:12][N:13](C)C)#[N:2].Cl.[CH3:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][CH2:22]N.C(O)C>C(O)(=O)C>[F:9][C:8]1[CH:7]=[CH:6][C:5]([F:10])=[C:4]2[C:3]=1[C:1]([NH:2][CH2:22][CH2:21][C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([CH3:17])[CH:19]=1)=[N:13][CH:12]=[N:11]2
Reactant: COc1ccc(CCN)cc1C
Reactant: CN(C)C=Nc1c(F)ccc(F)c1C#N
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CCNc2ncnc3c(F)ccc(F)c23)cc1C
Yield: 58 %

Procedure:
N′-(2-Cyano-3,6-difluorophenyl)-N,N-dimethylformamidine (1.65 g, 7.9 mmol) and 3-methyl-4-methoxyphenethylamine hydrochloride (2.4 g, 11.8 mmol) were combined in acetic acid (2.55 mL) and absolute ethanol (15 mL) and heated to reflux for 16 h. Upon cooling, the solvent was removed under reduced pressure and the remaining solid was slurried with water, suction filtered and washed with water, dried in vacuum at 45° C. to give 1.51 g (58%) of (5,8-difluoroquinazolin-4-yl)-[2-(4-methoxy-3-methylphenyl)-ethyl]-amine as an off-white solid. LC/MS: 330.18 (M++1). 1H NMR (CDCl3): δ 8.67 (s, 1H), 7.35 (m, 1H), 6.94-7.09 (m, 3H), 6.79 (d, J=9.0 Hz, 1H), 6.65-6.80 (br, 1H), 3.87 (q, J=6.9 Hz, 2H), 3.83 (s, 3H), 2.93 (t, J=6.9 Hz, 2H), 2.22 (s, 3H). M.P. 162-169° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:12]1[C:19]2[CH:18]3[CH2:20][CH:17]3[CH2:16][C:15]=2[C:14]([C:21]([NH2:23])=O)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[CH2:5]([N:12]1[C:19]2[CH:18]3[CH2:20][CH:17]3[CH2:16][C:15]=2[C:14]([C:21]#[N:23])=[N:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)c1nn(Cc2ccccc2)c2c1CC1CC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: N#Cc1nn(Cc2ccccc2)c2c1CC1CC21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask equipped with a drying tube under N2 atmosphere was charged with anhydrous DMF (50 mL). The flask was cooled to 0° C. and thionyl chloride (4.84 mL, 66.5 mmol) was added dropwise over a period of 2 min. After stirring for an additional 10 min, a suspension of 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide, (14.0 g, 55.3 mmol) in DMF (90 mL) was added over 5 min using an addition funnel. The mixture was slowly warmed to rt and stirred for 20 min at which time additional thionyl chloride (3.05 mL, 41.9 mmol) was added as a pre-mixed solution in DMF (20 mL). The reaction was stirred for an additional 20 min and a second pre-mixed solution of thionyl chloride (6.0 mL, 82.5 mmol) in DMF (20 mL) was added. The reaction was stirred for an additional 15 min and NaHCO3 (sat. aq., 50 mL) was added followed by H2O (100 mL). The mixture was stirred for 10 min and concentrated to near dryness in vacuo. The residue was diluted with EtOAc (350 mL) and H2O (250 mL). The layers were separated and the aqueous phase was back-extracted with EtOAc (250 mL). The combined organics were washed with NaHCO3 (sat. aq., 400 mL), and brine (400 mL), dried over MgSO4, filtered, and concentrated to give 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonitrile as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.37 (3H, m), 7.25 (2H, m), 5.31 (1H, d, J=14.8 Hz), 5.24 (1H, d, J=14.8 Hz), 2.86, (1H, dd, J=16.4, 6.4 Hz), 2.72 (1H, d, J=16.0 Hz), 2.19 (1H, m), 1.87 (1H, m), 1.07 (1H, m), 0.32 (1H, m). 13C APT NMR (100 MHz, CDCl3): δ up: 154.4, 135.3, 130.0, 118.9, 114.3, 55.9, 26.2, 16.9; down: 129.2, 128.6, 128.1, 24.2, 14.4. HPLC/MS: Discovery® C18 column (5μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=2.23 min, ESI+=236.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]([O:11][CH2:12][CH3:13])[C:9]#[N:10])=[O:6].C(N(CC)CC)C.[SH2:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]([O:11][CH2:12][CH3:13])[C:9]([NH2:10])=[S:24])=[O:6]
Reactant: CCOC(C#N)NC(=O)c1cccc(Cl)c1
Reactant: S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(NC(=O)c1cccc(Cl)c1)C(N)=S

Procedure:
Into a solution of 3-chlorobenzoylamino(ethoxy) acetonitrile (1 g) in toluene (50 ml) containing triethylamine (1 g) was passed hydrogen sulphide gas. The precipitated product (0.72 g) was collected and crystallised from chloroform-light petroleum. m.p. 136°-137°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:10][N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.O.[OH:52]N1C2C=CC=CC=2N=N1.[Cl:62][C:63]1[C:70]([Cl:71])=[CH:69][CH:68]=[CH:67][C:64]=1[CH2:65][NH2:66].CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:19][S:20][C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:10][N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3].[Cl:62][C:63]1[C:70]([Cl:71])=[CH:69][CH:68]=[CH:67][C:64]=1[C:65]([NH2:66])=[O:52]
Reactant: On1nnc2ccccc21
Reactant: NCc1cccc(Cl)c1Cl
Agent: CC(C)(C)OC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)CN1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[2(R)-(t-butoxycarbonyl)amino-3-triphenylmethylmercaptopropyl]-L-proline (0.08 g, 0.153 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.035 g, 0.184 mmol), and 1-hydroxybenzotriazole hydrate (HOBT) (0.025 g,0.184 mmol) were dissolved in DMF (2 mL), treated with 2,3-dichlorobenzylamine (0.025 mL, 0.184 mmol), and brought to pH 7 with Et3N (0.026 mL, 0.184 mmol). After stirring at ambient temperature for 18 h the mixture was concentrated to dryness, and the residue was partitioned between EtOAc and H2O, the organic layer separated, washed with aq satd NaHCO3, brine, and dried (Na2SO4). Filtration and concentration provided the title compound. 1H NMR (CD3OD) δ 7.1-7.5 (m, 18H), 4.53 (d, 1H, J=8 Hz), 4.26 (d, 1H,J=8 Hz), 3.64-3.76 (m, 1H), 2.96-3.14 (m, 2H), 2.52-2.66 (m, 1H), 2.1-2.5 (m, 5H), 1.6-1.9 (m, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[N:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][NH:20][C:15]([C:12]2[CH:13]=[C:14]3[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]3[CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:10][CH:11]=2)=[O:16])=[CH:24][CH:25]=1
Reactant: NCCc1ccncc1
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)NCCc3ccncc3)ccc12
Yield: 34.2 %

Procedure:
This compound was prepared according to the method of Example 15, using 78 mg (0.282 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 36 μL (0.295 mmol, 1.05 equiv) 4-(2-aminoethyl)pyridine as starting materials, to give 35 mg (35%) of white crystals: mp 123-126° C.; Anal. calcd for C22H26N4O.¼H2O: C, 72.01; H, 7.28; N, 15.27. Found: C, 71.77; H, 7.45; N, 15.23.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:27])[NH:12][C@H:13]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C@@H:14]([CH3:17])[CH2:15][CH3:16])[N:10]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>C(Cl)Cl>[Si:20]([O:19][CH2:18][C@@H:13]([NH:12][C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:3][CH:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:5]2)[S:7][CH:8]=1)=[O:27])[C@@H:14]([CH3:17])[CH2:15][CH3:16])([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21]
Reactant: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.35 g, 3.26 mmol) (obtained as described in Reference Example 38(4)) in methylene chloride (68 ml) were added methanesulfonyl chloride (758 μl, 9.79 mmol) and triethylamine (1.37 ml, 9.79 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S,2S)-1-(t-butyldimethylsilyloxymethyl)-2-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.55 g, yield 97%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH2:40]>>[CH3:35][N:36]([CH3:41])[CH2:37][CH2:38][CH2:39][NH:40][C:31](=[O:33])[CH2:30][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=2)=[N:9]1
Reactant: CN(C)CCCN
Reactant: COC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: CN(C)CCCNC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21

Procedure:
The representative procedure for amide formation was used in the reaction of methyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.025 g, 0.048 mmol) with 3-(dimethylamino)propylamine (1 mL). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.7-7.3 min) afforded N1-[3-(dimethylamino)propyl]-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white powder (0.015 g, 0.025 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (m, 1H), 7.96 (m, 1H), 7.76 (m, 1H), 7.43 (t, 1H), 7.30 (m, 2H), 4.93 (s, 2H), 3.12 (m, 2H), 2.82 (m, 2H), 2.50 (s, 6H), 1.73 (m, 2H); MS (M−H) 593.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:24][CH2:25][CH2:26]O>CC(=O)OCC>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:26][CH2:25][Br:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCCBr
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCBr)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.150 mL (2.1 mmol) of 2-bromoethanol. MS (m/z, ES+): 446.30 (79BrM+1, 100%), 448.30 (81BrM+1, 80%); 1H NMR (400 MHz, DMSO-d6) δ: 7.30 (d, 1H), 5.67 (d, 1H), 4.49 (t, 2H), 4.16 (t, 2H), 3.73 (t, 2H), 1.72 (p, 2H), 1.3-1.45 (m, 2H), 1.25 (s, 20H), 0.85 (t, 3H); EA found for C21H35BrO4: C, 58.93; H, 8.52; calcd: C, 58.47; H, 8.18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[N:9]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH:26]1[CH2:28][CH2:27]1>C1COCC1>[CH3:17][O:16][C:14]([C:10]1[CH:11]=[C:12]([O:13][CH2:25][CH:26]2[CH2:28][CH2:27]2)[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]=1)=[O:15]
Reactant: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC2CC2)n(-c2ccccc2F)n1
Temperature: 50 °C

Procedure:
150 mg (0.635 mmol) of methyl 1-(2-fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylate were dissolved in 8 ml of THF. 207 mg (0.635 mmol) of cesium carbonate and 400 mg (2.96 mmol) of bromomethyl-cyclopropane were added and the mixture was heated to 50° C. for 6 h. Then the mixture was filtrated and the solvent removed in vacuo. The crude title compound was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:25]=[C:24]2[C:26]3=[C:27]4[C:17]([CH:18]=[CH:19][CH:20]=[C:21]4[CH:22]=[CH:23]2)=[CH:16][CH:15]=[C:14]3[CH:13]=1.Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>C(#N)C>[Br-:10].[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[CH2:29][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([CH2:11][C:12]2[CH:25]=[C:24]3[C:26]4=[C:27]5[C:17]([CH:18]=[CH:19][CH:20]=[C:21]5[CH:22]=[CH:23]3)=[CH:16][CH:15]=[C:14]4[CH:13]=2)[CH:4]=1
Reactant: BrCc1cc2ccc3cccc4ccc(c1)c2c34
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Clc1c(Cl)[n+](Cc2ccc3ccccc3c2)cn1Cc1cc2ccc3cccc4ccc(c1)c2c34
Product: [Br-]

Procedure:
4,5-Dichloroimidazole (0.18 g, 1.33 mmol) and potassium hydroxide (0.08 g, 1.46 mmol) will be dissolved in a minimum volume of acetonitrile and stirred at reflux for 30 min. 2-(Bromomethyl)pyrene (2.95 g, 10.0 mmol) will be added and the mixture will be returned to reflux for 3 h. The mixture will be filtered hot to remove the KBr generated. 2-(Bromomethyl)naphthalene (2.21 g, 10.0 mmol) will be added to the filtrate and the mixture will be returned to reflux for 6 h. The volatile components will be removed under reduced pressure to yield the product.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2].O>C(Cl)Cl.CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C@@H:5]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2\C3=C(CCCC3)CCN2C(C)=O)cc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1
Reaction time: 5 h
Yield: 94.6 %

Procedure:
In a glove box, a 500 ml steel autoclave was charged with (E)-2-acetyl-1-(p-methoxybenzylidene)-1,2,3,4,5,6,7,8-octahydroisoquinoline (2.1 g, 7.06 mmol) (prepared according to example 2) 130 ml of methanol, a solution of (+)-CYBIPHEMP (8.2 mg, 0.0142 mmol) and [Ru(TFA)2 (COD)]2 --(H2O) (6.3 mg, 0.007 mmol) in 30 ml of methylene chloride and 5 ml of a solution of 0.0035 mmol of Ru(TFA)2 (BIPHEMP) in methanol. The hydrogenation was run at 100° and 60 bar for 5 h. Work-up as described in example 3 afforded 2.0 g of (S)-2-acetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, [α]D20 =+45.9° (c=1, methanol), optical purity 86%: e.e. 88.3%.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.C1C(=O)N([I:19])C(=O)C1.CCOC(C)=O>S(O)(C(F)(F)F)(=O)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[I:19]
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1OCc2c1ccc(Br)c2I
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-2-benzofuran-1(3H)-one (5.00 g, 23.5 mmol) at 0° C. in TfOH (100 mL) was added NIS (5.55 g, 24.6 mmol). The mixture was stirred at room temperature over night; LC analysis of the reaction mixture indicated completion of the reaction. The reaction mixture was then poured slowly into ice-water (1 L) with stirring. To the solution was then added EtOAc (500 mL) and subsequently stirred for 10 min. The mixture was filtered and the organic layer separated. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with water (500 mL), brine (500 mL), dried over Na2SO4, filtered, concentrated to dryness; it was absorbed into silica gel and separated with the solvent systems of (hexanes/EtOAc=1/1) to yield 5-bromo-4-iodo-2-benzofuran-1(3H]-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.80 (d, J=7.8 Hz, 1H), 7.74 (d, J=8.5 Hz, 1H), 5.07 (s, 2H).
Reaction SMILES: CC1(C)O[CH:5]([O:7][C:8](=[O:30])[CH:9](C)[O:10][C:11]2[CH:23]=[C:22]3[C:14]([C:15]4[C:20]([CH2:24][CH3:25])([CH2:21]3)[CH2:19][CH2:18][C:17](=[O:26])[CH:16]=4)=[C:13]([Cl:27])[C:12]=2[Cl:28])[CH2:4][O:3]1.Cl.[C:33](=O)(O)[O-:34].[Na+].[Cl-].[Na+]>CC(C)=O>[Cl:27][C:13]1[C:12]([Cl:28])=[C:11]([O:10][CH2:9][C:8]([O:7][CH2:5][CH:4]([OH:3])[CH2:33][OH:34])=[O:30])[CH:23]=[C:22]2[C:14]=1[C:15]1[C:20]([CH2:24][CH3:25])([CH2:21]2)[CH2:19][CH2:18][C:17](=[O:26])[CH:16]=1
Reactant: CCC12CCC(=O)C=C1c1c(cc(OC(C)C(=O)OC3COC(C)(C)O3)c(Cl)c1Cl)C2
Reactant: O=C([O-])O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC12CCC(=O)C=C1c1c(cc(OCC(=O)OCC(O)CO)c(Cl)c1Cl)C2
Reaction time: 2 h

Procedure:
A mixture of 165 mg of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl [(5,6-dichloro-9a-ethyl-3-oxo-1,2,9,9a-tetrahydro-3H-fluoren-7-yl)oxy]acetate from Example 109, Step A is dissolved in 100 ml. of 0.075 N hydrochloric acid and 20 ml. of acetone and heated, with stirring at 50°-55° C. for 2 hours. The mixture is cooled and neutralized with a solution of sodium bicarbonate. The solution is saturated with sodium chloride and extracted two times with 100 ml. portions of 20% tetrahydrofuran in ether. The extract is dried over Na2SO4. After filtration, the filtrate was concentrated to a yellow oil that solidified on standing. After recrystallization from tetrahydrofuran-ether-petroleum ether, there is obtained 110 mg. of product, m.p. 135°-138° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(C(C)C)CC)(C)C.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>O1CCCC1>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Fluoro-4-trifluoromethyl-2-nitrobenzene (5.1 g) was dissolved in tetrahydrofuran (100 mL) and diisopropylethylamine (5.5 ml) and 4-amino-1-tert-butoxycarbonylpiperidine (5.37 g) were added. The mixture was stirred at room temperature for 3 hr. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate and the extract solution was dried and concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-trifluoromethyl-2-nitrophenyl)aminopiperidine.