Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([C:9](O)=[O:10])[NH:6][N:5]=1)([O-:3])=[O:2].B.C1COCC1.Cl>>[N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])n[nH]1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CO)[nH]n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A mixture of 3-nitro-1H-pyrazole-5-carboxylic acid (4.71 g, 30 mmol), BH3/THF (75 mL, 1 mol/L, 75 mmol) was stirred at 60° C. for 2 h. The mixture was cooled to room temperature and 4M HCl (19 mL, 75 mmol) was added. It was stirred at 70° C. for 2 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and brine (100:100 mL). The aqueous phase was extract with ethyl acetate (4×50 mL). The combined organic layer was dried on Na2SO4 and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford 330d (3.5 g, 79%) as a white solid. MS-ESI: [M+H]+ 144.2
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:24][CH2:25]2)=[CH:16][CH:15]=1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccncc3)CC2)cc1
Yield: 47.2 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl) acetamide (0.85 g), 1-(pyridin-4-yl)piperazine (0.64 g) and potassium carbonate (0.81 g) in dimethylformamide (10 ml) was stirred at 60-70° C. for 5 hr. The reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1)to give a yellow solid(0.6 g). The obtained yellow solid was crystallized from ethyl acetate-methanol to give the title compound (0.37 g) as white crystals, m.p.=164-166° C.
Reaction SMILES: Br[C:2]1[N:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:8])=[O:5].CN(C=O)C.[NH:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11](=[O:20])[N:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[CH:27]=[CH:28][CH:29]=[N:30][C:2]=1[C:39]1[CH:40]=[N:36][NH:37][CH:38]=1)[CH3:8])=[CH:18]2
Reactant: C[C@H](NC(=O)c1cccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: OB(O)c1cn[nH]c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C[C@H](NC(=O)c1cccnc1-c1cn[nH]c1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide (52) (125 mg, 0.26 mmol) in a 1:1 mixture of DMF and EtOH (9 mL), 1H-pyrazole-4-boronic acid (37 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (0) (21 mg, 0.018 mmol) and aqueous Na2CO3 solution (1.0 M, 0.78 mL, 0.78 mmol) were added sequentially. The resulting mixture was stirred at 85° C. for 16 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC plate (10% MeOH-DCM) to afford the product (S)-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-(1H-pyrazol-4-yl)nicotinamide (compound 58). ESI-MS m/z: 471.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C)C=O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1
Temperature: 50 °C
Reaction time: 0.42 h
Yield: 55.8 %

Procedure:
To a solution of pyrazole (68 mgs) in anhydrous dimethylformamide was added sodium hydride (44 mgs). The reaction mixture was stirred at 50° C. for 25 minutes. 4-Bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (280 mgs) in anhydrous dimethylformamide was added. The reaction mixture was stirred at 70° C. under argon for 2.5 hours. The reaction mixture was quenched with water (1 ml) and the solvents were removed in vacuo. The crude residue was partitioned between dichloromethane and water, dried (MgSO4) and the solvents removed in vacuo to give a crude product. This was purified using flash chromatography to yield 4-Pyrazol-1-ylmethyl-piperidine-1-carboxylic acid tert-butyl ester (148 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:47])C(=O)C1.O>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:47])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 80 °C
Yield: 82.2 %

Procedure:
To a solution of 1 g of 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 8 mL of carbon tetrachloride was added portionwise 0.1 g of benzoyl peroxide and 0.56 g of NBS. The resulting mixture was heated to 80° C. for 1.5 h. 0.1 g of NBS was added and the reaction mixture was heated to 80° C. overnight. An additional 0.1 g of NBS was added and the reaction mixture was heated to 80° C. for 2 h. It was then poured into water and extracted with dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (heptane 1/toluene 1 followed by pure toluene) to give 1.02 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester. 1 WO02067912
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[OH:17][CH:15]1[CH2:14][CH2:13][CH:12]([CH2:11][O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:18])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[O:16]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(=O)O2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(O)O2)cc1

Procedure:
To a suspension of (±)-dihydro-5-(p-toluensulfonyloxymethyl)-2(3H)-furanone (example 57) (5.20 g, 19.26 mmol) in anhydrous toluene (125 mL) at −78° C. was added DIBAL (1.5 M in toluene, 13.5 mL, 20.22 mmol) dropwise. The solution was allowed to stir at −78° C. for 2 h. water was then added to the mixture and the reaction mixture was brought to rt. The mixture was filtered through a CELITE diatomaceous earth and the organic layer was collected, dried (MgSO4) and concentrated to give the title compound as a 1:1 mixture of cis and trans isomers (4.2 g, 80%).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.[CH3:15][CH2:16][O:17][C:18]([CH:20]([C:24]([CH3:26])=O)[C:21]([CH3:23])=O)=[O:19]>>[CH2:16]([O:17][C:18]([C:20]1[C:21]([CH3:23])=[N:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][C:3]([F:13])([F:14])[F:2])=[CH:10][CH:9]=2)[C:24]=1[CH3:26])=[O:19])[CH3:15]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CCOC(=O)c1c(C)nn(-c2ccc(OC(F)(F)F)cc2)c1C
Yield: 72 %

Procedure:
In analogy to the procedure described in Example 38A], (4-trifluoromethoxy-phenyl)-hydrazine hydrochloride and ethyl diacetoacetate gave, after extraction (3× Et2O), drying (Na2SO4) and evaporation, the title compound in 72% yield as orange oil. MS: 328.9 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[C:22]([F:25])[CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2c(F)ccc(F)c21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2c(F)ccc(F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5,8-Difluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[C:28]1([C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH2:36]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:34]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: BrCc1ccccc1-c1ccccc1
Product: O=c1c2sc3ccccc3c2n(Cc2ccccc2-c2ccccc2)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-phenylbenzyl bromide and subsequently deptrotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.71 (s, 2H), 7.34 (d, J=8 Hz, 1H), 7.40-7.90 (m, 12H), 8.30 (d, J=8 Hz, 1H); Ret. time=3.22 min., m/z=399.0.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:21][C:16]3([CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Reactant: CC1(N)CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.60 g, 2.5 mmol), 1-methylcyclopentylamine hydrochloride (0.5 g, 3.7 mmol) and triethylamine (1.03 ml, 7.4 mmol) in ethanol (2.5 ml) was stirred for 16 h at 50° C. and then for 24 h at 65° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 1M hydrochloric acid. The crude product was isolated by filtration, dried and recrystallised from acetic acid to give 208 mg (26%) of the title compound; mp >300° C. (dec.); 1H-NMR (DMSO-d6): δ1.43 (s, 1H), 1,53-1.72 (m, 6H), 1.92-2.10 (m, 2H), 6.91 (br s, 1H), 7.10 (s, 1H), 10.52 (br s, 1H).
Reaction SMILES: C([Zn][CH2:4][CH3:5])C.[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13](S(C)(=O)=O)=[C:14]([C:26]#[N:27])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9]([C:11]1[S:12][C:13]([CH2:4][CH3:5])=[C:14]([C:26]#[N:27])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:18][CH:17]=1)=[O:10])[CH3:7]
Reactant: CC[Zn]CC
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(CC)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Add diethylzinc (1.0M in hexanes, 16 mL, 16 mmol) to a solution of 3-(4-tert-butyl-phenyl)-4-cyano-5-methanesulfonyl-thiophene-2-carboxylic acid ethyl ester (2.78 mmol) in 15 mL of anhydrous CH2Cl2 and stir under nitrogen at room temperature for 5 days. Cool to 0° C. and carefully quench with ice followed by 10 mL of saturated NH4Cl. Filter the mixture through Celite® and rinse the filter pad with 100 mL of CH2Cl2. Wash the combined organic layers with brine (1×20 mL), dry over Na2SO4, filter and evaporate. Chromatograph over silica gel with 100% toluene to give the title compound as a clear oil, 625 mg (66%). MS (FAB)=341 (M+); HPLC=98%.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([O:44][CH2:45][CH2:46][OH:47])=[CH:41][CH:42]=2)[NH:37][C:36]=1[C:48]([OH:50])=O.[NH2:51][CH2:52][C:53]1[C:54]([F:70])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:64]#[N:65])[C:56]([Cl:59])=[CH:57][CH:58]=1>CN(C=O)C>[Br:34][C:35]1[C:43]2[C:38](=[CH:39][C:40]([O:44][CH2:45][CH2:46][OH:47])=[CH:41][CH:42]=2)[NH:37][C:36]=1[C:48]([NH:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([O:60][C:61]2[CH:62]=[C:63]([C:64]#[N:65])[CH:66]=[C:67]([Cl:69])[CH:68]=2)[C:54]=1[F:70])=[O:50]
Reactant: O=C(O)c1[nH]c2cc(OCCO)ccc2c1Br
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4cc(OCCO)ccc4c3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
HATU (0.061 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) were added to a solution of 3-bromo-6-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.048 g, 0.161 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at room temperature. The mixture was partitioned between water and EtOAc, followed by washing of the organic layer with a 15% solution of Na2CO3. The organic layer was separated and dried over MgSO4. The EtOAc was evaporated to yield a residue which was triturated in acetone to afford the title compound (0.059 g, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.78 (s, 1H), 8.37 (t, 1H), 7.80 (s, 1H), 7.48-7.54 (m, 2H), 7.40-7.47 (m, 2H), 7.35 (d, 1H), 6.87 (s, 1H), 6.82 (d, 1H), 4.86 (t, 1H), 4.59 (d, 2H), 3.97 (t, 2H), 3.72 (q, 2H). MS m/z 592 (M+1).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.O[C:7]12[CH2:16]C3CC([CH2:15][CH:9]([C:10]3=[O:17])[CH2:8]1)[CH2:14]2.CI.[H-].[Na+]>O>[CH3:3][O:4][C:5]12[CH2:1][CH:2]3[CH2:14][CH:7]([CH2:8][CH:9]([C:10]3=[O:17])[CH2:15]1)[CH2:16]2
Reactant: C1CCOC1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC12CC3CC(C1)C(=O)C(C3)C2
Reaction time: 25 h

Procedure:
THF 5 ml solution of 5-hydroxy-2-adamantanone 100 mg and methyl iodide 0.113 ml was cooled at 0° C., and sodium hydride (60%, oil suspension) 48.2 mg was added therein, and the temperature of the reaction mixture was gradually changed to room temperature, then stirred for 25 hours. The reaction mixture was cooled again, and water was added thereto, then THF was removed by concentration in vacuo. The thus obtained residue was extracted with chloroform and dried by adding anhydrous sodium sulfate. After separation of the drying agent, the filtrate was concentrated in vacuo. Residue was purified by means of silica gel column chromatography (Wako gel, C200, n-hexane: ethyl acetate=10:1) to obtain the product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(O)C>O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(F)c(OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Charge methyl 4-fluoro-3-hydroxybenzoate (519 mg, 3.05 mmol), 4-(bromomethyl)-1-fluorobenzene (577 mg, 3.05 mmol), K2CO3 (843 mg, 6.10 mmol) and ethanol (10 mL) to a flask. The mixture was then stirred at room temperature overnight. Water was added to the reaction mixture at 0° C., filtered, and the solid dried and purified by flash column chromatograph to give 571 mg of the title compound (67%). 1H NMR (400 MHz, CDCl3): δ 3.90 (3H, s), 5.13 (2H, s), 7.06-7.15 (3H, m), 7.41-7.45 (2H, m), 7.63-7.67 (1H, m), 7.71 (1H, dd, J=2.0 Hz, 8.4 Hz).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1>N1C=CC=CC=1>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[C:9]([I:14])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:6]
Reactant: Nc1cccnc1I
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccnc1I
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Ethyl chloroformate (0.91 mL, 9.5 mmol) is added to a solution of 3-amino-2-iodo-pyridine (1.4 g, 6.36 mmol) in 15 mL of pyridine cooled at 0° C. The mixture is stirred at 0° C. for 2 hours and allowed to warm slowly to room temperature. At this time, excess pyridine is removed in vacuo. The residue is diluted with EtOAc and washed with water, 1N HCl and saturated NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by column chromatography eluting with 30% EtOAc/hexanes to give the title compound (1.2 g, 4.11 mmol) as a beige solid.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.CCOCC.[Mg].[CH3:14][N:15]([CH3:28])[C:16]1(C#N)[CH2:25][CH2:24][C:19]2([O:23][CH2:22][CH2:21][O:20]2)[CH2:18][CH2:17]1>C1COCC1>[CH:3]1([CH2:2][C:16]2([N:15]([CH3:28])[CH3:14])[CH2:25][CH2:24][C:19]3([O:23][CH2:22][CH2:21][O:20]3)[CH2:18][CH2:17]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: ICC1CCCC1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)C1(CC2CCCC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of iodomethylcyclopentane (31.5 g, 150 mmol) in abs. ether (150 ml) was added dropwise to a mixture of magnesium (3.64 g, 150 mmol) in abs. ether (30 ml) in such a manner that the ether boiled slightly. Then the reaction solution was boiled under reflux for 30 min. and cooled to RT, and a solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile B-1 (10.5 g, 50 mmol) in abs. THF (100 ml) was added dropwise. The reaction solution began to boil and a white solid precipitated. Boiling was carried out for 6 h under reflux, followed by stirring overnight at RT. For working up of the reaction mixture, 20% NH4Cl solution (200 ml) was added, while cooling with ice, and extraction with ether (3×100 ml) was carried out. The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue that remained was purified by flash chromatography with EA/EtOH (20:1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH2:18]([N:1]([CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred slurry of trans-4-aminomethyl-cyclohexanecarboxylic acid (5.00 g, 31.8 mmol) and K2CO3 (4.40 g, 127.2 mmol) in MeOH (100 mL) cooled to 0° C. was added benzyl bromide (7.94 mL, 66.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. Most of the volatiles were removed in vacuo before addition of water (100 mL). The aqueous mixture was extracted with Et2O (2×200 mL) before adjusting to pH 5-6 by addition of 2 N HCl. The aqueous phase was extracted with DCM (3×200 mL) and the combined DCM extracts dried over Na2SO4 before concentrating in vacuo to afford trans-4-[(dibenzylamino)-methyl]-cyclohexanecarboxylic acid (3.22 g, 43%) as an off-white solid, m/z 338 [M+1]+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.O1CCOC[CH2:15]1>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:15])=[O:12])=[CH:7][CH:8]=1
Reactant: C1COCCO1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1ccc(Br)cc1
Reaction time: 18 h

Procedure:
HCl in dioxane (4M, 61.1 mL) was added to a solution of 3-(4-bromophenyl)propanoic acid in methanol (60 mL) at room temperature. The reaction was stirred 18 h and then concentrated under vacuum. The crude product was purified by flash chromatography on silica gel using a 0-50% ethyl acetate-n-heptane gradient to afford 5.1 g of product as a colorless oil.
Reaction SMILES: [CH:1]([Si:4](Cl)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:12][C:13]1[N:14]([CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25])[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[N:17]=1.N1C=CN=C1>CN(C=O)C>[Br:12][C:13]1[N:14]([CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][O:25][Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[N:17]=1
Reactant: O=[N+]([O-])c1cn(CCC(O)CO)c(Br)n1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](OCC(O)CCn1cc([N+](=O)[O-])nc1Br)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
Triisopropylsilyl chloride (2.50 mL, 11.7 mmol) was added to a solution of diol 131 (3.11 g, 11.1 mmol) and imidazole (1.66 g, 24.4 mmol) in anhydrous DMF (30 mL) under N2 and then the mixture was stirred at room temperature for 18 h. The resulting mixture was added to ice-water (200 mL) and extracted with EtOAc (4×200 mL). The extracts were washed with water (200 mL) and then evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-20% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 20-33% EtOAc/petroleum ether gave 4-(2-bromo-4-nitro-1H-imidazol-1-yl)-1-[(triisopropylsilyl)oxy]-2-butanol (132) (4.60 g, 95%) as a white solid: mp (CH2Cl2/pentane) 90-91° C.; 1H NMR (CDCl3) δ 7.89 (s, 1H), 4.24 (dd, J=7.7, 6.2 Hz, 2H), 3.74 (dd, J=9.6, 3.5 Hz, 1H), 3.62 (m, 1H), 3.53 (dd, J=9.6, 6.8 Hz, 1H), 2.59 (d, J=3.8 Hz, 1H), 1.95-1.82 (m, 2H), 1.17-1.03 (m, 21H). Anal. (C16H30BrN3O4Si) C, H, N.