Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:9]4[O:8][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[N:11][C:10]=34)=[O:18])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: O=C(O)c1cccc2oc(N3CCOCC3)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(N3CCOCC3)nc12

Procedure:
Following general procedure GP-C1, a mixture of 2-morpholinobenzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-morpholino-benzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O.[CH2:39]([N:46]([CH2:80][CH2:81][O:82][Si](C(C)(C)C)(C)C)[C:47]([C:49]1[C:54]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:53]([OH:63])[N:52]=[C:51]([CH2:64][C:65]2([C:70]3[C:79]4[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=4)[CH:73]=[CH:72][CH:71]=3)[CH2:69][CH2:68][CH2:67][CH2:66]2)[N:50]=1)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([N:46]([CH2:80][CH2:81][OH:82])[C:47]([C:49]1[C:54]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:53]([OH:63])[N:52]=[C:51]([CH2:64][C:65]2([C:70]3[C:79]4[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=4)[CH:73]=[CH:72][CH:71]=3)[CH2:66][CH2:67][CH2:68][CH2:69]2)[N:50]=1)=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)Cc1ccccc1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid benzyl-[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-amide (370) (380 mg, 0.54 mmol). The yield was 190 mg, 60%, of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:12].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[C:13]#[N:14]
Reactant: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(F)cc([N+](=O)[O-])c1N

Procedure:
A suspension of EXAMPLE 45A (22.7 g), zinc cyanide (22.6 g) and tetrakis(triphenylphosphine) palladium (7.78 g) in anhydrous DMF (300 mL) was heated at 80° C. for 22 hours. After cooling, the reaction mixture was partitioned between ethyl acetate (500 mL) and brine (500 mL). The organic phase was washed with water and concentrated. Recrystallization of the concentrate from methanol provided EXAMPLE 45B.
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1.S(Cl)([Cl:30])=O>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:30][CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH3:17])[CH:13]=[CH:12][C:11]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CO)s3)cc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3ncc(CCl)s3)cc12
Reaction time: 1 h
Yield: 74 %

Procedure:
N-{2-[5-(Hydroxymethyl)-1,3-thiazol-2-yl]-4-methyl-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (0.55 g) was dissolved in absolute tetrahydrofuran (25 ml), and this solution was ice-cooled. Thionyl chloride (0.15 ml) and N,N-dimethylformamide (one drop) were added, and the mixture was stirred for 1 hr under ice-cooling, and then at room temperature for 7 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (0.427 g, yield 74%) as pale-yellow crystals. melting point 194-195° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[C:15]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1
Reactant: O=C(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCOCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.9 %

Procedure:
tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (420, 2.06 mmol) was then taken up in CH3CN (20 mL) along with nicotinic acid (253 mg, 2.06 mmol) and EDCI (434 mg, 2.3 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford tert-butyl 2-(2-(nicotinamido)ethoxy)ethylcarbamate (280 mg, 44%). MS calculated for C15H23N3O4: 309.17. found: [M+H]+ 310.
Reaction SMILES: [F:1][C:2]([F:22])([CH2:20][OH:21])[C@@:3]([NH:13]S(C(C)(C)C)=O)([CH2:11][F:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].Cl>CO.O1CCOCC1>[NH2:13][C@@:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10])([CH2:11][F:12])[C:2]([F:22])([F:1])[CH2:20][OH:21]
Reactant: CC(C)(C)S(=O)N[C@](CF)(c1ccccc1F)C(F)(F)CO
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@](CF)(c1ccccc1F)C(F)(F)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid [(S)-2,2-difluoro-1-fluoromethyl-1-(2-fluoro-phenyl)-3-hydroxy-propyl]-amide (intermediate F4.1) (145.5 mg, 426 μmol) in methanol (2.5 ml) was cooled to 0° C. and treated with hydrochloric acid (4 M in dioxane; (533 μl, 2.13 mmol). The solution was left to warm to room temperature and stirred for 1 hour. After removal of the solvent at reduced pressure the solid residue was dissolved in water (5 ml), then extracted with ethyl acetate (2×10 ml). The organic layers were extracted with water (5 ml), thereafter the combined aqueous layers treated with a solution of sodium carbonate (2 M) to adjust the pH to 9-10. Extraction with ethyl acetate (3×35 ml), combination of the organic layers and evaporation at reduced pressure after drying over sodium sulphate yielded the crude (S)-3-amino-2,2,4-trifluoro-3-(2-fluoro-phenyl)-butan-1-ol (78 mg, 78% yield) as a colorless oil. Evaporation of the first 2 ethyl acetate layers followed by the treatment with a solution of sodium carbonate and proceeding as described above yielded another fraction (22 mg) of product. MS (ISN): m/z=238.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[CH:4][N:3]=1.CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:10][C:8](=[O:9])[C:7]3[C:2]([N:1]=2)=[N:3][CH:4]=[N:5][CH:6]=3)[CH:19]=1
Reactant: NC(=O)c1cncnc1N
Reactant: COC(=O)COCCc1cccc(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CCOCc2nc3ncncc3c(=O)[nH]2)c1

Procedure:
In analogy to example 3.3, 4-amino-5-pyrimidinecarboxamide and (2-m-tolyl-ethoxy)-acetic acid methyl ester (prepared from 2-m-tolyl-ethanol [1875-89-4] in analogy to example 3.1-3.2) reacted in the presence of LiHMDS in THF to yield the title compound (after purification of the crude product with column chromatography (silica gel, EtOAc/MeOH) and crystallization from TBME) as white solid. MS: m/e=295.5 [M−H−].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].O.COCCOC>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:28]3[CH:29]=[CH:30][S:26][CH:27]=3)[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: OB(O)c1ccsc1
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COC(=O)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(-c3ccsc3)cc12
Temperature: 90 °C

Procedure:
3-(1-Benzenesulfonyl-5-bromo-1H-indol-3-yl)-propionic acid methyl ester 89 (200 mg, 0.474 mmol) was combined with 3-thienyl boronic acid (67.0 mg, 0.52 mmol), triphenylphosphine (9.0 mg, 0.03 mmol), Pd(OAc)2 (4.0 mg, 0.015 mmol), K2CO3 (90 mg, 0.65 mmol), 1,2-Dimethoxyethane (DME, 4.0 mL) and H2O (0.4 mL) and was heated at 90° C. for 48 hours. The reaction was allowed to cool to room temperature and the solvent was evaporated. The resulting residue was dissolved in EtOAc and washed with brine. The organic layer was dried over MgSO4, filtered, and evaporated. The residue was purified with flash silica gel chromatography (20% EtOAc/Hexanes) to obtain the ester 91 as a white solid, (110 mg, M+1=426.1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][C:21]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41](O)=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>>[CH3:29][C:26]1[CH:25]=[CH:24][C:23]([CH:22]([N:30]2[C:38]3[C:33](=[CH:34][C:35](/[C:39](/[CH3:44])=[CH:40]/[C:41]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:42])=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[C:21]2[CH:20]=[CH:19][C:18]([CH3:17])=[CH:46][CH:45]=2)=[CH:28][CH:27]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccc(C)cc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2ccc(C)cc2)c2ccc(C)cc2)c1

Procedure:
0.50 g of compound 54 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.96 g of ethyl 4-(2-aminophenoxy)butyrate and 1.74 g of 3-[1-(4,4'-dimethylbenzhydryl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.O>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[CH2:8][O:3][CH2:2][CH2:1][OH:4]
Reactant: OCCO
Reactant: BrCc1ccc2ccccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCCOCc1ccc2ccccc2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol, 95% in oil) in THF (3 mL). 2-(Bromomethyl)naphthalene (330 mg, 1.5 mmol) was added to the reaction, and the residual 2-(bromomethyl)naphthalene was transferred to the reaction tube with additional THF (1 mL). (Bu)4NI (55 mg, 0.15 mmol) was then added, and the reaction was heated at 60° C. for 18 h and then rt for 4 h. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (1×1 mL), and the combined organic layers were concentrated. The crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes (fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the title compound (101 mg, 33%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]#[CH:21]>>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)[CH2:21][C:20]#[CH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: C#CCBr
Product: C#CCN(C(=O)OC(C)(C)C)c1ccc(C(=O)OC)nc1
Yield: 90 %

Procedure:
Using the method described in J. Med. Chem., 1980, 23, 1405, methyl 5-(N-tert-butoxycarbonylamino)pyridine-2-carboxylate was reacted with prop-2-ynyl bromide to give methyl 5-[N-tert-butoxycarbonyl-N-(prop-2-ynyl)amino]pyridine-2-carboxylate in 90% yield. A mixture of the product so obtained and trifluoroacetic acid was stirred at 0° C. for 1 hour and evaporated. There was thus obtained methyl 5-(N-prop-2-ynylamino)pyridine-2-carboxylate in 90% yield, as a gum.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:63][C:64]1[CH:65]=[CH:66][C:67]([O:79][CH3:80])=[C:68]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([C:76](=[O:78])[CH3:77])[CH:71]=2)[CH:69]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:80][O:79][C:67]1[CH:66]=[CH:65][C:64]([NH:63][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:69][C:68]=1[C:70]1[CH:75]=[CH:74][CH:73]=[C:72]([C:76](=[O:78])[CH3:77])[CH:71]=1
Reactant: COc1ccc(N)cc1-c1cccc(C(C)=O)c1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1-c1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23 %

Procedure:
To a 40 mL vial equipped with a stir bar was placed 1-iodo-4-nitrobenzene (1.26 g, 5.07 mmol), cesium carbonate (2.20 g, 6.76 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (316 mg, 0.507 mmol), and a solution of (5′-amino-2′-methoxy-biphenyl-3-yl)-ethanone (I-47, Y═H, Z═NH2, R1═CH3, R2═COCH3) synthesized above (816 mg, 3.38 mmol) in toluene (13.5 mL). The mixture was stirred for 10 minutes and then tris(dibenzylideneacetone)dipalladium(0) (310 mg, 0.338 mmol) and the mixture was heated to 110° C. for 16 hours. The reaction was cooled to room temperature and then filtered through Celite. The filtrate was treated with water (40 mL), 1M HCl (40 mL) and then Extracted with ethyl acetate (2×75 mL). The organic portions were combined, washed with brine (75 mL), dried (MgSO4) and concentrated. The crude material was purified by column chromatography utilizing 35% EtOAc/hexanes as the eluent to produce 277 mg of 1-[2′-methoxy-5′-(4-nitro-phenylamino)-biphenyl-3-yl]-ethanone (I-49, Y═H, Q=NH, R1═CH3, R2═COCH3, R3═NO2) as a dark orange solid in 23% yield.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][NH2:22])[CH:17]=[CH:18][CH:19]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.20 ml 2-(3-fluoro-phenyl)-ethyl-amine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 2:1) to give 478 mg colorless viscous oil (100%). MS (ISP) 286.2 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Br)(Br)[Br:23]>C(COC)OC.CCOCC>[Br:23][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CO)c1)OC(C)C
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccc(OC)c(CBr)c1)OC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.2 g of ethyl 3-[3-(hydroxymethyl)-4-methoxyphenyl]-2-isopropoxypropanoate was dissolved in 15 ml dimethoxyethane. 1.2 ml phosphorus tribromide was added thereto under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction solution was diluted with ether and washed with water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was subjected to silica gel column chromatography, to give 2.6 g of ethyl 3-[3-(bromomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate from fractions eluted with hexane-ethyl acetate (4:1).
Reaction SMILES: CC1(P(C(C)(C)C)C(C)(C)C)[C:4](C2C=CC=CC=2)([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)C1.[CH:26]1[C:38]2[NH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[CH:29]=[CH:28][CH:27]=1.C[Mg]Cl.ClC1C=CC(C)=CC=1.[Cl-].[NH4+]>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].C(P(C(C)(C)C)C1(C)CC1(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.O.C1COCC1>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([N:37]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:38]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:7][CH:6]=1
Reactant: CC(C)(C)P(C(C)(C)C)C1(C)CC1(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: C[Mg]Cl
Solvent: Cc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 98.5 %

Procedure:
Allylpalladium(II) chloride dimer ([PdCl(π-allyl)]2) (5.8 mg, 0.025 mol %) and di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine (cBRIDP) (22.2 mg, 0.1 mol %) were placed into a 50 mL, two-necked, round bottomed flask equipped a gas inlet, and the flask was evacuated and filled with nitrogen. Subsequently, to the mixture was added dehydrated THF (8.2 mL, 101.0 mmol, 1.6 equivalents), and the mixture was stirred at room temperature for 1 minute to prepare a THF solution of an equivalent mixture of PdCl(π-allyl)(cbridp) and cBRIDP (a catalyst solution) as a pale yellow liquid. Separately, a 200 mL, four-necked, round-bottomed flask equipped with a Teflon® coated magnetic stirring bar, condenser, dropping funnel, thermometer, and a gas inlet was evacuated and filled with nitrogen. Carbazole (10.9 g, 65.0 mmol, 1.03 equivalents) and dehydrated xylenes (66 mL) were charged into the flask, and the mixture was cooled to 5° C. using an ice bath. Subsequently, to the mixture was added a THF solution of methylmagnesium chloride (MeMgCl) (3.22 mol/L, 20.0 mL, 64.4 mmol, 1.02 equivalents) (containing THF in an amount of 17.3 mL (15.4 g, 213.6 mmol, 3.4 equivalents)) dropwise via the dropping funnel over 10 minutes at such a rate that the temperature of the reaction solution was kept at 20° C. or lower, and then the dropping funnel was washed with dehydrated xylenes (11 mL). Subsequently, to the solution were added 4-chlorotoluene (7.5 mL, 63.1 mmol, 1.0 equivalent) and the catalyst solution (8.2 mL) successively, and the solution was stirred for 1 hour under reflux. GC analysis at this point to check progress of the reaction reveals that 4-chlorotoluene (GC retention time: 2.8 minutes) has been completely consumed. After cooling the reaction mixture to room temperature, to the mixture were added water (25 mL) and ammonium chloride (1.7 g, 31.8 mmol, 0.5 equivalents). The aqueous layer was separated off, and the organic layer was concentrated under reduced pressure to give oily residue, which was purified by silica gel column chromatography (eluent: n-hexane/toluene=2/1) to afford 16.0 g of N-(4-methylphenyl)carbazole as a white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[S:9][C:10]([C:12](OCC)=[O:13])=[CH:11][C:7]=3[C:6]=2[CH:21]=1.[NH3:23]>>[Br:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[CH:19]3[CH2:20][CH:17]([CH2:18]3)[C:8]3[S:9][C:10]([C:12]([NH2:23])=[O:13])=[CH:11][C:7]=3[C:6]=2[CH:21]=1
Reactant: CCOC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: N
Product: NC(=O)c1cc2c(s1)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 45 °C
Yield: 100 %

Procedure:
A pressure tube containing a solution of ethyl 9-bromo-8-fluoro-5,6-dihydro-4H-4,6-methanobenzo[3,4]cyclohepta[1,2-b]thiophene-2-carboxylate (32 mg, 0.08 mmol) in methanolic ammonia (5 mL of 7.0M ammonia in methanol) was warmed to 45° C. for two weeks. Evaporation of the reaction mixture furnished the title compound (31 mg, 0.08 mmol, 100%) as a pale brown solid: 1H NMR (500 MHz, d4-methanol) delta 1.61-1.68 (m, 2H), 2.93-3.02 (m, 2H), 3.59 (td, J=7.33, 4.26 Hz, 1H), 3.67 (td, J=8.04, 3.78 Hz, 1H), 7.05 (d, J=9.46 Hz, 1H), 8.18 (d, J=6.94 Hz, 1H), 8.39 (s, 1H); M+1=352/354.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[C:26](Cl)(=[O:28])[CH3:27]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[NH:25][C:26](=[O:28])[CH3:27])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1ccc(F)cc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 25.7 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenylamine (142 mg, 0.4 mmol) and acetyl chloride (32.7 μL, 0.4 mmol) and following the procedure as outlined in Example 1, 41 mg of N-{2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-4-fluoro-phenyl}-acetamide was isolated as a yellow foam in 100% purity @ 254 nm; LCMS (APCI): 399 [M+H]+.