Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34](O)=[O:35].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:29]2[C:30]3[C:25](=[C:24]([Cl:23])[CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:27][CH:28]=2)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: CC(C)(C)c1ccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (1.0 g, 3.15 mmol) in acetonitrile (40 ml) were added 5-chloronaphthalenecarboxylic acid (651 mg, 3.15 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (725 mg, 3.78 mmol) and 1-hydroxybenzotriazole hydrate (482 mg, 3.15 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (200 ml), and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (1.04 g, 66%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27](F)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15].Cl.[F:33][C:34]1([F:39])[CH2:38][CH2:37][NH:36][CH2:35]1.O>CS(C)=O>[Cl:8][C:9]1[C:10]([O:23][C:24]2[CH:25]=[N:26][C:27]([N:36]3[CH2:37][CH2:38][C:34]([F:39])([F:33])[CH2:35]3)=[C:28]([Cl:30])[CH:29]=2)=[CH:11][C:12]([F:22])=[C:13]([CH:21]=1)[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15]
Reactant: FC1(F)CCNC1
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(N3CCC(F)(F)C3)c(Cl)c2)cc1F

Procedure:
Triethylamine (0.21 mL, 1.51 mmol) was added to a mixture of 5-chloro-4-[5-chloro-6-fluoropyridin-3-yl)oxy]-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 150 mg, 0.38 mmol) and 3,3-difluoropyrrolidine hydrochloride salt (60 mg, 0.41 mmol), in DMSO (3.8 mL) and the reaction heated at 80° C. for 120 hours. The mixture was diluted to 5 mL by the addition of water and the mixture purified by preparative HPLC. The title compound was obtained as a beige solid (49 mg, 27%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:34])=[O:24])[CH3:21]>>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:34][C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:27]=3[NH:26][C:25]([C:23]([O:22][CH2:20][CH3:21])=[O:24])=[CH:33]4)[N:7]=2)[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1
Reactant: COc1cc(Nc2nc(Cl)ncc2F)cc(OC)c1
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Product: CCOC(=O)c1cc2cccc(Nc3ncc(F)c(Nc4cc(OC)cc(OC)c4)n3)c2[nH]1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-N4-(3,5-dimethoxyphenyl)-5-fluoro-4-pyrimidineamine with 2-ethoxycarbonyl-7-aminoindole gave N4-(3,5-dimethoxyphenyl)-N2-(2-ethoxycarbonylindol-7-yl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 24.21 min.; purity: 91%; MS (m/e): 452 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1)(=[O:27])[CH3:26]>>[CH2:18]([C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:35][C:32]3[CH:31]=[CH:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:34][CH:33]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: O=C1NN=C(Cc2ccccc2)/C1=C1\C=C(Cl)c2ccccc2N1
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3Cc3ccccc3)Nc3ccccc32)cc1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-benzyl-1H-pyrazol-5(4H)-one and 4-actamidothiophenol using a procedure analogous to the one described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.94 (s, 2H) 2.11 (s, 3H) 6.77 (s, 1H) 7.23-7.32 (m, 3H) 7.42-7.50 (m, 2H) 7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H); ESI-MS: m/z calc'd for C27H22N4O2S 466.15. found 467.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CC1(C)CC(Nc2nccc(-c3ccc(-c4ccccn4)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Step D of Example 172, starting from [4-(4-bromophenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-tributylstannanyl-pyridine. Yield: 85 mg (44%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH3:28].N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(Cl)c1
Reactant: CCCBr
Agent: N
Product: CCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (21 mg, 65%) from (7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 1-bromopropane (30 mg, 0.24 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.92 (t, J=7.3 Hz, 3H), 1.61-1.75 (m, 2H), 2.02-2.35 (m, 6H), 2.45-2.63 (m, 3H), 2.75 (t, J=6.5 Hz, 2H), 2.87-2.98 (br, 1H), 3.00-3.08 (br, 1H), 3.30 (dt, J=10.6, 4.0 Hz, 1H), 3.35-3.48 (m, 2H), 6.94 (s, 1H), 6.99 (s, 1H), 7.21-7.25 (m, 1H), 7.44 (d, J=1.5 Hz, 1H) ppm. MS (CI, NH3): 401.1 (base, M+H).
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[C:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Cl-].[Zn+2].[Cl-]>[Cl:4][P:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: ClP(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: ClP1Oc2ccccc2-c2ccccc21

Procedure:
According to the present invention, the preparation of the arylphosphonite antioxidant is performed in an one-pot reactor. First of all, excessive phosphorous trichloride, 2-phenylphenol, and a trace amount of zinc chloride catalyst are put into the reactor and heated to proceed the first stage esterification and intramolecular cyclization reaction. The reaction temperature preferably between 30° C. and 200° C. The reaction equation of the esterification and cyclization are shown as the reaction equation (1). Whether the reaction is completed or not, it is determined by a 31P nuclear resonance spectroscopy. After the excessive phosphorous trichloride is recovered by vacuum distillation, the 6-chloro-6H-dibenz[c,e][1,2]oxaphosphorin (CDOP) is obtained.
Reaction SMILES: C[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3](Cl)=[O:4].[CH-:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:23][C:18]1[C-:22]([C:3](=[O:4])[CH2:2][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:21]=[CH:20][CH:19]=1.[CH-:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.[Fe+2:28]
Reactant: CC(CCCCC(=O)c1ccccc1)C(=O)Cl
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc[c-]1C(=O)CCCCCC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
2-Methyl-6-benzoylhexanoylchloride (assumed to be 0.065 mole) and ferrocene (12.0g; 0.065 mole) in dry methylene chloride (500 ml) were stirred at 0.5° and aluminium chloride (17g; 0.13 mole) was added. The mixture was stirred for 30 mins at 0°-5°, then ice was added slowly and the organic fraction separated. The aqueous fraction was extracted with chloroform and the combined organic fractions were washed with water and dried (magnesium sulphate) to yield a brown oil which was recrystallised from petroleum ether to yield orange needles of pure 2-methyl-6-benzoylhexanoylferrocene mp 75° (40%).
Reaction SMILES: [C:1]([C:5]1[N:9]=[CH:8][NH:7][C:6]=1[CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2]>CC(C)=O.[O-2].[O-2].[Mn+4]>[C:1]([C:5]1[N:9]=[CH:8][NH:7][C:6]=1[CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc[nH]c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(C)(C)c1nc[nH]c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
Manganese dioxide (30 g, 0.35 mol) was added to a heterogeneous solution of (5-tert-butyl-3H-imidazol-4-yl)-methanol (4.97 g, 0.03 mol) in acetone (700 ml) and the resulting mixture was stirred at room temperature for 4 h. The mixture was filtered through a pad of Celite and the pad was washed with acetone. The filtrate and washings were combined and evaporated. The residue was triturated with ether to afford, as a colorless solid, 5-tert-butyl-3H-imidazole-4-carbaldehyde (2.50 g, 51%). (Hayashi, Personal Communication (2000)).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9])=O.C([O-])(=O)C.[Na+].[OH:18][NH2:19]>C(O)C>[OH:18][N:19]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: COc1ccc(C=O)cc1C#N
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C=NO)cc1C#N
Temperature: 80 °C
Reaction time: 6 h

Procedure:
5-Formyl-2-methoxybenzonitrile, sodium acetate and hydroxyamine were dissolved in ethanol, followed by stirring at 80° C. for 6 hours to obtain 5-[(hydroxyimino)methyl]-2-methoxybenzonitrile. APN: 175.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([S:31][CH3:32])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[C:20]([S:26][CH3:27])[CH:19]=2)[CH:15]=1)[CH2:11]O.C(Br)(Br)(Br)[Br:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([S:31][CH3:32])[CH:30]=1)[CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([S:24][CH3:25])[CH:21]=[C:20]([S:26][CH3:27])[CH:19]=2)[CH:15]=1)[CH2:11][Br:34]
Reactant: CSc1cc(COc2cc(CO)cc(OCc3cc(SC)cc(SC)c3)c2)cc(SC)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1cc(COc2cc(CBr)cc(OCc3cc(SC)cc(SC)c3)c2)cc(SC)c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 286.8 %

Procedure:
3,5-Bis-(3,5-dimethylthiobenzyloxy)benzyl alcohol (17.0 g, 0.033 mol) and carbon tetrabromide (14.2 g, 0.0043 mol) were dissolved in 100 ml of tetrahydrofuran. To this, triphenylphosphine (11.3 g, 0.043 mol) was added portionwise. at the temperature of 1.0 to 10° C. After completion of the addition, the mixture was stirred for 7 hours keeping the mixture at the same temperature. Then, the reaction mixture was poured into 300 ml of ice-water and the resulting mixture was extracted with chloroform. The extract was purified by means of chromatography, giving 7.0 g of 3,5-bis(3,5-dimethylthiobenzyloxy)benzyl bromide
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH2:19]([O:23][C:24](Cl)=[O:25])[CH:20]([CH3:22])[CH3:21]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:24]([O:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:25])[N+:7]([O-:8])=[C:6]([NH:9][C:24]([O:23][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:25])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCC(C)C)[n+]1[O-]
Reaction time: 2 h

Procedure:
20.7 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are mixed with 250 ml. of methylene chloride and 35 ml. of triethylamine and cooled to 5° C. 40 Ml. of chloroformic acid isobutyl ester are added dropwise while stirring. After completion of the addition, the mixture is stirred at 5° C. for 15 minutes and then at room temperature for 2 hours. The solution is treated with 200 ml. of water and extracted with methylene chloride. The organic phase is evaporated and the residue is crystallized from ethanol. There is obtained diisobutyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 137°-139° C. (decomposition).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2=[N:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:2]([C:30]3[CH:29]=[N:28][C:27]([F:26])=[CH:32][CH:31]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccc(F)nc3)cnc12
Temperature: 150 °C
Yield: 56 %

Procedure:
In a sealed tube, a mixture of 3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (115 mg, 0.25 mmol), 2-fluoro-5-pyridine-boronic acid (38.4 mg, 0.27 mmol), PdCl2(PPh3)2 (8.7 mg, 0.01 mmol) and Na2CO3 (2.0 M solution in water, 0.43 mL) in DME (1 mL) was heated at 150° C. for 17 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95:5→7:3) to yield the title compound (64 mg, 0.14 mmol, 56%) as a white solid. MS: 455 [M+1]+; HPLC: AtRet=3.14; TLC: RF 0.34 (hexane/TBME 1:1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].Cl.N>CO.O1CCOCC1>[CH2:18]([O:17][C:8]1[N:7]=[C:6]2[C:11]([NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][Br:1])=[C:10]([NH2:16])[N:9]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCBr)c2n1
Agent: Cl
Agent: N
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCBr)c2n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.8 %

Procedure:
To a solution of the compound (1 g, 2.79 mmol) obtained in Step (i) in methanol (2 ml) was added a 4N-hydrochloric acid in dioxane (2 ml), and the mixture was stirred at room temperature for 3.5 hours. The mixture was neutralized by addition of 28% aqueous ammonia at 0° C., and the mixture was stirred for one hour. The precipitated crystals were collected by filtration, washed twice with water (2 ml) and further washed twice with methanol (2 ml), and dried to give the subtitle compound (882 mg) as a white solid. Yield: 92%
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C>[C:15]([O:19][C:20](=[O:29])[NH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[CH:4][N:3]=2)[CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4ccccc4c23)CCO1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-9H-pyrimido[4,5-b]indole (0.045 g, 0.221 mmol), morpholin-2-ylmethyl-carbamic acid tert-butyl ester (0.055 g, 0.25 mmol) and triethylamine (0.10 mL, 0.75 mmol) in DMF (0.70 mL) was heated to 120° C. in a microwave reactor for 1 hour. The cooled solution was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic extract was dried (Na2SO4), filtered and concentrated. Flash column chromatography, eluting with ethyl acetate, gave the title compound as a yellow solid (0.021 g, 0.0548 mmol, 25%). LC-MS (3) Rt 5.57 min; m/z (ESI) 384 [MH+].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH:22]2[CH:20]([CH:21]2[CH2:24][OH:25])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH:22]2[CH:20]([CH:21]2[CH:24]=[O:25])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCC1C2CN(Cc3ccccc3)CC12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=CC1C2CN(Cc3ccccc3)CC12
Temperature: -65 °C
Yield: 75.2 %

Procedure:
Oxalyl chloride (0.88 ml, 17.73 mmol) was added to a stirred flask of DCM (100 ml) under N2 and the solution cooled to an internal temperature of −65° C. DMSO (1.26 ml, 17.73 mmol) was then added dropwise, keeping the internal temperature at −65° C. or below at all times. A solution of (3-benzyl-3-azabicyclo[3.1.0]hex-6-yl)methanol (2.00 g, 9.85 mmol) in DCM (50 ml) was then added to the reaction mixture slowly, again making sure the internal temperature did not rise above −65° C. After this addition was complete, triethylamine (5.90 ml, 42.35 mmol) was slowly added to the reaction, again making sure the internal temperature did not rise above −65° C. After addition was complete the reaction was allowed to warm up to r.t. and solvent removed in vacuo. The residue was purified by column chromatography (25% EtOAc in heptane) to give the title compound as a light yellow oil (1.49 g, 76%). LCMS purity 90%, m/z 202 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 2.11 (2H, m), 2.44 (1H, m), 2.50 (2H, d, J=9.3 Hz), 3.07 (2H, d, J=9.3 Hz), 3.64 (2H, s), 7.21-7.35 (5H, m), 9.31 (1H, d, J=4.8 Hz).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[O:7])=[CH:4][CH:3]=1.Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:13]=2)=[CH:18][CH:19]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: O=C(NCCc1ccc(-c2ccc(O)cc2)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)c3ccc(F)cc3)cc2)cc1
Yield: 20 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-(4-fluoro-benzamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(4-fluoro-benzamido)ethyl]-4'-hydroxy-biphenyl and ethyl 2-bromo-2-methyl-propionate analogous to Example 1. Yield: 20% of theory; m.p. 135° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH3:16][N:17]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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>[OH:11][C:8]([C:6]1[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=[C:2]([C:16]#[N:17])[CH:7]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1cc(Cl)nc(C(F)(F)F)c1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(O)c1cc(C#N)nc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
A solution of 2-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]propan-2-ol (0.230 g, 0.960 mmol, from Step B) and zinc cyanide (0.676 g, 5.76 mmol) in N-methylpyrrolidinone (4 mL) was degassed by bubbling a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.22 g, 0.19 mmol) was added and degassed similarly for 5 additional minutes. The vial was sealed and heated in the microwave to 140° C. for 10 minutes. The reaction mixture was worked up by partitioning between water and ethyl acetate, extracting (3×), and drying the combined extracts over sodium sulfate. The dried extract was then filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes afforded product (110 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, J=1.5 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 1.62 (s, 6H); 19F NMR (282 MHz, CDCl3) δ−68.39 (s); LCMS (M+H)+: 231.1.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[N+](=[CH2:31])=[N-].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1>C1COCC1.CCOCC>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:28])[C@@H:13]([OH:27])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O:7][CH3:31])=[O:6]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C

Procedure:
Deoxycholic acid (0.54 g, 1.4 mmol) in THF (10 ml) at 0° C. was treated dropwise with freshly prepared diazomethane in ether (prepared in the usual manner from diazald) until the yellow colour persisted. After 15 minutes at 0° C. the solvent was evaporated to yield a white foam (0.60 g). The compound would not recrystallise, although gas chromatography showed the product to be 99% pure. The product was further purified by preparative silica tlc. (solvent system: EtOAc/CH2Cl2 /AcOH--10:10:1) to afford pure methyl deoxycholate2 (0.45 g, 80%) as a foam: 1H NMR (60 MHz; CDCl3) δ0.67 (3H, s, 18-CH3), 0.92 (3H, s, 18-CH3), 2.18 (2H, s [exchanges on adding D2O], 3α and 12α OH's), 3.2-3.7 (1H, m. 3β-H), 3.65 (3 H, s, --OMe), 3.8-4-1 (1H, m, 12β-H); IR (nujol mull) 3368 (OH's), 1740 (C=O) cm-1 ; MS: Found m/z 388.2951; C25H40O3 (M-H2O) requires 388.2977.