Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH2:7]([N:9]([CH2:13][CH3:14])[C:10](Cl)=[O:11])[CH3:8]>CC(C)=O>[CH2:7]([N:9]([CH2:13][CH3:14])[C:10]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])=[O:11])[CH3:8]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=C1NCCN1
Solvent: CC(C)=O
Product: CCN(CC)C(=O)N1CCNC1=O

Procedure:
A mixture of 34,4 g ethylene urea and 54,2 g N,N-diethylcarbamyl chloride is heated under nitrogen at 110° for 3 hrs. The reaction mixture is cooled and diluted with 200 ml acetone. It is filtered and the filtrate evaporated off to dryness. The oily product is chromatographed on a column of 450 g of silica gel. The fraction which eluted from 3% methanol in chloroform yields 1-(N,N-diethylcarbamoyl)-2-oxo-tetrahydroimidazole as a colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C.[F:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1O>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[F:40])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CC[C@@H]2O)cc1
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O[C@H]1CCN(Cc2ccccc2)C[C@H]1COc1ccccc1F
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 32 %

Procedure:
After dissolving 1.49 g of cis-1-benzyl-4-hydroxy-3-(p-toluenesulfonyloxymethyl)piperidine in 8 ml of N,N-dimethylformamide, 0.71 ml of 2-fluorophenol and 1.22 g of anhydrous potassium carbonate were added and the mixture was stirred at 100° C. for 50 minutes. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with a 5N sodium hydroxide solution, water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (402 mg, 32% yield).
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1.[CH3:17][N:18]=[C:19]=[S:20].C(OC(C)C)(C)C.C>CCCCCC.C(O)C.C(OCC)(=O)C.O.O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[CH3:17][NH:18][C:19]([C:12]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=2)[CH2:16][CH2:15][CH2:14][O:13]1)=[S:20]
Reactant: CN=C=S
Reactant: c1ccc(C2CCCO2)nc1
Agent: [Li]CCCC
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNC(=S)C1(c2ccccn2)CCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.8 %

Procedure:
A mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 80 cc) is added dropwise and in the course of 15 minutes to a 1.6 M solution of n-butyllithium in hexane (75 cc), kept under a nitrogen atomosphere and at a temperature of about -60° C. A solution of 2-(pyrid-2-yl)-tetrahydrofuran (15 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 80 cc) is then added in the course of 20 minutes. After stirring for 30 minutes at the same temperature, a solution of methyl isothiocyanate (8.8 g) in a mixture of anhydrous hexamethylphosphorotriamide and anhydrous tetrahydrofuran (47/53 by volume; 80 cc) is added in the course of 20 minutes. The reaction mixture is subsequently stirred for 45 minutes at about -60° C. and then for 1 hour whilst allowing the temperature to rise gradually to about 20° C. It is then run into a mixture of distilled water (600 cc) and ethyl acetate (400 cc). After decantation, the aqueous solution is extracted twice with ethyl acetate (800 cc in total). The organic extracts are combined, washed three times with distilled water (1500 cc in total), dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 45° C. The product obtained (6.6 g) is dissolved in boiling diisopropyl ether (350 cc); decolourising charcoal (0.5 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 30 minutes at 0° C. The resulting crystals are filtered off, washed twice with diisopropyl ether (10 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. The product obtained (7.7 g) is combined with a product (0.8 g) prepared under the same conditions, and the combined product is dissolved in boiling ethanol (30 cc); decolourising charcoal (0.2 g) is added to the solution, which is filtered hot, and the filtrate is then cooled for 1 hour at 0° C. The resulting crystals are filtered off, washed twice with ethanol (10 cc in total) and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. N-Methyl-2-(pyrid-2-yl)-tetrahydrofuran-2-carbothioamide (6 g), melting at 115° C., is thus obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: Cc1c(Br)cc(F)cc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: Cc1c(Br)cc(F)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) solution of 3-bromo-5-fluoro-2-methyl-benzoic acid (3 g, 12.9 mmol) in dry THF (20 mL) was added borane THF complex (25.8 mL, 1 M in THF, 25.8 mmol) slowly. The resulting mixture was stirred at room temperature overnight, then quenched with MeOH and concentrated. The residue was purified by column chromatography to give (3-bromo-5-fluoro-2-methyl-phenyl)-methanol. 1H-NMR (400 MHz, CDCl3) δ ppm 7.25 (dd, J=8.6 Hz, J=3.1 Hz, 1H), 7.15 (dd, J=8.6 Hz, J=2.3 Hz, 1H), 4.71 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].CS(C)=O>O>[C:24]([O:23][C:21]([CH:20]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Reaction time: 18 h
Yield: 78 %

Procedure:
(a)(i) A mixture of N-hydroxyphthalimide (24.5g), anhydrous potassium carbonate (16.5g), t-butyl α-bromophenylacetate (41g) and dimethylsulphoxide (225 ml) was stirred for 18 hours and was then poured into water (1.2 liters). The precipitated solid was filtered off, washed well with water, dried, and crystallised from industrial methylated spirits to give N-[α-(t-butoxycarbonyl) benzyloxy] phthalimide (41g, 78%); m.p. 120.6°-121.5°.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]1=[O:13]>C(O)(=O)C.[Zn]>[O:13]=[C:3]1[CH2:2][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4]1
Reactant: N#Cc1ccc2c(c1)C(Br)(Br)C(=O)N2
Agent: [Zn]
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)CC(=O)N2
Yield: 36.1 %

Procedure:
A solution of 3,3-Dibromo-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile (10.5 grams, 33.3 mmole) and Zn dust (22.0 grams, 338.5 mmole) in acetic acid (250 ml) was stirred at room temperature for 45 minutes. The mixture was filtered through celite and concentrated to dryness. The resulting oil was diluted with 300 ml water and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide and brine, dried over MgSO4, filtered, and concentrated to give a white solid (1.9 g). MW 158.
Reaction SMILES: O.O.[Na+].[CH3:4][N:5]([CH3:9])[C:6](=[S:8])[S-:7].[NH2:10][C:11]1[N:16]=[C:15]([CH2:17]Cl)[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1>C(O)C.O>[NH2:10][C:11]1[N:12]=[C:13]([O:19][CH3:20])[CH:14]=[C:15]([CH2:17][S:8][C:6](=[S:7])[N:5]([CH3:9])[CH3:4])[N:16]=1
Reactant: COc1cc(CCl)nc(N)n1
Reactant: CN(C)C(=S)[S-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(CSC(=S)N(C)C)nc(N)n1

Procedure:
18.5 g of dimethyldithiocarbamic acid sodium salt dihydrate and 17.4 g of 2-amino-4-chloromethyl-6-methoxypyrimidine are refluxed in 100 ml of ethanol for 30 minutes. After the mixture has been cooled, it is diluted with about 1 litre of water, and the product which has precipitated is separated and dried. The yield is 23.0 g (89% of theory) of 2-amino-4-methoxy-6-dimethylthiocarbamoylthiomethyl-pyrimidine, m.p. 118°-120° C.
Reaction SMILES: [N:1]1C=CC=C(C(N)C)C=1.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20](=O)[CH3:21])=[CH:12][CH:11]=1.N.CO.C([BH3-])#N.[Na+]>C(O)(=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]([NH2:1])[CH3:21])=[CH:12][CH:11]=1
Reactant: CC(N)c1cccnc1
Reactant: CC(=O)c1ccnc2ccccc12
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1ccnc2ccccc12

Procedure:
The title compound was prepared by the same procedure for preparing 1-pyridin-3-yl-ethylamine from 1-quinolin-4-yl-ethanone, (1.71 g, 10 mmol, Aldrich), 2 M ammonia solution in methyl alcohol, (40 mL, 80 mmol, Aldrich), acetic acid (10 mL, J. T. Baker) and sodium cyanoborohydride (5.0 g, 80 mmol, Aldrich). The title compound obtained in form as light yellow solid in 100% yield (1.72 g, 10 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[O:17])[CH:10]=[CH:11][C:12]=2[O:13]C)=[CH:5][CH:4]=[N:3]1.ClC(Cl)C.BrB(Br)Br>O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH:15][C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)=[O:17])[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:5][CH:4]=[N:3]1
Reactant: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: O
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(Cl)cc2)ccc1O
Temperature: 25 °C

Procedure:
To a mixture of 1-[3-(2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(4-chloro-phenyl)-urea (6.35 g, 17.8 mmol) and dichloroethane (500 mL), tribromoborane (10 mL, 106 mmol) was added. The mixture was allowed to warm to room temperature. After stirring over the weekend, the mixture was cooled in an ice bath and a mixture of ice cold ammonium hydroxide and water (ca. 100 mL) was added slowly. The mixture was transferred into a separatory funnel and extracted with methylene chloride and water. Solid in the water phase was filtered off and washed with water to give 1-[3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea as a white solid (4.92 g, 90% pure, 12.7 mmol, 71%). Combined organic phases were dried over MgSO4, filtered, and concentrated to afford additional 1-[3-(2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(4-chloro-phenyl)-urea as a white solid (1.71 g, 4.99 mmol, 28%). Overall yield: 99%. LCMS m/z (%)=343.1 (M+H). 1H NMR (400 MHz, CDCl3) δ: 9.60 (br s, 1H), 8.78 (s, 1H), 8.53 (s, 1H), 7.48-7.42 (m, 3H), 7.32-7.27 (m, 4H), 6.91-6.89 (m, 1H), 6.21 (d, J=1.8 Hz, 1H), 3.68 (s, 3H).
Reaction SMILES: [CH2:1]([S:5][C:6]1C=C[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].BrC1[S:17]C(SCCCC)=CC=1.C([Li])CCC>>[CH2:1]([S:5][C:6]1[S:17][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1ccc(Br)s1
Reactant: CCCCSc1ccc(C(=O)O)cc1
Agent: [Li]CCCC
Product: CCCCSc1ccc(C(=O)O)s1

Procedure:
The experimental procedure is as described for compound 2, with use of compound 7 (8.99 g, 0.036 mol) and n-butyllithium (15.0 ml, 2.5M in hexane. 0.037 mol). A white solid was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:35]=[C:36]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:37]2[C:42]([CH:43]=1)=[C:41]([O:44][CH3:45])[CH:40]=[CH:39][CH:38]=2>>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH:43]=[C:34]([CH2:33][O:1][CH:2]1[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[S:21][CH:22]=[CH:23][CH:24]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1)[CH:35]=[C:36]2[O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3cccs3)cc2)C(O)C1
Reactant: COCCCOc1cc(CCl)cc2c(OC)cccc12
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3cccs3)cc2)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 1 g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate [Example 123 b)] with 3-chloromethyl-5-methoxy-1-(3-methoxy-propoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-3-[8-methoxy-4-(3-methoxy-propoxy)-naphthalen-2-ylmethoxy]-4-{4-[3-(thiophen-2-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow, viscous oil; MS: 706 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27](Cl)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]6[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([N:37]7[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]7)[CH:26]=6)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:34]([NH2:36])=[O:35])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cc(N4CCNCC4)ncc3Cl)cc1-2
Reaction time: 24 h
Yield: 55.6 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 211 (1 g, 0.0018 mol) and piperazine (3 g, 0.036 mol) in EtOH (4 mL). The reaction was run at 95° C. for 24 h. After allowing the reaction mixture to cool down, the volatiles were removed under vacuum. The residue was triturated with H2O and finally with EtOH to yield 0.572 g of the title compound (yield: 55%). 1H NMR (300 MHz, d6-DMSO): δ 2.71 (s, broad, 4H), 2.86-3.30 (m, 4H), 3.39 (s, broad, 4H), 6.07 (s, 2H), 6.85 (s, 1H), 6.93-6.95 (dd, 1H, J=8.2 Hz, 1.9 Hz), 7.00 (d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=1.9 Hz), 7.24-7.30 (m, 3H), 7.38-7.41 (dd, 1H, J=8.2 Hz, 1.74 Hz), 7.49 (s, 1H), 8.12 (s, 1H), 10.32 (s, 1H). M+1=573.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([OH:21])=O)=[CH:5][N:4]=1.C1C=CC2N(O)N=[N:28]C=2C=1.C(Cl)CCl.[OH-].[NH4+]>CN(C=O)C.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)[C:6]([C:19]([NH2:28])=[O:21])=[CH:5][N:4]=1
Reactant: On1nnc2ccccc21
Reactant: CSc1ncc(C(=O)O)c(NC2(c3ccccc3)CC2)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc(C(N)=O)c(NC2(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxylic acid (646 mg, 2.15 mmol) and HOBt.H2O (395 mg, 2.58 mmol) in DMF (3.5 mL), EDC (515 mg, 2.69 mmol) was added. The mixture was stirred at room temperature for 20 min. Ammonium hydroxide (244 mg, 4.30 mmol) was added. It was stirred at room temperature for 1 h. Water was added to induce precipitation, the solids were collected by filtration to give 2-(methylthio)-4-(1-phenylcyclopropylamino)pyrimidine-5-carboxamide (636 mg). MS 301.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[CH3:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C1(C)C=CC=CC=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.C(O)C>[CH3:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:14][N:13]=3)=[O:10])=[CH:4][C:3]=2[C:24]([F:27])([F:26])[F:25])[CH:32]=[CH:31][N:30]=1
Reactant: O=C(Cc1ccc(Br)c(C(F)(F)F)c1)Nc1ccc(-c2ccccc2)cn1
Reactant: Cc1cc(B(O)O)ccn1
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: CCO
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(CC(=O)Nc3ccc(-c4ccccc4)cn3)cc2C(F)(F)F)ccn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube were added 2-(4-bromo-3-(trifluoromethyl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 46-7 (73 mg, 0.17 mmol), 2-methylpyridin-4-ylboronic acid (35 mg, 0.255 mmol), Pd(PPh3)4 (12 mg, 0.017 mmol), toluene (0.8 mL), ethanol (0.2 mL) and 2M Na2CO3 (0.5 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooled down to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with saturated NaHCO3 aqueous solution and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2-(4-(2-methylpyridin-4-yl)-3-(trifluoromethyl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 46 as white solid. MS m/z 448.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.48-8.45 (m, 2H), 8.28 (d, 1H, J=8.4 Hz), 7.92 (dd, 1H, J1=8.4 Hz, J2=2.4 Hz), 7.75 (s, 1H), 7.61 (dd, 1H, J1=8.0 Hz, J2=1.2 Hz), 7.54-7.52 (m, 2H), 7.47-7.43 (m, 2H), 7.39-7.37 (m, 1H), 7.28 (d, 1H, J=7.6 Hz), 7.14 (s, 1H), 7.10 (d, 1H, J=5.2 Hz), 3.86 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>O1CCCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([OH:16])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCCC(=O)c1ccc(CC(C)C)cc1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Product: CCCC[C@@H](O)c1ccc(CC(C)C)cc1
Reaction time: 5 h
Yield: 30 %

Procedure:
4'-Isobutylpentanophenone (2.1 g) was added to a solution of (+)-B-chlorodiisopinocampheylborane (3.57 g) in tetrahydrofuran (7 ml) at -25° C. After stirring for 5 hours, the solvent was removed and the residue was dissolved in ethyl ether (30 ml). To this solution was added diethanolamine (2 ml), and the mixture was stirred for 2 hours. The solid was filtered off and washed with ethyl ether. The combined filtrates were concentrated and the residue was chromatographed on silica gel (hexane:dichloromethane =1:2) to give (R)-1-(4-isobutylphenyl)pentan-1-ol (635 mg).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C>C1COCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([B:21]([OH:22])[OH:20])=[CH:13][C:12]=2[CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2oc(B(O)O)cc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
n-Butyllithium 2.5M in hexanes (5.6 mL) was added slowly to a solution of 5-methoxybenzofuran (13.5 mmol) in dry THF (30 mL) at −78° C. After 1 h stirring at −78° C., triisopropylborate (27.0 mmol) was added dropwise and the mixture was stirred for another 20 min at −78° C. The dry ice bath was removed and HCl 2N (aq. 40 mL) was added and the mixture allowed to warm to r.t. and then poured in water (50 mL). The resulting aqueous solution was extracted with ether, the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a beige powder (2.40 g). 1H NMR δ ppm 8.49 (s, 2 H) 7.45 (d, 1 H) 7.38 (s, 1 H) 7.18 (d, 1 H) 6.93 (dd, 1 H) 3.78 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C@@H:9]([F:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:25])[CH2:21][CH:20]([CH3:22])[O:19][B:18]([CH:23]=[CH2:24])[O:17]1>>[F:12][C@@H:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][C:2](/[CH:24]=[CH:23]/[B:18]3[O:17][C:16]([CH3:25])([CH3:15])[CH2:21][CH:20]([CH3:22])[O:19]3)=[CH:3][CH:4]=2)[CH2:8]1
Reactant: C=CB1OC(C)CC(C)(C)O1
Reactant: F[C@@H]1CCN(Cc2ccc(Br)cc2)C1
Product: CC1CC(C)(C)OB(/C=C/c2ccc(CN3CC[C@@H](F)C3)cc2)O1

Procedure:
The title compound was synthesized according to the method of Example A51A, except substituting (R)-1-(4-bromobenzyl)-3-fluoropyrrolidine (1.07 g, 4.15 mmol) and 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane (0.77 mL, 4.57 mmol) which gave 1.40 g, 91% of a pale orange solid; MS ESI [M+H]+ 332.3, calcd for [C19H27BFNO2+H]+ 332.22.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[N:6][C:7]=1[NH2:8].[CH2:27]([O:34][C:35]([NH:37][C:38](=NC(OCC1C=CC=CC=1)=O)SC)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[C:28]1([CH2:27][O:34][C:35]([NH:37][C:38]2[NH:1][C:2]3[C:7]([N:8]=2)=[N:6][CH:5]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]4[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=4[CH:26]=2)[CH:3]=3)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c(N)c3)cc2C1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)cc2C1
Temperature: 50 °C
Yield: 89.5 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(5,6-diaminopyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (example 15, step 2) (0.23 g, 0.65 mmol) in acetic acid (10 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (0.27 g, 0.76 mmol) and the resulting mixture was heated at 50° C. After 4 h the reaction mixture was concentrated then suspended in ethyl acetate (10 mL). Filtration followed by washing the cake with ethyl acetate (2×10 mL) provided 1,1-dimethylethyl 7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (0.3 g, 91% yield) as a white solid. MS (EI) for C28H29N5O5: 516 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([CH:22]([OH:27])[C:23]([F:26])([F:25])[F:24])[N:21]=1)[C:12]([O:14]C(C)(C)C)=[O:13].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:19]=[C:20]([CH:22]([OH:27])[C:23]([F:26])([F:24])[F:25])[N:21]=1)[C:12]([OH:14])=[O:13]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2F)nc(C(O)C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cc(-c2ccc(F)cc2F)nc(C(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl 2-(2,4-difluorophenyl)-6-(2,2,2-trifluoro-1-hydroxyethyl)isonicotinate (0.56 g, 1.44 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL). The mixture was stirred at ambient temperature. After 18 h, additional trifluoroacetic acid (1 mL) was added and the mixture was stirred at ambient for 1 h. The mixture was concentrated to dryness to give the title compound (0.43 g). MS 334.2 (M+1).