Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[F:39][C:27]([F:26])([F:38])[C:28]1[CH:29]=[C:30]([S:34]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)(=[O:35])=[O:36])[CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCNS(=O)(=O)c3cccc(C(F)(F)F)c3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 19 mg (0.11 mmol) 3-trifluoromethyl-benzenesulfonyl chloride. MMR was consistent with the proposed compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>C1(O)C=CC=CC=1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=2[O:9][CH3:10])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COc1c(Cl)ccnc1C
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: COc1c(Nc2ccc(C(C)(C)C)cc2)ccnc1C

Procedure:
7.9 g of 4-chloro-3-methoxy-2-methylpyridine and 22.4 g of 4-tert-butylaniline are heated at 120° C. for 8 hours in 20 g of phenol. After cooling, the mixture is poured into NaOH and the product is extracted using methylene chloride. After concentrating, the excess of amine is distilled off in vacuo and the residue is crystallized using hexane. 9.5 g=55%
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH2:8][CH2:9][OH:10])[CH3:7].[Na]>>[C:1]([CH2:2][CH2:3][O:10][CH2:9][CH2:8][N:6]([CH3:7])[CH3:5])#[N:4]
Reactant: CN(C)CCO
Reactant: C=CC#N
Agent: [Na]
Product: CN(C)CCOCCC#N
Reaction time: 24 h

Procedure:
530 g of acrylonitrile are added dropwise to 890 g (10 mols) of dimethylaminoethanol and 0.3 g of dissolved sodium at room temperature. The mixture is left to stand for 24 hours and low-boiling constituents are distilled off.
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:14].[Na+].[Na+].Cl[Pd:18]Cl>O>[Pd:18].[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Na+:14].[Na+:14].[Na+:14]
Reactant: Cl[Pd]Cl
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Na+]
Solvent: O
Product: [Pd]
Reaction time: 10 h

Procedure:
Sodium citrate (8.07 g) was dissolved in 807 ml of water, to which was added 56 ml of 6.7×10-3M PdCl2. This mixture was further diluted with 403 ml of water. The mixture was heated to boiling for 10 hours to form a Pd-sodium citrate colloid solution. To this was added 2 g fluorinated carbon (fluorine content 28%, median particle size less than one micrometer, surface area 130 m2 /g) together with 100 ml methanol. The solution was evaporated and the solid was reduced in hydrogen for 14 hours at 300° C. The resultant catalyst contained approximately 0.7% Pd. The catalyst was a partially wettable, black, slightly sticky powder.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1)=[O:3].[Cu](C#N)[C:26]#[N:27]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[NH2:1][C:2]([C:4]1[CH:9]=[C:8]([C:26]#[N:27])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1)=[O:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1
Reactant: N#C[Cu]C#N
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(C#N)n2)CC1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
tert-Butyl {1-[4-(aminocarbonyl)-6-chloropyridin-2-yl]piperidin-4-yl}carbamate (Intermediate 16) (100 mg, 0.282 mmol), copper cyanide (101 mg, 1.13 mmol), Pd(dba) (103 mg, 0.11 mmol) and Dppf (250 mg, 0.45 mmol) were placed in anhydrous dioxane (5 ml) under argon. The mixture was heated at 100° C. for 5 h, then diluted with EtOAc (20 ml) and filtered through celite. The mixture was washed with sodium bicarbonate (2×20 ml), brine (20 ml), dried over sodium sulphate and concentrated in vacuo. The brown residue was purified by flash chromatography eluting with DCM and MeOH mixtures to give the title compound as a brown solid (61 mg).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.NCC1CCN([NH:27][C:28](=[O:41])[NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][CH:31]=2)CC1>>[CH2:39]([O:38][C:36](=[O:37])[C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([N:27]2[CH2:7][CH2:6][CH:18]([CH2:10][NH:11][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:17][CH2:16]2)=[O:41])=[CH:35][CH:34]=1)[CH3:40]
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CCOC(=O)c1ccc(NC(=O)NN2CCC(CN)CC2)cc1
Product: CCOC(=O)c1ccc(NC(=O)N2CCC(CNC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1
Yield: 46.6 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.150 g, 0.63 mmol) and 3-(4-aminomethyl-1-piperidinyl)-1-(4-ethoxycarbonylphenyl) urea (0.305 g, 1.0 mmol) according to the procedure used in example 2 to give 0.080 g of the title compound as a white solid.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:22]2[CH2:24][CH:23]2[C:25]#[N:26])(O)[CH3:20])=[CH:15][CH:14]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[C:35]([CH2:37][S:38][CH3:39])[CH:36]=1)[NH:33][CH:32]=[CH:31]2>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:22]2[CH2:24][CH:23]2[C:25]#[N:26])([C:31]2[C:30]3[C:34](=[C:35]([CH2:37][S:38][CH3:39])[CH:36]=[C:28]([F:27])[CH:29]=3)[NH:33][CH:32]=2)[CH3:20])=[CH:15][CH:14]=1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Reactant: CC(O)(c1ccc(Cl)cc1)C1CC1C#N
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(F)cc2c(C(C)(c3ccc(Cl)cc3)C3CC3C#N)c[nH]c12

Procedure:
367 mg (1.66 mmol) of indium(III) chloride and 0.12 ml (1.58 mmol) of trifluoroacetic acid were added to 350 mg (1.58 mmol) of the compound from Example 75A and 308 mg (1.58 mmol) of the compound from Example 11A in 9 ml of dichloromethane at RT, and the mixture was heated under reflux for 15 min. It was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 32.5 mg (5% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH3:30])=[N:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH3:30])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1CNCCN1c1cnc(Nc2cc(Br)cn(C)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
A mixture of 230d (1.9 g, 3.97 mmol) and trifluoroacetic acid (4 mL) was stirred at room temperature for 1 h. It was then concentrated under reduced pressure to afford crude 230e (1.45 g, 97%), which was used in the next step without further purification. MS: [M+H]+ 381.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][C:21]=1[F:28]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][C:21]=1[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(CO)cc1F

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and (4-bromo-3-fluorophenyl)methanol (Intermediate 9), the title compound was obtained as a dark brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1.O.CN([CH:24]=[O:25])C>>[Cl:6][C:7]1[C:12]([CH:24]=[O:25])=[N:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])[N:8]=1
Reactant: CN(C)C=O
Reactant: CC1CCCCN1c1cncc(Cl)n1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.25 h
Yield: 57 %

Procedure:
Phosphoryl chloride (1.62 mL) was added dropwise to DMF (5 ml) at 0° C. The mixture was stirred for 15 min, and a solution of 2-chloro-6-(2-methylpiperidin-1-yl)pyrazine (1.85 g) in DMF (1 mL) was added dropwise thereto. The mixture was stirred at 80° C. for 16 hr, water (5 ml) was added at 0° C., and the mixture was stirred at room temperature for 1.5 hr. The mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by recrystallization (ethyl acetate-hexane) to give the title compound (1.18 g, 57%) as a colorless powder.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[CH:8]=[C:9]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[NH2:31])[CH:28]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1.[C:35](=O)(O)[O-].[Na+]>CO>[CH3:6][C:7]1[CH:8]=[C:9]([C:24]2[CH:25]=[N:26][N:27]([CH2:29][C@@H:30]([C:32]([O:34][CH3:35])=[O:33])[NH2:31])[CH:28]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:12]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(C[C@H](N)C(=O)O)c2)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](N)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 70 °C

Procedure:
Concentrated sulfuric acid (16 uL, 0.3 mmol) was added to a stirred solution of 3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]-L-alanine (100 mg, 0.3 mmol) in MeOH (1 mL). The reaction mixture was heated to 70° C. overnight, cooled to room temperature, and treated with aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc, washed with sodium hydroxide solution (1N, 2×) and brine, dried over sodium sulfate, concentrated under reduced pressure to afford methyl 3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]-L-alaninate. MS ESI calcd. for C19H26F3N6O2 [M+H]+ 421. found 421. 1H NMR (500 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.34 (s, 1H), 7.26 (d, J=4.6 Hz, 1H), 7.06 (s, 1H), 4.25-4.34 (m, 2H), 3.78-3.80 (m, 1H), 3.62 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[O:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[N-:21]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:21][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[OH:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccnc(C(=O)c2ccc(F)cc2C(F)(F)F)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccnc(C(O)c2ccc(N)cc2C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
2-(4-fluoro-2-trifluoromethylbenzoyl)-4-methylpyridine (4.5 g) and sodium azide (1.3 g) were suspended in dimethylsulfoxide (30 ml), and the mixture was heated with stirring overnight under nitrogen atmosphere at 90° C. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (30 ml), and to the solution was added aluminum lithium hydride (1.2 g) under ice-cooling, and the mixture was stirred for 1 hour under nitrogen atmosphere under ice-cooling. Water (1.2 ml), 15% aqueous solution of sodium hydroxide (1.2 ml) and water (3.6 ml) were added to the mixture, and the mixture was stirred, dried over anhydrous magnesium sulfate, and filtrated. The solvent of the filtrate was distilled off, to give (4-amino-2-trifluoromethylphenyl)(4-methylpyridin-2-yl)methanol (3.6 g) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH3:26][O:27][CH2:28][C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][O:27][CH3:26])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COCC(=O)O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (206 mg, 0.57 mmol) and methoxyacetic acid (48 μl, 0.63 mmol) in DCM (5 ml) was treated with a solution of WSCDI (120 mg, 0.63 mmol), HOBt (85 mg, 0.63 mmol) and NMM (69 μl, 0.63 mmol) in DCM (10 ml) and stirred at room temperature for 18 hours. The reaction mixture was washed with sat. NaHCO3 solution followed by brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with Et2O to afford the title compound as a colourless oil (230 mg, 93%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[N:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:6]#[N:7])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: N#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 9 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 21.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH:2]([CH3:13])[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][CH:6]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CCc1ccc(C(=O)C(C)Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCc1ccc(C(=O)C(C)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
A mixture of 17.2 g of 2-bromo-4'-ethylpropiophenone, 12.5 g of 4-benzylpiperidine and 9.9 g of potassium carbonate in 250 ml of dry ethanol is heated under reflux for 4 hours, with stirring. The inorganic product is filtered off and washed with ethanol and the alcohol phase is concentrated in vacuo. The oily residue is taken up in diethyl ether and the mixture is extracted twice with dilute hydrochloric acid. After it has been rendered clearly alkaline with sodium hydroxide, the acid aqueous phase is then extracted three times with ethyl acetate. The organic phases are combined, washed with water until the washings are neutral, dried and evaporated in vauco. This give 19.15 g of an oily residue.
Reaction SMILES: [CH:1]([OH:14])([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>O1CCCC1.ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:14][CH:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1=COCCC1
Reactant: CCCCCCCCCCCC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(O)OC1CCCCO1
Temperature: 25 °C
Yield: 25 %

Procedure:
Dodecanediol (23.000 g) was dissolved in 230 ml of dry tetrahydrofuran and 40 ml of dichloromethane, and 10 mg of p-toluenesulfonic acid and 9.578 g of dihydropyran were added thereto. The mixture was stirred at room temperature for a day. Triethylamine (1.0 ml) was added thereto to stop the reaction and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8.132 g of dodecanediol monotetrahydropyranyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](O)=[O:11]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Solvent: C1CCOC1
Product: OCCc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a solution of (2-bromo-4-fluorophenyl)acetic acid (1.5 g, 6.44 mmol) in tetrahydrofuran (10 mL) was added 1M solution of borane-tetrahydrofuran complex in tetrahydrofuran (9.66 mL, 9.66 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. The reaction mixture was quenched by the addition of 2N hydrochloric acid (50 mL), extracted with ethyl acetate (200 mL). The organic layer washed with brine (50 mL) dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (100 g) eluting with hexane/ethyl acetate (5/1) to afford 1.30 g (92%) of the title compound as colorless oil:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:3]=[C:2]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C

Procedure:
The solution of methyl 2-(3-bromophenyl)acetate (288.9 mg, 1.26 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.97 mmol), PdCl2(dppf) (35.5 mg, 4.8% mmol) and K2CO3 (268.1 mg, 1.94 mmol) in DMF (20 mL) was stirred at 90 degree under N2 overnight. After cooling to room temperature, the mixture was filtered with celite, diluted with EtOAc, washed with water, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by a standard method to get desired product. LC-MS: m/z (M+H)=332.4
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH:13]=C.[O:15]=[O+][O-].[BH4-].[Na+]>CO.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH2:12][CH2:13][OH:15]
Reactant: C=CCc1c(Br)ccc2c1COC2=O
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1OCc2c1ccc(Br)c2CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-bromo-4-prop-2-en-1-yl-2-benzofuran-1(3H)-one (1.27 g, 5.02 mmol) in MeOH (50 mL) and DCM (50 mL) was bubbled O3 at −78° C. until the solution turned blue; excess ozone was removed on high vacuum. After the solution's color changed to colorless, NaBH4 (0.8 g, 20 mmol) was added to the reaction mixture and it was subsequently stirred at room temperature for 30 min. LC and TLC indicated that reaction had gone to completion. The solvent was removed on high vacuum; the residue was then re-dissolved in EtOAc and washed with water, dried over Na2SO4, filtered and concentrated to dryness. The organic residue was absorbed onto silica gel and was separated on silica gel column to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][CH:20]=[N:21][CH:22]=2)=[O:16])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][C:25]=1[F:33]>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15]([C:17]3[CH:18]=[N:19][CH:20]=[N:21][CH:22]=3)=[O:16])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:26][C:25]=1[F:33]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cncnc1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1)c1cncnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using pyrimidine-5-carboxylic acid[5-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-amide (example 52 a) and B-(4-chloro-3-fluorophenyl)-boronic acid (CAN 137504-86-0) as starting materials; LC-MS (UV peak area/ESI) 97.7%, 425.0448 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][CH2:20][N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:29][C:30]([OH:47])([CH3:46])[CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>>[CH3:29][C:30]([OH:47])([CH3:46])[CH2:31][N:32]1[CH:36]=[C:35]([C:2]2[CH:28]=[CH:27][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][CH2:20][N:21]6[CH2:22][CH2:23][O:24][CH2:25][CH2:26]6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:34]=[N:33]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3CCN3CCOCC3)nc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CCN4CCOCC4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-bromo-2-[2-(2-morpholin-4-yl-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 460. MS (ESI+) 522.2. 1H NMR (400 MHz, DMSO) δ 8.34 (d, J=8.3, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.38 (dd, J=8.3, 1.7, 1H), 7.30 (d, J=1.6, 1H), 4.95 (t, J=6.5, 2H), 4.72 (s, 1H), 4.39 (t, J=5.0, 2H), 4.04 (s, 2H), 3.45 (t, J=5.0, 2H), 3.43-3.38 (m, 4H), 2.82 (t, J=6.5, 2H), 2.46-2.35 (m, 4H), 1.10 (s, 6H).