Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16](=[O:32])[C:17]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].[Al]>CN(C=O)C.C(OCC)(=O)C.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.[Cu](I)I>[CH2:8]([O:15][C:16](=[O:32])[C:17]1[CH:22]=[C:21]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)c1cc(I)ccc1OCc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Pd(PPh3)2Cl2 (194 mg, 0.277 mmol), copper iodide (106 mg, 0.554 mmol) and triethylamine (0.8 mL, 5.44 mmol) were added to a solution of 2-benzyloxy-5-iodo-benzoic acid benzyl ester (1.23 g, 2.77 mmol) and trimethylsilyl acetylene (0.5 mL, 3.32 mmol) in anhydrous DMF (15 mL) at room temperature. The flask was covered with aluminum foil and stirred overnight. The mixture was diluted with ethyl acetate (50 mL) and washed with water (3×), 1N HCl (1×) and brine (1×), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes) to afford 1.07 g (93%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H, J=2 Hz); 7.52 (dd, 1H, J=9.1, 1 Hz); 7.38 (m, 10H); 6.95 (d, 1H, J=9.1 Hz); 5.31 (s, 2H); 5.17 (s, 2H); 0.1 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.Cl.Cl.[NH:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)[CH2:20]1)=[O:15]
Reactant: c1cnc(C2CCNC2)cn1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2cnccn2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 2-pyrrolidin-3-yl-pyrazine trihydrochloride (15.5 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (7.0 mg). Calcd for C18H15ClN4O2: 354.0884, found 354.0885.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Cl.Br[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd]Cl.COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccncc1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Fc1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 117.5 %

Procedure:
A mixture of 4-fluorobenzeneboronic acid (38.7 g, 276 mmol), 4-bromopyridine hydrochloride (48.9 g, 250 mmol), [1,4-butanediylbis(diphenylphosphine-κP)] dichloropalladium (Organometallics 1998, 17, 661; 1.52 g, 2.5 mmol), 1,2-dimethoxyethane (500 mL) and sodium carbonate solution (2M, 440 mL) was degassed with bubbling nitrogen and stirred at 80° C. for 24 hours. The mixture was cooled and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give crude title compound as a brown solid (50.87 g) which was used without further purification. 1H NMR (360 MHz, CDCl3) δ 8.65 (2H, m), 7.61 (2H, m), 7.49 (2H, dd, J 1.6, 4.6 Hz), and 7.09 (2H, m).
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:16])[CH:4]=1)=O.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=2)=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH3:16][C:5]1[CH:4]=[C:3]([CH2:1][NH:31][C:27]2[CH:26]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:32])[F:33])=[CH:20][CH:21]=3)[CH:30]=[CH:29][CH:28]=2)[CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)COc1ccc(CNc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.7 %

Procedure:
To a solution of ethyl (4-formyl-2-methylphenoxy)acetate (0.2 g, 0.9 mmol) in anhydrous CH2Cl2 (8 mL) was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.214 g, 0.9 mmol). The resulting mixture was stirred under nitrogen at room temperature for 15 mins, prior to addition of sodium triacetoxyborohydride (0.267 g, 1.26 mmol) and acetic acid (0.052 mL, 0.9 mmol). The resultant mixture was stirred for 18 h prior to quenching by cautious addition of sat. sodium bicarbonate solution (20 mL) the reaction mixture was then extracted CH2Cl2 (20 mL). The organic extract separated by hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (Silica, 40 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (0.342 g).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:21]1[CH:26]=[C:25]([O:27]C)[CH:24]=[CH:23][C:22]=1[N:29]1[CH:33]=[CH:32][CH:31]=[N:30]1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:20][C:17]1[N:18]=[CH:19][C:14]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]([C:21]4[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=4[N:29]4[CH:33]=[CH:32][CH:31]=[N:30]4)=[N:7][C:8]=3[CH:13]=2)=[CH:15][N:16]=1
Reactant: COc1ccc(-n2cccn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)n1c(-c2cc(O)ccc2-n2cccn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 13.8 %

Procedure:
To a solution of 5-[1-tert-butyl-2-(5-methoxy-2-pyrazol-1-yl-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (Example 2) (75 mg, 0.17 mmol) in CH2Cl2 (10 mL) is added BBr3 (1M in THF) (0.5 mL, 0.51 mmol) at 0° C. under nitrogen atmosphere. The solution is warmed to room temperature and stirred for 48 hours. The solution is cooled down to 4° C. and saturated NaHCO3 solution (5 mL) is added. The mixture is extracted with EtOAc (3×10 mL) and the combined organic layer is dried (MgSO4), filtered and concentrated and the residue is purified by silica gel flash chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (10 mg, 14%) as a white foam. LCMS (ESMS): m/z 426.20 (M++1)
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[Br-].[S:23]1[CH:27]=[CH:26][N:25]=[C:24]1[Zn+].C(=O)([O-])[O-].[Na+].[Na+]>[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>[S:23]1[C:27]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=4)[N:10]=3)[CH:5]=[CH:6][N:7]=2)=[CH:26][N:25]=[CH:24]1
Reactant: [Zn+]c1nccs1
Reactant: FC(F)(F)c1cccc(Nc2nc3c(Cl)nccn3n2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: FC(F)(F)c1cccc(Nc2nc3c(-c4cncs4)nccn3n2)c1
Temperature: 90 °C
Yield: 5.7 %

Procedure:
8-Chloro-N-[3-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyrazin-2-amine (100 mg, 0.319 mmol), 2-thiazolyl zinc bromide (0.5 M in THF, 5 mL, 0.478 mmol), sodium carbonate (2M) (0.24 mL, 0.5 mmol) and tetrakis(triphenyl phosphine) palladium (11 mg, 0.05 mmol) are dissolved and degassed in a mixture of toluene:ethanol (1:1, 4 mL). The reaction mixture is heated 4 hours at 90° C. in a sealed tube. When the reaction is completed, the reaction mixture is cooled down to rt and filtrated through a celite pad and washed with ethyl acetate (10 mL). The filtrate is concentrated and purified by flash chromatography on a silica gel column using (60-120) mesh to get the product as a yellow solid (6.6 mg, 6%); LCMS (method A): mass found (M+H+, 363), Rt (min): 4.50 area % 95.5 (max), 93.5 (254 nm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:37]([S:40](Cl)(=[O:42])=[O:41])([CH3:39])[CH3:38].N1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][S:40]([CH:37]([CH3:39])[CH3:38])(=[O:42])=[O:41])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CC(C)S(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NS(=O)(=O)C(C)C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reaction time: 76 h
Yield: 11.2 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (5 mL) was added at 0° C. potassium bis(trimethylsilyl)amide (0.91 M in tetrahydrofuran, 1.51 mL, 1.38 mmol). After stirring for 15 min at this temperature isopropylsulfonyl chloride (319 mg, 2.24 mmol) was added and stirring was continued at ambient temperature for 76 h. Further isopropylsulfonyl chloride (107 mg, 0.75 mmol) and pyridine (454 mg, 5.74) were added and stirring was continued for 24 h. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane 50:30:20 to 20:60:20) afforded the title compound (29 mg, 11%) as a yellow solid. MS: m/e 455.2 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[OH:27].O>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:15]=1[O:27][CH2:5][CH2:4][CH2:3][CH2:2][Br:1]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: ClC(Cl)=CCOc1cc(Cl)c(OCCCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
A reaction vessel was charged with 22.67 g of 1,4-dibromobutane, 11.06 g of potassium carbonate and 200 ml of N,N-dimethylformamide, to which a solution of 20.16 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol dissolved in 80 ml of N,N-dimethylformamide was slowly added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 300 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 21.77 g of 3,5-dichloro-4-(4-bromobutyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (yield, 74%), nD25.0 1.5666.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]([C:30](O)=[O:31])=[CH:24]2>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C@H:3]([NH:2][C:30]([C:25]2[NH:26][C:27]3[C:23]([CH:24]=2)=[CH:22][C:21]([F:20])=[CH:29][CH:28]=3)=[O:31])[C:4]([N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[O:5])=[CH:14][CH:15]=1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCOCC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCOCC1)c1cc2cc(F)ccc2[nH]1

Procedure:
(S)-2-Amino-3-(4-fluoro-phenyl)-1-morpholin-4-yl-propan-1-one hydrochloride (0.48 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (0.48 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 48 hour reaction time, washed with acid first then base) and the product purified by chromatography on silica gel eluted with 20, 30, 40, 50 and 75% ethyl acetate in hexanes. Yield 189 mg, 95%; HPLC (60/40) 4.76 minutes (97%); PBMS 414 (MH+, 100%);
Reaction SMILES: N1C=CC=CC=1.C(B1OB(C=C)OB([CH:17]=[CH2:18])O1)=C.[OH:19][C:20]1[C:21]([N+:30]([O-:32])=[O:31])=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([O:25][CH3:26])=[O:24].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[N+:30]([C:21]1[C:20]([O:19][CH:17]=[CH2:18])=[CH:29][CH:28]=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24])([O-:32])=[O:31]
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=COc1cccc(C(=O)OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 120 h
Yield: 75.1 %

Procedure:
A mixture of copper (II) acetate (11.98 g, 65.9 mmol) and dichloromethane (80 mL) were stirred at room temperature for 10 minutes, before the addition of 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane compound with pyridine (1:1) (10.63 g, 44.2 mmol, 0.67 eq), methyl 3-hydroxy-2-nitrobenzoate (U.S. Publication No. 2012/0035194 A1 [0202]) (13 g, 65.9 mmol), pyridine (26.7 mL, 330 mmol), and molecular sieves (1 g). The resulting deep blue mixture was stirred at room temperature for 5 days, with the reaction mixture opened to the air. The reaction mixture was filtered through a pad of CELITE®, washing with some dichloromethane. The filtrate was washed with 3M aqueous ammonium acetate (2×), water, brine, and then dried, filtered and concentrated in vacuo. The crude product mixture was purified via ISCO (0% to 20% of EtOAc/DCM in 15 minutes, 120 g column) to give methyl 2-nitro-3-(vinyloxy)benzoate (7.42 g, 33.2 mmol, 50.4% yield). HPLC: RT=2.487 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=246 [M+Na]+; 1H NMR (400 MHz, chloroform-d) δ 7.77 (dd, J=7.8, 1.2 Hz, 1H), 7.55 (t, J=8.1 Hz, 1H), 7.38 (dd, J=8.4, 1.3 Hz, 1H), 6.61 (dd, J=13.6, 5.9 Hz, 1H), 4.95 (dd, J=13.6, 2.4 Hz, 1H), 4.69 (dd, J=5.9, 2.4 Hz, 1H), 3.93 (s, 3H), 1.56 (s, 1H), 0.03 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C1(C)C(C)=CC=CC=1>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc(I)cc1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1C
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(I)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Under argon, 4-hydroxyphenyl 4-iodophenyl ketone (380 mg) obtained in Example 177 and 4-dimethylaminopyridine (158 mg) were added to xylene (11 ml), and the admixture was stirred at room temperature. After 2 hours, 4-chloro-6,7-dimethoxyquinoline (262 mg) was added, and the admixture was refluxed with heat overnight. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then with chloroform/ethyl acetate, followed by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1), to obtain 459 mg of the title compound (yield: 77%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19](Cl)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:31])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[S:23][C:22]3[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[N:20][C:19]([C:36]4[CH:35]=[N:34][C:33]([CH3:32])=[CH:38][CH:37]=4)=[N:18][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCCN(C)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: COCCN(C)C(=O)N1CCN(Cc2cc3nc(-c4ccc(C)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid (2-methoxy-ethyl)-methyl-amide (Example 27) was reacted with 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine via General Procedure A. Purification on silica yielded 154. NMR (CDCl3): 2.58-2.60 (m, 4H, 2×CH2), 2.65 (s, 3H, CH3), 2.92 (s, 3H, CH3), 3.31-3.33 (m, 4H, 2×CH2), 3.36 (s, 3H, CH3), 3.38-3.41 (m, 4H, 2×CH2), 3.55-3.58 (m, 4H, 2×CH2), 3.87 (s, 2H, CH2), 3.90-3.92 (m, 4H, 2×CH2), 4.06-4.09 (m, 4H, 2×CH2), 7.26 (d, H, ArH, J=8.13 Hz), 7.33 (s, H, ArH), 58.58 (dd, H, ArH, J=8.07 Hz), 9.52 (d, H, ArH, J=1.86 Hz). MS: (ESI+): MH+ 526.45
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])(O)=O.[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>[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OCc1ccc(B(O)O)cn1
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: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc(CO)nc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89 mg, 0.2 mmol) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid (61.2 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was diluted in MeOH, treated with Si-Thiol (100 mg), the resin was filtered off and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0 to 20% MeOH) afforded the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4 min, UPLC-MS (Condition 3) tR=0.87 min, m/z=475.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.76 (m, 1H) 1.77-1.86 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.11-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.12-4.22 (m, 1H) 4.61 (d, J=5.87 Hz, 2H) 4.84 (d, J=3.13 Hz, 1H) 5.47 (t, J=5.87 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.53 (d, J=8.21 Hz, 1H) 7.74-7.88 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]#[N:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(N(CC)CC)C.Cl.[NH2:38][OH:39]>O>[OH:39]/[N:38]=[C:25](/[C:23]1[N:22]=[CH:21][N:20]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]=1)\[NH2:26]
Reactant: N#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: N/C(=N\O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture containing 1-trityl-1H-imidazole-4-carbonitrile (1.6 g, 4.77 mmol), ethanol (20 ml), triethylamine (1.995 ml, 14.31 mmol) and hydroxylamine hydrochloride (0.663 g, 9.54 mmol) was heated to 70° C. and stirred 4 h. The mixture was cooled with an ice bath, some water (10 ml) was added and the precipitated product filtered and washed well with water. The product was dried with vacuum at 40° C. 1H-NMR (400 MHz; DMSO-d6): δ 5.43-5.50 (m, 2H), 7.01 (d, 1H), 7.04-7.13 (m, 6H), 7.36-7.46 (m, 10H), 9.10 (d, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[C:28]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:27]=3[O:41][CH3:42])=[O:24])=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].O.[Li+].[OH-].Cl>CO>[C:32]([C:30]1[CH:29]=[C:28]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:27]([O:41][CH3:42])=[C:26]([NH:25][C:23](=[O:24])[NH:22][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]([O:11][C:9]3[CH:8]=[CH:7][N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=3)=[CH:13][CH:14]=2)[CH:31]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)cc(NS(C)(=O)=O)c3OC)c3ccccc23)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(NC(=O)Nc2ccc(Oc3ccnc(C(=O)O)c3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 89.9 %

Procedure:
To a solution of 4-{4-[3-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-ureido]-naphthalen-1-yloxy}-pyridine-2-carboxylic acid methyl ester (Example 11) (1.184 g, 2 mmol) in MeOH (12 mL) was added water (2 mL) and LiOH (58 mg, 2.4 mmol). The resulting mixture was stirred at room temperature for 19 h then neutralized with 2N HCl. The resulting suspension was concentrated to dryness and the residual solid triturated with a mixture of methylene chloride and acetonitrile (300 mL, 2:1). The inorganic salt was filtered and the mother liquor concentrated to give the title compound as a dark tan solid (1.04 g, 90%).