Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=[O:21])C(F)(F)F)=[CH:7][N:8]2[CH2:11][C:12]([NH:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.C[Si](C)(C)[O-:24].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16]([OH:21])=[O:24])=[CH:7][N:8]2[CH2:11][C:12](=[O:13])[NH:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CNC(=O)Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: C[Si](C)(C)[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CNC(=O)Cn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-[6-Chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-N-methyl-acetamide was suspended in DCE and treated with (2.2 eq.) of sodium trimethylsilanolate. After shaking at room temperature for 20 min, the mixture was concentrated in vacuo and purified by prep. HPLC to give the title compound.
Reaction SMILES: Br[CH2:2][CH:3]([F:5])[F:4].[NH:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:4][CH:3]([F:5])[CH2:2][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7]1
Reactant: FC(F)CBr
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CC(F)F)c2ncccc12
Temperature: 70 °C

Procedure:
2-Bromo-1,1-difluoroethane (677 μl, 8.51 mmol) was added to a suspension of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate (500 mg, 2.84 mmol) and K2CO3 (1177 mg, 8.51 mmol) in DMF (2838 μl) at RT. The mixture was heated at 70° C. for 14 h and purified by column chromatography (SiO2; DCM/MeOH) to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:19])[N:3]=1.CC([O-])=O.[Na+].C(O)C>[Pd].C1(C)C=CC=CC=1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([S:8]([C:7]2[CH:6]=[N:5][C:4]([CH3:19])=[N:3][CH:2]=2)(=[O:9])=[O:10])=[CH:16][CH:15]=1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2Cl)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)c2cnc(C)nc2)cc1
Yield: 83.4 %

Procedure:
A mixture of 4-chloro-5-(4-methoxy-benzenesulfonyl)-2-methylpyrimidine (468 mg, 1.57 mmol), prepared by the method described in example 1 part E, 10% Pd/C (50 mg), NaOAc (128 mg, 1.57 mmol), ethanol (5 mL) and toluene (15 mL) was hydrogenated at 40 psi (Parr Shaker Apparatus) overnight. The mixture was filtered through a pad of silica gel, and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel (67:33 hexanes/EtOAc) to provide 5-(4-methoxy-benzenesulfonyl)-2-methylpyrimidine (346 mg, 84%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.06 (s, 2H), 7.90 (d, J=9.9 Hz, 2H), 7.01 (d, J=9.9 Hz, 2H), 3.88 (s, 3H), 2.80 (s, 3H); ESI MS m/z 265 [(M+H)+, calcd for C12H13N2O3S, 265.1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.B(O)(O)[C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=1>COCCOC.C(=O)(O)[O-].[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:18]([C:17]1[C:12]([NH:11][C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[C:13]2[S:22][C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([OH:33])=[O:32])=[CH:27][CH:26]=3)=[CH:20][C:14]2=[N:15][CH:16]=1)#[N:19]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C(=O)O)cc4)sc23)c(Cl)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (500 mg, 1.05 mmol), 4-carboxylphenylboronic acid (350 mg, 2.12 mmol) and 100 mg of tetrakis(triphenylphosphine)palladium(0) in 50 mL of ethylene glycol dimethyl ether and 35 mL of saturated aqueous sodium bicarbonate is heated at reflux for 1 hour. The reaction mixture is cooled to room temperature and partitioned between water and ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of chloroform to 10% methanol in chloroform to provide 4-{6-cyano-7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-2-yl}benzoic acid as yellow crystals, mp>300° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.78 (s, 1H), 7.86 (d, J=8 Hz, 2H), 8.03 (d, J=8 Hz, 2H), 8.03 (s, 1H), 8.08 (s, 1H), 8.64 (s, 1H), 9.80 (s, 1H), 13.14 (s, 1H); MS 470.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:10]1([P:16](Cl)(Cl)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOCC>[C:10]1([P:16]2(=[O:17])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH2:3][N:2]2[CH3:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CNCc1ccccc1
Solvent: CCOCC
Product: CN1Cc2ccccc2P1(=O)c1ccccc1

Procedure:
The procedure of Example 36 was employed utilizing N-methyl-N-benzylamine and phenyl phosphonic dichloride. The reaction of the dilithio compound and the phenyl phosphonic dichloride was conducted at -60° C. The residue produced as a result of the distillation process was slurried in ether to yield 1-phenyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a white solid. A second crop was obtained and the combined product yield was recrystallized from carbon tetrachloride and petroleum ether to yield 1-phenyl-2-methyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.25 g, 15% yield) having a melting point of 129°-130° C. and the following analysis:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Reactant: OB(O)c1ccccc1
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: COCCOC
Product: COC(=O)c1cc(-c2ccccc2)cc(C)c1N
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of 5.0 g (0.021 mol) of 2-amino-5-bromo-3-methyl-benzoic acid methyl ester and 2.8 g (0.023 mol) of phenyl boronic acid in 150 mL of dimethoxyethane was added 20.5 mL of a 2.0M aqueous solution of Na2CO3 and 1.18 g (1.02 mmol) of Pd(PPh3)4. The reaction mixture was evacuated and filled with N2 three times and was then heated to reflux overnight. The reaction was then cooled to room temperature, and poured into ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel using gradient elution (100% hexane to 4/1 hexane/ethyl acetate) to provide 2.5 g (50%) of 4-amino-5-methyl-biphenyl-3-carboxylic acid methyl ester. Electrospray Mass Spec: 241.8 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[CH:12])=[CH:9][S:8][C:7]=1[NH2:13])=[O:5])[CH3:2].I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NC(C)C)(C)C>CC#N.[Cu](I)I.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>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[C:12][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][S:8][C:7]=1[NH2:13])=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: C#Cc1csc(N)c1C(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1c(C#Cc2ccccc2)csc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
2-Amino-4-ethynyl-thiophene-3-carboxylic acid ethyl ester (0.075 g, 0.385 mmol) was dissolved in anhydrous CH3CN (2.0 mL). This was treated with iodobenzene (0.129 mL, 1.15 mmol) followed by diisopropylamine (0.272 mL, 1.92 mmol). The solution was then degassed and treated with copper iodide (0.0018 g, 0.010 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.014 g, 0.019 mmol). The reaction was then stirred at room temperature for 30 min. The reaction was concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15 EtOAc/85 hexanes) to afford the title compound (0.081 g, 78%). MS m/e (CI) 272.0 (M+H)+.
Reaction SMILES: C1C2C(COC([NH:18][CH:19]([CH3:36])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:28]=4)[NH:23][N:22]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:18][CH:19]([CH3:36])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])[CH:28]=2)[NH:23][N:22]=1
Reactant: CC(Cc1n[nH]c2ccc(OC(=O)C(C)C)cc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(N)Cc1n[nH]c2ccc(OC(=O)C(C)C)cc12
Temperature: 25 °C

Procedure:
A solution of 2-methyl-propionic acid 3-(2-(9fluorenylmethoxycarbonylamino)propyl)-1H-indazol-5-yl ester (0.16 g, 0.33 mmol) in a 1:4 mixture of piperidine and dimethylformamide (2.5 mL) is stirred at ambient temperature. The reaction mixture is poured into dilute aqueous sodium bicarbonate and the resulting mixture is extracted first with ethyl acetate and then with methylene chloride. The combined organic extracts are dried (MgSO4) and concentrated. The residue is purified by chromatography.
Reaction SMILES: C(Cl)CCl.[NH2:5][CH2:6][C:7]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:8]=1[CH2:9][CH:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH:11]([F:13])[F:12].[C:28]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:27][C:25]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:11]([F:13])[F:12])=[C:7]([CH:26]=1)[CH2:6][NH:5][C:37](=[O:38])[C@@H:36]1[CH2:40][CH2:41][CH2:42][N:35]1[C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CN)C(F)F)cc1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C(F)F)cc1
Yield: 72.3 %

Procedure:
EDC (0.402 g, 2.10 mmol) was added to a stirred mixture of N-{1-[2-(aminomethyl)-4-chlorobenzyl]-2,2-difluoroethyl}-N-(4-methoxyphenyl)amine (0.550 g, 1.61 mmol), N-Boc-L-proline (0.347 g, 1.61 mmol) and HOAT (0.286 g, 2.10 mmol) in DMF (2.8 mL). After 18 h the mixture was partitioned between EtOAc and water. The organic phase was washed with 1 M citric acid, saturated aqueous NaHCO3 and brine, dried (Na2SO4) and evaporated in vacuo to give N-(5-Chloro-2-{3,3-difluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-1-tert-butoxycarbonyl-L-prolinamide (0.626 g) as an oil; MS m/z=538.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.[CH2:29]([NH2:32])[CH2:30][CH3:31].COC1C(OC)=CC=C(C2C=C3C(=CC=2)C(=O)CC3)C=1OCC(C)(C)C(NC)=O>>[CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22]3)[C:4]=1[O:5][CH2:6][C:7]([CH3:11])([CH3:12])[C:8]([NH:32][CH2:29][CH2:30][CH3:31])=[O:10]
Reactant: CCCN
Reactant: COc1ccc(-c2ccc3c(c2)CCC3=O)c(OCC(C)(C)C(=O)O)c1OC
Agent: CNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)CCC3=O)ccc(OC)c1OC
Product: CCCNC(=O)C(C)(C)COc1c(-c2ccc3c(c2)CCC3=O)ccc(OC)c1OC

Procedure:
From 3-[2,3-Dimethoxy-6-(1-oxo-indan-5-yl)-phenoxy]-2,2-dimethyl-propionic acid (Compound 205) and propan-1-amine following the procedure for preparation of Compound 206. Purification by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) afforded the title compound as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.[H-].[Na+].[C:35]([O:39][CH3:40])(=[O:38])[CH2:36][SH:37].CN(C=O)C>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8](=[C:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:32])[CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH2:22][CH2:23]3)[C:4]3=[N:5][CH:6]=[CH:7][C:2]([S:37][CH2:36][C:35]([O:39][CH3:40])=[O:38])=[C:3]3[CH2:12][CH2:11][C:10]=2[CH:13]=1
Reactant: O=C(Cc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(Cl)ccnc32)CC1
Reactant: COC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CSc1ccnc2c1CCc1cc(Cl)ccc1C2=C1CCN(C(=O)Cc2cccnc2)CC1
Yield: 15 %

Procedure:
A mixture of the title compound from Example 250 (0.26 grams), sodium hydride (0.08 grams, 60% in mineral oil), methyl thioglycolate (0.19 mL) and anhydrous DMF (15 mL) was stirred while being irradiated with a 200 W lamp for 16 hours. The mixture was diluted with MeOH, concentrated in vacuo, diluted with CH2Cl2 and water, and washed with 1N aqueous NaOH and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo and the residue purified by preparative plate chromatography (silica gel) using 3% MeOH-CH2Cl2 to afford the title compound (0.05 grams, 15%, MH+ 534).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:28])([OH:27])[CH3:26])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1.[CH:32](=O)[CH3:33].C(O)(=O)C.[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>CO>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:30][CH3:31])[C:9]3[C:14]([O:15][CH2:16][C@H:17]4[O:22][CH2:21][CH2:20][N:19]([CH2:32][CH3:33])[CH2:18]4)=[CH:13][N:12]=[C:11]([C:23]#[C:24][C:25]([CH3:26])([OH:27])[CH3:28])[C:10]=3[N:29]=2)=[N:4][O:5][N:6]=1
Reactant: CC=O
Reactant: CCn1c(-c2nonc2N)nc2c(C#CC(C)(C)O)ncc(OC[C@@H]3CNCCO3)c21
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCO[C@H](COc2cnc(C#CC(C)(C)O)c3nc(-c4nonc4N)n(CC)c23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of the compound of Example 4 (0.13 g, 0.30 mmol) in MeOH (4 mL) at 0° C. was added acetaldehyde (0.034 mL, 0.61 mmol) and acetic acid (0.052 mL. 0.90 mmol). This was followed by the addition of NaCNBH3 (0.048 g, 0.76 mmol). The reaction was allowed to warm to RT. After 18 h, the reaction was poured into 50% aq. NaHCO3. The solution was cooled to 0° C. and the resultant precipitate was collected to give 0.10 g of the desired compound. MS (ES+) m/z 456.4 (M+H)+.
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:58]([NH:60][O:61][CH3:62])=[O:59])=[N:53][C:54]([Br:57])=[CH:55][CH:56]=1.C(OP1(=O)CC2C=CC(=CC=2)NC2=NC(=C(C(F)(F)F)C=N2)NC2C=CC(=NC=2C(NC)=O)C2=CN(N=C2)CCCCO1)C>>[Br:57][C:54]1[N:53]=[C:52]([C:58](=[O:59])[NH:60][O:61][CH3:62])[C:51]([NH:50][C:26]2[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]3[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=3[O:48][CH3:49])[N:25]=2)=[CH:56][CH:55]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CONC(=O)c1nc(Br)ccc1N
Agent: CCOP1(=O)Cc2ccc(cc2)Nc2ncc(C(F)(F)F)c(n2)Nc2ccc(nc2C(=O)NC)-c2cnn(c2)CCCCO1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NOC)n2)c(OC)c1)OCC
Yield: 23 %

Procedure:
This material was prepared analogously to compound 1B using 3-Amino-6-bromo-N-methoxypyridine-2-carboxamide (Compound 46D, 302.0 mg, 1.227 mmol) and diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 612.6 mg, 1.350 mmol) to isolate 189 mg of the title compound (23%). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 11.88 (s, 1H), 9.21 (br. s., 1H), 8.87 (br. s., 1H), 8.44 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.38 (br. s., 1H), 7.06 (s, 1H), 6.90 (d, J=8.1 Hz, 1H), 3.96-4.05 (m, 4H), 3.74 (s, 3H), 3.70 (s, 3H), 3.29 (d, J=21.2 Hz, 2H), 1.20 (t, J=7.0 Hz, 6H)
Reaction SMILES: I[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:8][C:7]([CH3:17])=[N:6][C:5]=2[N:4]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:3]=1.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].C(=O)([O-])[O-].[K+].[K+]>C(O)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>[CH3:17][C:7]1[N:8]=[C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:10]2[C:2]([C:32]3[CH:33]=[C:28]([CH:29]=[CH:30][CH:31]=3)[C:26]#[N:27])=[CH:3][N:4]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]=2[N:6]=1
Reactant: Cc1nc(N2CCOCC2)c2c(I)cn(COCC[Si](C)(C)C)c2n1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(N2CCOCC2)c2c(-c3cccc(C#N)c3)cn(COCC[Si](C)(C)C)c2n1
Temperature: 90 °C

Procedure:
To a solution of 5-iodo-2-methyl-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C24) (100 mg, 0.21 mmol), (3-cyanophenyl)boronic acid (62 mg, 0.42 mmol) and potassium carbonate (100 mg, 0.72 mmol) in a mixture of ethanol and water (4:1, 5 mL) was added dichlorobis(triphenylphosphine)palladium (15 mg, 21 μmol). The reaction mixture was degassed and purged with nitrogen; this procedure was carried out a total of three times. After the reaction mixture had heated at 90° C. for 3 hours, it was allowed to cool and concentrated in vacuo. Purification via preparative thin layer chromatography (Eluent: 1:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 52 mg, 0.12 mmol, 57%. LCMS m/z 451.3 [M+H+].
Reaction SMILES: [NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>CO>[NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:10]=1
Reactant: C[C@H](CCc1ccc(C#CCCCc2ccccc2)s1)C(N)O
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCc1ccc(C(=O)CCCCc2ccccc2)s1)C(N)O
Temperature: 0 °C
Yield: 82 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-phenylpent-1-ynyl)thiophen-2-yl]butan-1-ol (387 mg, 1.18 mmol) obtained in Example 49 was dissolved in methanol (4 ml), and 6N sulfuric acid (4 ml) was added thereto followed by heating under reflux for 4 hours. The reaction solution was cooled to 0° C. and made alkaline (pH 14) with a 1N aqueous sodium hydroxide solution, and the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacua. The residue was purified by chromatography on a silica gel column (Chromatorex NH (100-200 mesh)) (elution solvent; dichloromethane:methanol=1:0-50:1) to afford (2R)-amino-2-methyl-4-[5-(5-phenylpentanoyl)thiophen-2-yl]butan-1-ol (336 mg, 82% yield). This compound was dissolved in methanol, and oxalic acid (88 mg, 0.97 mmol) was added thereto to precipitate crystals. The crystals were recrystallized from methanol to afford the tide compound (332 mg, 78% yield) as white crystals.
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][N:15]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:14][CH2:13]3)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)COc1ccccc1C2=C1CCNCC1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of 3.61 g of 4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidine, 2.6 g of ethyl 3-bromopropionate, 1.8 g of potassium carbonate and 25 ml of N,N-dimethylformamide was stirred at 80° C. for 2 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water and extracted with hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dried and concentrated to give 4.2 g of yellowish brown liquid, which was purified by column chromatography on silica gel (eluent: chloroform) to give 3.9 g of pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([OH:13])=O)=[CH:4][NH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC[N:16](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:16][C:11]([C:3]1[C:2]([Cl:1])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[NH:5][CH:4]=1)=[O:13]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1[nH]cc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]cc(C(N)=O)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-3-carboxylic acid (0.075 g, 0.368 mmol) in DMF (1 mL) was added DIPEA (0.097 mL, 0.553 mmol) and HATU (0.168 g, 0.442 mmol). Ammonia was bubbled through the reaction mixture for 5 min. and the reaction stirred at RT for 1 h. The crude material was purified by HPLC. The desired fractions were collected and lypholized to afford methyl 4-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylate (0.044 g, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.40-12.56 (m, 1H) 7.54 (d, 1H) 7.29 (br. s., 1H) 7.13 (br. s., 1H) 3.80 (s, 3H). MS: m/z 203.0 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[CH:12]1([O:15][C:16]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:14][CH2:13]1>C(OCC)C>[CH:12]1([O:15][C:16]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=2[CH2:18][NH2:19])[CH2:14][CH2:13]1
Reactant: N#Cc1ccc(F)cc1OC1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1ccc(F)cc1OC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 0° C. suspension of lithium aluminum hydride in THF (1M, 15 mL, 15 mmol) was added 2-cyclopropoxy-4-fluorobenzonitrile in 14 mL diethyl ether dropwise. The reaction solution was stirred for 3 hours, gradually warming to room temperature, at which point it was recooled to 0° C., an additional 8 mL lithium aluminum hydride in THF (1M, 8 mmol) added, and stirred for an additional 90 minutes. The reaction was quenched by sequential addition of 0.9 mL water, 0.9 mL 15% NaOH(aq), and 2.7 mL water. The reaction was filtered through celite with diethyl ether rinses, dried over MgSO4, and concentrated to afford 2-cyclopropoxy-4-fluorobenzylamine of sufficient purity to carry on as crude. 1H-NMR (400 MHz, Chloroform-d) δ 7.17-7.08 (m, 1H), 6.96 (dd, J=10.9, 2.4 Hz, 1H), 6.61 (td, J=8.3, 2.5 Hz, 1H), 3.78-3.66 (m, 3H), 0.89-0.72 (m, 4H).