Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15](=[O:33])[N:16]3[CH2:19][CH2:20][N:21]([CH3:32])[C:22]([O:24]CC3C=CC=CC=3)=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH:40]([N:43](C(C)C)[CH2:44]C)(C)C.CN(C)C(Cl)=O>C(Cl)Cl.[Pd]>[CH3:40][N:43]([CH3:44])[C:22]([N:21]([CH3:32])[CH2:20][CH2:19][N:16]1[C:17]2[C:12](=[N:11][CH:10]=[C:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:18]=2)[C:13]([OH:39])=[C:14]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:15]1=[O:33])=[O:24]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd]
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN(C)C(=O)N(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.255 g, 0.48 mmol) in CH2Cl2 (20 mL) was combined with diisopropylethylamine (0.42 mL, 2.4 mmol), dimethylcarbamic chloride (0.22 mL, 2.4 mmol) and Pd/C (0.030 g, 10% w/w). The resulting suspension was flushed with nitrogen and evacuated several times the charged with hydrogen under a balloon and stirred at ambient temperature overnight. The reaction mixture was filtered, washed with CH2Cl2, and concentrated in vacuo. The residue was washed with EtOAc:Hexanes 1:1, filtered and the filtrate was concentrated in vacuo. The residue was triturated with water and the resulting suspension was filtered to afford the title compound as an off-white crystalline solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.25 (t, J=7.05 Hz, 3 H), 2.59 (s, 6 H), 2.80 (s, 3 H), 3.26-3.30 (m, 2 H), 4.17 (s, 2 H), 4.23 (q, J=7.16 Hz, 2 H), 4.32 (t, J=6.21 Hz, 2 H), 7.11-7.18 (m, 2 H), 7.38-7.43 (m, 2 H), 8.11 (s, 1 H), 8.50 (d, J=1.47 Hz, 1 H); ES+ MS: 471 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[C:13](O)(=[O:15])[CH3:14]>[OH-].[Na+]>[C:13]([NH:1][CH2:2][C:3]1[N:8]=[C:7]([S:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: COc1cc(CN)nc(SC)n1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CNC(C)=O)nc(SC)n1

Procedure:
A mixture of 3.05 g (16.5 mmole) of 6-aminomethyl-4-methoxy-2-methylthiopyrimidine (from Example 4) and 50 ml of glacial acetic acid was heated at reflux for 16 hours, and was then evaporated. The residue obtained was dissolved in 20 ml of five percent aqueous sodium hydroxide solution and extracted with four 30 ml portions of chloroform. The combined extracts were washed twice with 30 ml portions of water and then with 30 ml of saturated aqueous sodium chloride solution. The combined extracts were then dried over magnesium sulfate and evaporated to provide 6-acetylaminomethyl-4-methoxy-2-methylthiopyrimidine as an off-white solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:23])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:24]S(C)=O.[H-].[Na+].IC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:11](=[O:23])[N:10]([CH3:24])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)N1CCC2(CC1)C(=O)NCN2c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CI
Product: CCOC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccc(F)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred and cooled (below 5° C.) mixture of 16 parts of ethyl 1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate, 200 parts of dimethyl sulfoxide and 200 parts of benzene are added 3.5 parts of a sodium hydride dispersion 50%. After stirring for 1 hour at a temperature below 5° C., there are added dropwise 10 parts of iodomethane at this temperature. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto water and the layers are separated. The aqueous phase is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated, yielding 14.7 parts (88%) of ethyl 1-(4-fluorophenyl)-3-methyl-4-oxo-1,3,8-triazaspiro[4,5]decane-8-carboxylate as a residue.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:20](=[O:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.C([O:34][C:35]1[CH:45]=[CH:44][C:38]([CH2:39][C:40]2([NH2:43])[CH2:42][CH2:41]2)=[CH:37][CH:36]=1)C1C=CC=CC=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH2:21][NH:43][C:40]2([CH2:39][C:38]3[CH:44]=[CH:45][C:35]([OH:34])=[CH:36][CH:37]=3)[CH2:42][CH2:41]2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1
Reactant: NC1(Cc2ccc(OCc3ccccc3)cc2)CC1
Reactant: CCOC(O)C(=O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(cc(O)cc2C(O)CNC2(Cc3ccc(O)cc3)CC2)N1

Procedure:
Prepared according to general method 3 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 253 mg (1 mmol) 1-(4-benzyloxy-benzyl)-cyclopropylamine. Yield: 47 mg (10%, trifluoroacetate); mass spectroscopy: [M+H]+=371.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[O:19]=[C:20]1[N:26]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C@@H:36]([C:49](O)=[O:50])[CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)=[O:34])[CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23]2[CH:52]=[CH:53][CH:54]=[CH:55][C:22]=2[NH:21]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[O:19]=[C:20]1[N:26]([CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C@H:36]([CH2:37][C:38]3[CH:47]=[C:46]([CH3:48])[C:41]4[NH:42][C:43](=[O:45])[O:44][C:40]=4[CH:39]=3)[C:49]([N:1]3[CH2:6][CH2:5][CH:4]([N:7]4[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]4)[CH2:3][CH2:2]3)=[O:50])=[O:34])[CH2:31][CH2:32]2)[CH2:25][CH2:24][C:23]2[CH:52]=[CH:53][CH:54]=[CH:55][C:22]=2[NH:21]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2oc(=O)[nH]c12
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
56 mg (0.22 mmol) ethyl (4-piperidin-4-yl-piperazin-1-yl)-acetate were added to a solution of 100 mg (0.20 mmol) (R)-1-carboxy-2-(4-methyl-2-oxo-2,3-dihydrobenz-oxazol-6-yl)-ethyl 4-(2-oxo-1,2,4,5,-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 71 mg (0.22 mmol) TBTU and 31 μL (0.22 mmol) triethylamine in 1 mL DMF and the reaction mixture was shaken overnight at RT. The reaction solution was purified by HPLC without working up; the fractions containing the product were concentrated by evaporation and lyophilised.
Reaction SMILES: C([O:8][C:9](=[O:37])[N:10]([CH2:12][C:13](=[O:36])[NH:14][CH2:15][CH:16]1[C:25]2[C:20](=[CH:21][C:22]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)(=[O:28])=[O:27])=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)C)C1C=CC=CC=1>CO.C(O)=O.[Pd]>[CH:9]([OH:37])=[O:8].[F:35][C:31]1[CH:30]=[C:29]([S:26]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[CH:16]([CH2:15][NH:14][C:13](=[O:36])[CH2:12][NH:10][CH3:9])[CH2:17][CH2:18][CH2:19]3)(=[O:28])=[O:27])[CH:34]=[CH:33][CH:32]=1
Reactant: CN(CC(=O)NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CNCC(=O)NCC1CCCc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Reaction time: 3 h
Yield: 144.2 %

Procedure:
To a stirring solution of ({[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-carbamoyl}-methyl)-methyl-carbamic acid benzyl ester (0.15 g) in 20 ml methanol and 2 ml formic acid at room temperature was added 0.1 gms of 10% palladium on carbon. After stirring for three hours the mixture was filtered thru Celite and the clear filtrate was concentrated to dryness. The residue was recrystallized from ethyl acetate and diethyl ether to give 0.090 gms of N-[6-(3-Fluoro-benzenesulfonyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-2-methylamino-acetamide formate salt: M+H=391.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:24][CH2:25][C@H:26]([OH:35])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+:37]>CO>[OH:1][CH2:2][C@@H:3]([NH:24][CH2:25][C@H:26]([OH:35])[CH2:27][O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O-:20])=[O:19])=[CH:16][CH:15]=2)=[O:13])=[CH:9][CH:10]=1.[Na+:37]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)COc3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)COc3ccccc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of methyl 4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-amino]carbonyl]benzoate (19.3 mg) in methanol (1.0 ml) was added 1N sodium hydroxide solution (40.3 μl) and the suspension was refluxed for 10 hours. An additional portion of 1N sodium hydroxide solution (40.3 μl) was added and the mixture was refluxed for 3 hours. After cooling to room temperature, the solvent was removed by evaporation to give sodium 4-[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]benzoate (20.6 mg) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[F:32])[NH2:28]>>[CH3:23][O:22][C:8]1[CH:7]=[C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:28][C:27]3[CH:29]=[CH:30][C:31]([F:32])=[C:25]([Cl:24])[CH:26]=3)[C:11]2=[CH:10][C:9]=1[O:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reactant: Nc1ccc(F)c(Cl)c1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCOCC1

Procedure:
condensing, 4-chloro-7-methoxy-6-(3-morpholino propoxy) quinazoline of the formula VII with 3-chloro-4-fluoroaniline to obtain gefitinib of formula I.
Reaction SMILES: [PH:1]([O:4][PH:5]([OH:7])=[O:6])([OH:3])=[O:2].[O:8]1[CH:10]=[CH:9]1.O.O1CCOCC1>CC(C)=O>[PH:1]([O:4][PH:5]([OH:7])=[O:6])([OH:3])=[O:2].[O:8]1[CH2:10][CH2:9]1
Reactant: C1=CO1
Agent: O=[PH](O)O[PH](=O)O
Solvent: O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: C1CO1

Procedure:
The hydrolysis of epoxy ethane diphosphonate to produce the dihydroxy ethane diphosphonate proceeds according to the following general reaction: ##EQU6## wherein R3 is the same as defined above. The aforementioned reaction may be carried out by mixing the epoxy ethene diphosphonate in a sufficient volume of water, i.e., at least stoichiometric quantities, preferably a molar ratio of water to EEDP of 1:1 to 20:1, and heating the resultant mass until substantially complete hydrolysis occurs. The use of greater than stoichiometric quantities of water functions as a diluent for the reaction system. It is also found that substantially water-miscible organic diluents which have a boiling point between about 50°C and 150°C, preferably from about 70°C to about 100°C, such as dioxane, acetone, lower alcohols (e.g., methanol, ethanol, propanol and butanol) are suitable as a reaction medium or diluent in which the above-described hydrolysis reaction can be conducted.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(OC)(C)C>C(O)CCC>[CH2:21]([NH:28][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reactant: NCc1ccccc1
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CN1CCN(S(=O)(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2)CC1

Procedure:
17.2 2.8 g (8.756 mmol) of 1-(4-chloro-3-nitrobenzenesulfonyl)-4-methylpiperazine are dissolved in 10 ml of 1-butanol, and 1.913 ml (17.5 mmol) of benzylamine are added. The reaction mixture is heated under reflux for 14 h. After cooling, MTBE is added, the precipitate formed is filtered off with suction and washed with MTBE and dried in vacuo, giving benzyl-[4-(4-methylpiperazine-1-sulfonyl)-2-nitrophenyl]amine; HPLC-MS [M+H]+ 391.2.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C(#N)C.[OH:23][S:24]([O-:26])=[O:25].[Na+:27]>O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]([C:12]3[CH:19]=[CH:18][C:15]([CH:16]([OH:17])[S:24]([O-:26])(=[O:25])=[O:23])=[CH:14][CH:13]=3)=[O:11])[CH2:6][CH2:5]2)[CH2:2][CH2:3]1.[Na+:27]
Reactant: O=S([O-])O
Reactant: O=Cc1ccc(C(=O)N2CCN(C3CC3)CC2)cc1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(c1ccc(C(O)S(=O)(=O)[O-])cc1)N1CCN(C2CC2)CC1
Temperature: 50 °C

Procedure:
A 100 mL flask was charged with 4-(4-cyclopropyl-piperazine-1-carbonyl)-benzaldehyde (2.58 g, 10.0 mmol, 1.0 eq), acetonitrile (30 mL), and water (1.0 mL) under nitrogen atmosphere. The reaction mixture was heated to 50° C. A solution of NaHSO3 (1.14 g, 11.0 mol, 1.1 eq) in water (2.0 mL) was added dropwise over 5 min. The reaction mixture was then cooled to 17° C. The product was collected by filtration as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1.C(Cl)[Cl:26]>O>[Cl:26][C:10]1[N:9]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[N:12][C:11]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: ClCCl
Reactant: CCOC(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1
Solvent: O
Product: CCOC(=O)c1nc(-c2ccccc2Cl)n(-c2ccc(Cl)cc2)c1Cl
Yield: 20 %

Procedure:
To a solution of ethyl 2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (270 mg, 0.75 mmol) in CH2Cl2 (5 mL) was added SO2Cl2 (1.6 mL, 20 mmol). The mixture was heated at reflux overnight, and diluted with water. The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography over silica gel (33% EtOAc in hexane) to give ethyl 5-chloro-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carboxylate (60 mg) in 20% yield as a white solid: LC-MS m/z 395.0 (MH+), retention time 3.45 min (method 1). This intermediate, which is an example of Formula X in Scheme 2, was converted into 5-chloro-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imidazole-4-carboxamide (Table entry 21).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][O:29][CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCO)cc3)cc2)CC1
Reactant: BrCc1cccnc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCOCc4cccnc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-bromomethyl-pyridine.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[Li]CCCC.[CH3:38][O:39][C:40]([CH3:48])([CH3:47])[C:41](N(OC)C)=[O:42]>O1CCCC1>[CH3:38][O:39][C:40]([CH3:48])([CH3:47])[C:41]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:21][CH3:22])[C:14]([O:19][CH3:20])=[C:15]([O:17][CH3:18])[CH:16]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:42]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CON(C)C(=O)C(C)(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)OC)c3n2)cc(OC)c1OC
Reaction time: 0.01 h
Yield: 8.9 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (233 mg, 0.410 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to −78° C. and treated with nBuLi (2.29M in hexanes, 0.25 ml, 0.57 mmol) dropwise. The solution was stirred for 30 seconds and then 2,N-dimethoxy-2,N-dimethyl-propionamide (198 mg, 1.23 mmol), dissolved in THF (5 ml), was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then at room temperature 30 minutes. The reaction mixture was quenched with saturated aqueous NaHSO4 and then partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a brown oil. The oil was purified by silica gel chromatography using 10-100% EtOAc in hexanes as eluant providing 14 mg (9%) of 2-methoxy-2-methyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as a yellow solid. MP 237.8-239.1° C., M+H=386.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1C(=O)N([Br:29])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:29][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][O:15][C:3]=2[C:2]([OH:1])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)c1ncc2c(-c3ccccc3)noc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Br)c2c(-c3ccccc3)noc2c1O
Yield: 61 %

Procedure:
Ethyl 7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (1.0 g, 3.52 mmol), NBS (0.94 g, 5.28 mmol), and benzoyl peroxide (85 mg, 0.352 mmol) were added to 30 mL of carbon tetrachloride and refluxed for 16 h. Silica gel (10 g) was added and the solvent was evaporated. The crude was purified by flash chromatography (0-40% EtOAc/hexanes) to give 780 mg of the title compound. MS: (+) m/z 363.26, 365.17 (M+1, 79Br/81Br).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:30]2[S:34][C:33]([CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:32][CH:31]=2)O1.O>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.COCCOC>[N:36]1([CH2:35][C:33]2[S:34][C:30]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=3)[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:31][CH:32]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC1(C)OB(c2ccc(CN3CCCC3)s2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2ccc(CN3CCCC3)s2)c1

Procedure:
3-Bromo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 3.1, 50 mg, 0.139 mmol), 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)pyrrolidine (0.180 mmol), (Ph3P)4Pd (8 mg, 6.94 μmol) 2 M Na2CO3 (0.104 mL, 0.208 mmol), water (0.8 mL) and DME (2.4 mL) were added to a vial, which was sealed and subjected to MW irradiation at 150° C. for 600 sec (very high absorbance). The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=1.92 min, m/z=447.4 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4].Br[C:46]1[N:47]=[CH:48][S:49][CH:50]=1>>[CH3:1][C:2]([CH3:44])([CH2:6][C:7]1[N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:46]3[N:47]=[CH:48][S:49][CH:50]=3)=[CH:17][CH:18]=2)[C:10]2[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:31][C:9]=2[N:8]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Reactant: Brc1cscn1
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(-c2cscn2)cc1)C(=O)O

Procedure:
The title compound was prepared with similar methods to those in Example 147 using 2,2-dimethyl-3-(5-(quinolin-2-ylmethoxy)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazol-2-yl)propanoic acid and 4-bromothiazole. MS (ESI): mass calcd. for C32H28N4O3S, 548.18; m/z found, 549.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 9.17 (d, J=1.6, 1H), 8.59 (d, J=8.5, 1H), 8.18-8.14 (m, 2H), 8.07 (d, J=8.1, 1H), 7.96 (d, J=8.2, 2H), 7.92-7.84 (m, 1H), 7.79 (d, J=8.4, 1H), 7.69 (t, J=7.4, 1H), 7.60 (d, J=9.4, 1H), 7.42 (s, 1H), 7.35 (d, J=8.3, 2H), 7.30 (d, J=9.4, 1H), 5.82 (s, 2H), 5.58 (s, 2H), 3.53 (s, 2H), 1.31 (s, 6H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO.O[C@H](C1C=CC=CC=1)C(O)=O>C(#N)C>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@:17]3([CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:16]2=[O:25])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCC3(CCCNC3)C2=O)CC1
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCNC3)C2=O)CC1
Temperature: 70 °C
Yield: 48.3 %

Procedure:
2-(cis-4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (7.00 g, 19.1 mmol) was dissolved in acetonitrile (50 mL) and methanol (7 mL) at r.t. After the starting material was completely dissolved, the solution was heated up to 70° C. To the above solution was slowly added a solution of (2R)-hydroxy(phenyl)acetic acid (1.45 g, 9.55 mmol) in acetonitrile (20 mL) at 65-70° C. After addition, the solution was heated at 74° C. for 10 min, and allowed to cool slowly to room temperature overnight. The crystalline formed was collected by filtration to afford 3.38 g of the desired product as (2R)-hydroxy(phenyl)acetic acid salt. The resulting salt (3.38 g) was dissolved in water (50 mL), and adjusted to pH˜12 with 40 mL aq K2CO3 solution (2.0 M). The mixture was extracted with dichloromethane (3 times). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated under reduced pressure to afford the desired product as a free base (colorless crystalline solid) (2.37 g). The absolute stereochemistry of this compound was established by X-ray single crystal structure determination of (2R)-hydroxy(phenyl)acetic acid salt of (5S)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one.