Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]2[N:13]([CH3:19])[C:14](=[CH2:18])[C:15]([CH3:17])([CH3:16])[C:4]=12.[OH:22][C:23]1[CH:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[C:26]2[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:25]=2[C:24]=1[N:42]=O>C1(C)C(C)=CC=CC=1>[F:21][C:2]([F:20])([F:1])[C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[N:6]=[C:5]2[N:13]([CH3:19])[C:14]3([C:15]([CH3:16])([CH3:17])[C:4]=12)[CH2:18][NH:42][C:24]1[C:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][C:26]=2[C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:35][C:23]=1[O:22]3
Reactant: C=C1N(C)c2nc(C(F)(F)F)cc(C(F)(F)F)c2C1(C)C
Reactant: O=Nc1c(O)cc(N2CCCCC2)c2oc3ccccc3c12
Solvent: Cc1ccccc1C
Product: CN1c2nc(C(F)(F)F)cc(C(F)(F)F)c2C(C)(C)C12CNc1c(cc(N3CCCCC3)c3oc4ccccc4c13)O2
Reaction time: 24 h

Procedure:
A mixture of 4,6-bis[trifluoromethyl]-1,3,3-trimethyl-2-methylenepyrrolo[2,3-b]pyridine (1.83 g; 0.0059 mol) and 2-hydroxy-1-nitroso-4-piperidinodibenzofuran (2.60 g; 0.01 mol) in xylene (50 ml) was stirred and heated under nitrogen and refluxed for 24 hours. A further portion of 2-hydroxy-1-nitroso-4-piperidinodibenzofuran (1.2 g; 0.0059 mol) was added and the reaction continued for a further 24 h. The resulting dark solution was evaporated to dryness and the resulting gum chromatographed over silica (eluent: 2% diethyl ether in petroleum ether 60/80) to give 4,6-bis[trifluoromethyl]-1,3,3-trimethyl-6'-piperidinospiro[2H-pyrrolo[2,3-b]pyridine-2,3'-[3H]-[2H-[1,4]benzoxazino[6,5-b]benzofuran]] as an orange solid (0.08 g; 3%), m.pt. 195°-205° C., λmax absorbance 498 nm (polyurethane). ##STR28##
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([OH:17])[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].[N+](=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N-]>ClCCl.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[C:31]([O:30][C:28](=[O:29])[CH2:27][O:17][C@H:13]1[C@H:12]2[CH2:16][C@H:15]([C@@H:10]([C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@H:3]3[C:1]#[N:2])=[O:9])[N:11]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)N1CCC[C@H]1C#N
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (322 mg) in dichloromethane (6 mL), were added rhodium acetate dimer (4.24 mg) and tert-butyl diazoacetate (0.27 mL). The mixture was stirred at room temperature for 4 hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (236 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)ccc1Br
Yield: 104.1 %

Procedure:
A solution of 4-bromo-3-methylphenol (4.72 g, 25.2 mmol), 3,4-dihydro-2H-pyran (3.18 g, 37.8 mmol) and pyridinium p-toluenesulfonate (0.628 g, 2.50 mmol) in dichloromethane (100 mL) was stirred at room temperature for 24 hrs. The reaction mixture was washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.11 g, including unreacted 3,4-dihydro-2H-pyran) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34]C)=[O:33])[CH:27]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O>[ClH:21].[C:36]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=2[Cl:21])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 81.2 %

Procedure:
A solution of N-(2,2-diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carbomethoxyphenoxy)propylamine (65 mg, 0.11 mmol) in MeOH (5 mL), H2O (1 mL), and 2.5N NaOH (0.5 mL) was heated at 50° C. for 3 h. The reaction was cooled, diluted with H2O, acidified with 3N HCl to pH=4, and extracted with EtOAc. The extracts were dried and the solvent removed. The residue was dissolved in Et2O and treated with 4N HCl in dioxane. The precipatated solid was filtered, washed with Et2O, dried, and concentrated to yield the titled compound (27 mg, 42%). MS (ESI) 569 (M+H+).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethoxymethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol/water 1:1 and with diethyl ether. The residue was purified by chromatography on silica gel (eluent: ethyl acetate/n-heptane 3:1) to yield 80 mg (31%) colorless powder.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=O)[O:18][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1)=[N+:2]=[N-:3].C[N:34](C=O)C>N>[N:1]([CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[C:17](=[O:18])[NH:34][C:19](=[O:31])[C:20]=2[C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH3:30])[CH:22]=2)=[CH:8]1)=[N+:2]=[N-:3]
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3cn(CCCN=[N+]=[N-])c4ccccc34)C(=O)OC2=O)c2ccccc21
Agent: N
Product: Cn1cc(C2=C(c3cn(CCCN=[N+]=[N-])c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
A solution of 2.50 g of 3-[1-(3-azidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)furan-2,5-dione in 13 ml of DMF and 18 ml of 33% aqueous ammonia was heated to 140° C. for 4 hours. The product was filtered off from the cooled mixture to give 2.27 g of 3-[1-(3-azidopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 222°-224° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH3:22][C:23]1([CH3:31])[S:27][CH2:26][NH:25][C@@H:24]1[C:28]([NH2:30])=[O:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:25]3[C@H:24]([C:28]([NH2:30])=[O:29])[C:23]([CH3:31])([CH3:22])[S:27][CH2:26]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)SCN[C@@H]1C(N)=O
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)SCN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)[C@@H]1C(N)=O

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (R)-5,5-dimethylthiazolidine-4-carboxamide hydrochloride in the presence of TBTU and DIEA to obtain the title compound as light yellow solid; MS (EI): m/e=427.4 [MH+].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(COS(C)(=O)=O)C1
Temperature: 0 °C
Yield: 92 %

Procedure:
Methane sulfonyl chloride (71 μl; 0.92 mmol; 1.0 eq.) was added to a solution of 2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (200 mg; 0.92 mmol; 1.0 eq.) and TEA (190 uL; 1.38 mmol; 1.5 eq.) in anhydrous DCM (3 mL) maintained at 0° C. and under nitrogen atmosphere. The reaction mixture was stirred at RT O/N. The reaction mixture was washed with 10% citric acid solution and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated to give the title compound as a brown oil (250 mg, 92%). 1H NMR (300 MHz, DMSO) δ 4.33-4.13 (m, 2H), 3.91-3.78 (m, 2H), 3.75-3.55 (m, 4H), 3.42 (td, J=11.6, 2.8 Hz, 1H), 3.20 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)[CH:9]=1)([O-])=O.NN>[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:13][N:12]=2)[CH:9]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: [Ni]
Agent: NN
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1

Procedure:
The invention provides a process for preparation of imatinib base and pharmaceutically acceptable acid addition salts thereof, comprising (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine; (e) reducing N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine using hydrazine in the presence of Raney nickel to obtain N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine; (f) condensing N-(5-amino-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine with 4-chloromethylbenzoyl chloride in the presence of an inorganic base to obtain 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; (g) condensing 4-chloromethyl-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide with an excess of N-methylpiperazine to obtain imatinib base; adding water or a mixture of water and an organic solvent; and isolating said imatinib base; and (h) optionally, converting imatinib base to a pharmaceutically acceptable acid addition salt of imatinib base.
Reaction SMILES: C([O:3][C:4](=[O:24])[C@H:5]([CH3:23])[NH:6][C:7](=[O:22])[C@H:8]([CH3:21])[NH:9][C:10](=[O:20])[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)C.[Li+].[OH-]>O1CCOCC1.O>[F:18][C:16]1[CH:17]=[C:12]([CH2:11][C:10]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:24])=[O:3])[CH3:23])=[O:22])[CH3:21])=[O:20])[CH:13]=[C:14]([F:19])[CH:15]=1
Reactant: CCOC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reaction time: 3 h

Procedure:
The title compound was prepared by dissolving 1.98 g (0.006 mols) of N-(N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester (from Example 85 below) in 60 mL dioxane and 15 mL of H2O and adding LiOH (0.25 g, 0.006 mol) that has been dissolved in 15 mL of H2O. After stirring for 3 hours, the dioxane was removed under reduced pressure and the residue diluted with EtOAc, the layers were separated and the aqueous layer acidified to pH 2. The aqueous layer was back extracted with EtOAc (4×100 ml), and the combined organics were dried over Na2SO4 and the solvent was removed under reduced pressure after filtration. The residue was recrystallized from EtOAc/isooctane giving 1.7 g (90%). C14H16F2N2O4 requires C, 53.50 H, 5.13 N, 8.91. Anal found C, 53.30 H, 5.26 N, 8.98.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([C:22](=[O:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1ccccc1C(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reaction time: 1 h
Yield: 42.3 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-(2-methoxybenzoyl)pyridin-2-yl)cyclopropanecarboxamide (0.50 g, 1.2 mmol) was suspended in 25 mL of methanol. Sodium borohydride (0.454 g, 12.0 mmol) was added in small portions. After stirring for one hour the reaction mixture was evaporated to dryness and purified on 40 g of silica gel utilizing a gradient of 15-70% ethyl acetate in hexanes to yield the pure product as a white solid (0.2125 g, 0.5078 mmol, 42%). ESI-MS m/z calc. 418.6. found 419.3 (M+1)+. Retention time 2.59 minutes.
Reaction SMILES: [C:1]([Si:5]([CH3:31])([CH3:30])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:42][O:43][C:44](=[O:55])[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52][CH2:53]Br)=[CH:47][CH:46]=1>>[CH3:42][O:43][C:44](=[O:55])[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][CH2:52][CH2:53][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:31])[CH3:30])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=2)=[CH:47][CH:46]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(Oc3ccccc3)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 61.8 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (200 mg, 0.455 mmol) was alkylated with NaHMDS (1M in THF, 0.55 mL, 0.55 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (128 mg, 0.501 mmol) to yield 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-phenoxy-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (173.1 mg). 1H NMR (CDCl3) δ7.94 (d, 2H), 7.32 (m, 2H), 7.25-7.19 (m, 3H), 7.09 (m, 1H), 6.98 (d, 2H), 6.88-6.81 (m, 3H), 3.88 (s, 3H), 3.84 (m, 1H), 3.64 (m, 1H), 3.50 (m, 1H), 2.95 (m, 1H), 2.76-2.57 (m, 4H), 2.37 (m, 2H), 2.03 (m, 1H), 1.92-1.67 (m, 3H), 1.56 (m, 1H), 1.46-1.25 (m, 3H), 0.84 (s, 9H), −0.04 (d, 3H), −0.15 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[O:12]=[C:13]([C:19](OCC)=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[NH4+].[NH4+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[O:9][CH2:8][CH2:7][N:6]3[C:19](=[O:20])[C:13]([OH:12])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([CH:11]=1)=[C:5]23
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Clc1ccc2c(c1)OCCN2
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)C1(O)C(=O)N2CCOc3cc(Cl)cc1c32
Temperature: 0 °C
Yield: 77.3 %

Procedure:
7-Chloro-3,4-dihydro-2H-1,4-benzoxazine (Japan Kokai JP No. 61-152984, U.S. Pat. No. 4,593,092) (19.77 g. 0.116 mol) was dissolved in 74 ml of acetic acid and to which diethyl ketomalonate 20.2 g (0.116 mol) was added dropwise at a room temperature. Then after refluxing for 20 minutes, the mixture was stand for overnight. After pouring into 500 ml of ice, ammonium carbonate was added to the solution. The resultant crystalline solid was collected by filtration, washed with water and dried to yield pale orange powders quantitatively. Recrystallization from ethanol afforded 26.67 g (77.3%) of the title compound as pale yellow prisms, mp 186°-187° C.
Reaction SMILES: CC1C=CC(C(O)=O)=CC=1.O[CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=[O:16].C(N1C=CN=C1)(N1C=CN=C1)=O.C(CN)O.CS(Cl)(=O)=O>>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][CH2:12][CH2:13][N:14]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(C(=O)NCCO)cc1
Agent: CS(=O)(=O)Cl
Agent: Cc1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: NCCO
Product: Cc1ccc(C2=NCCO2)cc1

Procedure:
This synthesis requires a brominated intermediate, which is prepared by a four-step process, as illustrated in FIG. 3. p-Toluic acid is first converted to N-(2-hydroxyethyl)-4-toluamide, using carbonyldiimidazole (CDI) and ethanolamine. This first intermediate is then converted to a N-[2-methanesulfonyloxy]-4-toluamide, using methanesulfonyl chloride. This second intermediate is then cyclized to form 2-(4-methylphenyl)oxazoline by processes analogous to those described in Example 7, below. This third intermediate is then brominated, using N-bromosuccinimide and benzoyl peroxide as described in Example 3, to produce 2-[(4-bromomethyl)phenyl]-oxazoline. This intermediate is then reacted with hydroxy compound [2], using a procedure similar to that described in Example 3, to give the desired compound, GERI-E6.
Reaction SMILES: Br[CH:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)[CH2:8][CH3:9])[CH3:7]
Reactant: CCOC(=O)C(Br)CC
Reactant: COc1ccc(S)cc1
Product: CCOC(=O)C(CC)Sc1ccc(OC)cc1

Procedure:
2-(4Methoxy-phenylsulfanyl)-butyric acid ethyl ester was prepared according to the general method as outlined in example 9. Starting from ethyl 2-bromobutyrate (10.71 g, 55 mmol) and 4-methoxythiophenol (7 g, 50 mmol), 5.19 g (40%); clear oil; MS: 255.2 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:20])[NH:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH:9](O)[CH3:10])(C)(C)C.[H-].[Na+].O>C1COCC1>[F:19][C:14]1[CH:13]=[C:12]([CH:8]2[CH:9]([CH3:10])[O:20][C:6](=[O:5])[NH:7]2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(O)C(NC(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1OC(=O)NC1c1ccc(F)c(F)c1
Temperature: 35 °C
Reaction time: 3 h

Procedure:
Into a well-stirred solution of [1-(3,4-difluorophenyl)-2-hydroxy-propyl]-carbamic acid-tert-butyl ester (0.43 g, 1.5 mmol) in THF (20 mL) was added 95% NaH (0.09 g, 3.8 mmol) at room temperature. When the reaction was carried out on a larger (>5 g) scale, 1.0 equivalent of KH and 1.5 eq. of NaH was used as the base. The resulting suspension was stirred for 3 h at about 35° C. (warm water bath) and then quenched carefully with ice. The biphasic mixture was extracted with 100 mL of EtOAc, washed with brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The two diastereomers were separated by column chromatography over silica gel (First isomer: 0.16 g, Rf=0.6, 3:1 hexane-EtOAc; second isomer: 0.18 g, Rf=0.5, 3:1 hexane-EtOAc). NOE experiments suggested that the first diastereomer had the methyl and the aryl group in trans configuration while the second diastereomer had cis relationship between the two groups. The 1H NMR spectrum for the trans diastereomer is as follows. 1H NMR (CDCl3) δ 1.49 (d, J=6.0 Hz, 3H), 4.37 (dq, J=6.0 Hz, J=7.2 Hz, 1H), 4.45 (d, J=7.2 Hz, 1H), 6.63 (br s, 1H), 7.08–7.28 (m, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1COCC1>[N:3]1([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCOC(=O)C(C)Br
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)n1ccnc1
Yield: 57.3 %

Procedure:
A suspension of 16.0 g (0.4 mol) of NaH-oil (60%) was washed with hexane to remove the oil and then resuspended in 400 mL of THF. This was then treated dropwise with a solution of 27.23 g (0.4 mol) of imidazole in 150 mL of THF and then refluxed for 1hour. This was then treated dropwise with a solution. of 72.4 g (0.4 mol) of ethyl 2-bromopropanoate in 100 mL of THF and the mixture heated at reflux for 2.5 hours. The mixture was filtered and the solvent removed under reduced pressure. The residue was taken up in Et2O and washed with H2O, then saturated NaCl. Drying over MgSO4 and treatment with charcoal gave the crude product. This was triturated with pentane and the pentane removed under reduced pressure to give 38.56 g (57.3% yield) of the product as an oil. The structure was confirmed by NMR and mass spectroscopy. MS m/z 169 (M+H+).
Reaction SMILES: FC1C=C([N+]([O-])=O)C=CC=1N(CC(F)(F)F)O.CC(C)CCO.[F:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]1[C@H:38]([CH:39]([CH3:41])[CH3:40])[CH2:37][O:36][CH:35]1[C:42]([F:45])([F:44])[F:43].[SiH](CC)(CC)CC.[OH-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl.O>[F:24][C:25]1[CH:30]=[C:29]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:27][C:26]=1[N:34]([CH2:35][C:42]([F:45])([F:44])[F:43])[C@H:38]([CH:39]([CH3:40])[CH3:41])[CH2:37][OH:36]
Reactant: CC(C)[C@@H]1COC(C(F)(F)F)N1c1ccc([N+](=O)[O-])cc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CC[SiH](CC)CC
Agent: O=[N+]([O-])c1ccc(N(O)CC(F)(F)F)c(F)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(C)CCO
Product: CC(C)[C@H](CO)N(CC(F)(F)F)c1ccc([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
(2R)-2-[2-Fluoro-4-nitro(2,2,2-trifluoroethyl)anilinol-3-methyl-1-butanol (Structure 38 of Scheme VIII, where R4=isopropyl, Rx=CF3. To a solution of (4R)-3-(2-fluoro-4-nitrophenyl)-4-isopropyl-2-trifluoromethyloxazolidine (1.8 g, 5.6 mmol) and Et3SiH (1.88 g, 16.1 mmol) in 15 mL CHCl3 was added TiCl4 (6 mL of a 1M solution in CH2Cl2, 6 mmol) at −78° C. The solution was stirred for 2 h, then allowed to warm to 0° C. and stirred for 2 h. The mixture was poured into 150 mL water and neutralized with 6N NaOH. The aqueous layer was extracted with CHCl3 (3×100 mL), and the combined organic layers washed with brine (150 mL), dried over MgSO4, filtered and concentrated. Flash chromatography (gradient elution, hexanes:EtOAc 9:1 to 3:1) afforded 1.6 g (88%) of (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol, an orange oil. Data for (2R)-2-[2-fluoro-4-nitro(2,2,2-trifluoroethyl)anilino]-3-methyl-1-butanol: Rf 0.3 (3:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.96 (dd, 1H, J=8.8, 2.3), 7.92 (dd, 1H, J=13.4, 2.5), 7.37 (dd, 1H, J=8.8, 8.8), 4.33-4.23 (m, 1H), 4.03-3.86 (m, 2H), 3.81-3.74 (m, 1H), 3.36-3,27 (m, 1H), 1.97-1.88 (m, 1H), 1.85 (broad s, 1H), 0.99 (d, 3H, J=6.6), 0.94 (d, 3H, J=6.6).