Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][N:9]1[C:15](=[O:16])[CH2:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)(OC(C)(C)C)=O.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(Cl)[Cl:38]>CN(C=O)C>[ClH:38].[NH2:8][N:9]1[C:15](=[O:16])[CH:14]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2
Reactant: CC(C)(C)OC(=O)NN1C(=O)Cc2ccccc2-c2ccccc21
Reactant: ClCCl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC1C(=O)N(N)c2ccccc2-c2ccccc21
Product: Cl
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 5-(N-Boc-amino)-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.03, 3.08 mmol) (Example 3) in DMF was treated with Cs2CO3 (1.10 g, 3.39 mmol) and warmed to 60° C. To this reaction mixture was added methyl bromoacetate (0.321 mL, 3.39 mmol) (Aldrich) and stirring was continued for 17 h. After cooling to 23° C., the mixture was diluted with CH2Cl2, washed with several portions of brine and dried over Na2SO4. The title compound was purified by chromatography (SiO2, CHCl3).
Reaction SMILES: [Mg:1].ClCCl.[CH3:5][OH:6].[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]2[NH:13][C:14]([S@:16]([CH2:18][C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)=[O:17])=[N:15][C:11]=2[CH:10]=1>O>[CH3:7][O-:8].[Mg+2:1].[CH3:5][O-:6].[Mg:1].[CH3:7][O:8][C:9]1[CH:30]=[CH:29][C:12]2[NH:13][C:14]([S@:16]([CH2:18][C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)=[O:17])=[N:15][C:11]=2[CH:10]=1
Reactant: CO
Agent: COc1ccc2[nH]c([S@@](=O)Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Mg]
Solvent: ClCCl
Solvent: O
Product: C[O-]
Product: [Mg+2]
Temperature: 42.5 °C
Reaction time: 2.5 h

Procedure:
The procedure is carried out as described in Raju et al, Organic Process Research & Development 2006, 10, 33-35, which is hereby incorporated by reference in its entirety. A solution of magnesium methoxide was prepared by adding magnesium turnings (1.31 g, 0.054 mol) and dichloromethane (5 mL) to methanol (150 mL) and stirring under nitrogen atmosphere for 2-3 hours, at 40-45° C. The solution was cooled to 5-10° C. and added to a stirred mixture of esomeprazole (42.0 g, 0.121 mol) and methanol (150.0 mL), and stirring was maintained for 3 hours. Water (2.0 mL) was added and stirring was continued for 1 hour and the solution was filtered. The mother liquor was distilled under reduced pressure at 35° C. Acetone (400 mL) was added and the mixture was stirred for 1 hour at 25-35° C. The precipitate was filtered and washed with acetone (200 mL), dissolved in methanol (222 mL) and water (8 mL) and stirred for about 30 minutes at 25-30° C. and filtered. The filtrate was suspended in water and stirred at 0-5° C. for about 45 minutes, filtered, washed with water (300 mL) and dried under reduced pressure to yield esomeprazole magnesium salt.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:16][CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(4-fluoro-benzyl)-piperidine (0.117 g, 0.6 mmol) in acetonitrile (5 ml) is treated with 2-(2-bromo-ethyl)-isoindole-1,3-dione (0.152 g, 0.6 mmol) and with triethylamine (0.084 ml, 0.6 mmol). The mixture is shaken at RT for 72 hours and the solvent evaporated. The crude product is purified by flash silica chromatography (methanol:dichloromethane, 1:19 elution) to afford 2-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione 1H NMR (400 MHz, CDCl3, selected values) δ 2.46 (d J 7.1 2H ), 2.60 (t J 6.8 2H ), 3.81 (t J 6.8 2H ), 6.94 (m 2H ), 7.05 (m 2H), 7.7 (dd J 3.0 5.3 2H), 7.84 (dd J 3.0 5.3 2H)
Reaction SMILES: [N:1]1([CH:6]([F:17])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[C:18](=O)([O-])[O-].[K+].[K+].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:7]([CH:6]([F:17])[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[CH2:18]
Reactant: O=C(c1ccc(F)cc1F)C(F)n1cncn1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccc(F)cc1F)C(F)n1cncn1

Procedure:
2-(1H-1,2,4-Triazol-1-yl)-2,2',4'-trifluoroacetophenone (10 g), anhydrous potassium carbonate (7.3 g), and methyltriphenylphosphonium bromide (15.5 g) were heated under reflux for 16 hours in 1,4-dioxan (250 ml), to which water (1.0 g) had been added.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][CH2:6][O:7][CH2:8]Cl)([CH3:4])[CH3:3].[C:10]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=[CH:14][C:13]([C:16]2[C:28]([Cl:29])=[CH:27][C:19]3[NH:20][C:21]([S:23]([CH3:26])(=[O:25])=[O:24])=[N:22][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C1COCC1>[C:10]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:15]=[CH:14][C:13]([C:16]2[C:28]([Cl:29])=[CH:27][C:19]3[N:20]([CH2:8][O:7][CH2:6][CH2:5][Si:2]([CH3:1])([CH3:3])[CH3:4])[C:21]([S:23]([CH3:26])(=[O:24])=[O:25])=[N:22][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
SEMCl (2.28 mL, 12.87 mmol) was added to a solution of 5-biphenyl-4-yl-6-chloro-2-(methylsulfonyl)-1H-benzimidazole (3.79 g, 9.9 mmol) and Hunig's base (2.08 mL, 11.88 mmol) in THF (20 mL) at 0° C. The reaction was stirred at rt for 3 h then partitioned between EtOAc and saturated aqueous NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. Chromatography over silica eluting with 5-25% EtOAc/hexanes afforded the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=C(C#N)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[ClH:19].[C:20]([OH:23])(=[O:22])[CH3:21]>>[ClH:19].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:21]([C:20]([OH:23])=[O:22])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccc(N)cc1C=C2
Reactant: CC(=O)O
Agent: Cl
Product: Nc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2

Procedure:
850 Mg. 8-amino-3-cyanodibenzo[b,f]-thiepin is refluxed in a mixture of 20 cc. acetic acid and 20 cc. concentrated hydrochloric acid for 48 hours. The suspended solid is filtered, washed with some acetic acid, dried overnight under vacuum at 70° C. to yield 600 mg. pure compound, m.p. 308°-311° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.[CH3:21][O:22][C:23]([C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3OC(C)(C)O[C:40](=[O:42])[CH:41]=3)[CH:31]=2)[O:28][CH:29]=1)=[O:24].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][O:22][C:23]([C:25]1[N:26]=[C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH2:41][C:40](=[O:42])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:31]=2)[O:28][CH:29]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: COC(=O)c1coc(-c2cccc(C3=CC(=O)OC(C)(C)O3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J2) (680 mg) and 2-[3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example L7) (820 mg) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (770 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)=[O:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1.CO>CN1CCCC1=O>[F:35][C:34]([F:36])([F:37])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:1]2[CH2:2][CH2:3][CH:4]([C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)=[O:8])[CH2:5][CH2:6]2)=[CH:28][CH:29]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: CC(=O)Nc1ccc(C(=O)C2CCNCC2)cc1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
To a stirred mixture of N-(4-(piperidine-4-carbonyl)phenyl)acetamide (3.82 mmol, 0.94 g) and potassium carbonate (11.45 mmol, 1.582 g) in N-methyl-2-pyrrolidinone (5 mL) was added 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (3.82 mmol, 1.286 g). The reaction was stirred at room temperature over the weekend. Methanol (30 mL) was added and the reaction was filtered. The filtrate was purified by strong cation exchange column chromatography to afford the title compound (1.51 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[CH:6]=[CH:5][C:4]=1[C:13]1[C:14]([CH2:26][O:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]2[CH3:25].Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[C:14]([CH2:26][O:27][C:28](=[O:36])[C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]3[CH3:25])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCOc1ccc(-c2ccc3c(c2COC(=O)c2ccc(C)cc2)C(C)=CC(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)cc1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
6-(2-Methoxy-4-methoxymethoxyphenyl)-5-(4-methylbenzoyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 2-1, 943 mg, mmol) was dissolved in 1,4-dioxane (9 mL), 4N HCl/1,4-dioxane solution (980 μL) was added thereto, and then the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL). The mixture was washed with water (80 mL)-saturated aqueous sodium hydrogen carbonate solution (20 mL), and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (687 mg) as a colorless amorphous product. (Yield 80%)
Reaction SMILES: Br[C:2]1[C:3]([Cl:13])=[CH:4][C:5]2[O:6][CH2:7][C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[C:14]1(/[CH:20]=[CH:21]/B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])O.[K+]>O1CCOCC1.O.C(OCC)(=O)C>[Cl:13][C:3]1[C:2](/[CH:21]=[CH:20]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:11][C:10]2[NH:9][C:8](=[O:12])[CH2:7][O:6][C:5]=2[CH:4]=1
Reactant: O=C1COc2cc(Cl)c(Br)nc2N1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C1COc2cc(Cl)c(/C=C/c3ccccc3)nc2N1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
6-Bromo-7-chloro-4H-pyrido[3,2-b][1,4]oxazin-3-one (22 g, 83.7 mmole) and trans-2-phenylvinylboronic acid (17.33 g, 117 mmole) were dissolved in 1,4-dioxane (300 mL) and the solution was degassed with argon. (Ph3P)4Pd (1.9 g, 2 mole %) was added, followed by a solution of potassium hydrogen carbonate (21 g, 210 mmole) in H2O (100 mL). The reaction was heated at reflux under argon overnight, then was cooled to room temperature and diluted with ethyl acetate (1 L). The solution was washed sequentially with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The residue was slurried with chloroform (120 mL), then diluted with diethyl ether (100 mL). The precipitated product was collected by filtration and washed with ether to provide the product (16.4 g, 68%) as an off-white solid.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:39]2[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=2)[CH:15]=1)[C:4]([OH:3])=[O:34]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: Cc1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(CC(C)C)C(=O)O)c2)cc1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-methyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.94 (t, J=6.60 Hz, 6H), 1.50-1.62 (m, 1H), 1.6 (s, 1H), 2.03-2.13 (m, 4H), 3.81 (t, J=7.80 Hz, 1H), 7.25-7.33 (m, 3H) 7.49-7.60 (m, 4H), 7.67-7.77 (m, 4H); Calcd for C26H25F3O2 (M+H) 427.18, Found 427.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH2:11])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.CC(C(Cl)=O)[C:21](Cl)=[O:22].[C:27]([O:30][CH2:31]C)(=[O:29])[CH3:28]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][NH:11][C:21](=[O:22])[CH2:28][C:27]([O:30][CH3:31])=[O:29])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CN)CCC1
Reactant: CC(C(=O)Cl)C(=O)Cl
Reactant: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(CNC(=O)CC(=O)OC)CCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Aminomethyl-cyclobutanecarboxylic acid ethyl ester (WO2006/100208) (1.26 g, 8.0 mmol) and triethylamine (0.88 ml, 9.6 mmol) are dissolved in 30 ml dichloromethane (DCM). The solution is cooled to 0° C. and methylmalonylchloride (0.88 ml, 8.0 mmol) in 10 ml DCM is added within 15 minutes. The reaction mixture is stirred for 1 hour at 0° C. followed by 72 hours stirring at room temperature. The reaction mixture is diluted with 400 ml ethyl acetate, and washed with NaHCO3 solution, 1N HCl and brine. Evaporation of the solvent provides the title compound as viscous oil. LC-MS (m/z, ES+): 258 (MH+), retention time: 1.28 mins (LC-MS method 8)
Reaction SMILES: C([O:5][C:6]([C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C>C(O)=O>[N:9]1[CH:10]=[CH:11][CH:12]=[N:13][C:8]=1[C:6]([OH:7])=[O:5].[CH:6]([O-:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ncccn1
Solvent: O=CO
Product: O=C(O)c1ncccn1
Product: O=C[O-]
Temperature: 70 °C

Procedure:
The carboxylic t-butyl ester was dissolved in one hundred times an equal volume of 96% formic acid, and the solution was heated to 70° C. for 2 h. At this time, TLC of an evaporated aliquot of the reaction mixture indicated complete conversion of the pyrimidine-carboxylic t-butyl ester. The formic acid was removed by rotary evaporation under high vacuum to afford the pyrimidine-carboxylic acid as a formate salt. Typically, the obtained product was >98% pure, but if necessary, the product was purified by preparative reverse-phase HPLC, or by flash chromatography on silica gel using EtOAc/hexanes, or by recrystallization.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.CS(O[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[F:34])(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: CS(=O)(=O)OCCc1ccccc1F
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccccc1CCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 85 °C

Procedure:
A mixture of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g, 0.019 mole), (2-fluorophenyl)ethyl methanesulfonate (4.47 g, 0.02 mole), K2CO3 (11 g) and 150 ml dimethylformamide was heated at 85° C. for 9 hours.
Reaction SMILES: C(NC(=O)[CH2:10][CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)C1C=CC=CC=1.C(N(CC)CC)C.Cl.[NH2:31][CH2:32][C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[C:35]([OH:43])[CH:34]=1.CC[O:46]C(OC(OCC)=O)=O>CN(C=O)C>[OH:43][C:35]1[CH:34]=[C:33]([CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])[CH2:32][NH:31][C:10](=[O:46])[CH2:11][CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CN)cc1O
Reactant: O=C(CCCc1c[nH]c2ccccc12)NCc1ccccc1
Reactant: CCOC(=O)OC(=O)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)CCc2c[nH]c3ccccc23)cc1O
Temperature: 0 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
A solution of 3-(3-indolyl)propanoic acid [II: R1 =R3 =H, R2 =(CH2)2COOH] (1.50 g), triethylamine (10 mL) and crude methyl 4-(aminomethyl)-2-hydroxybenzoate hydrochloride (3.46 g) in DMF (20 mL) was stirred at 20° C. for 10 minutes, then cooled to 0° C. DEPC (98%, 1.47 mL) was added, then the mixture was stirred at 20° C. for 17 hours. Workup and chromatography on silica gel, eluting with EtOAc:light petroleum (1:1) gave N-(3-hydroxy-4-methoxycarbonylbenzyl)-3-(3-indolyl)propanamide [II: R1 =R3 =H, R2 =(CH2)2CONHCH2Ph{3-OH, 4-COOMe}] (1.40 g, 50%); mp (EtOAc/light petroleum) 132°-133° C.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:22]([NH2:24])=[O:23])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.Cl.Cl.[F:47][C:48]1([F:56])[CH2:53][CH2:52][CH2:51][C@@H:50]([NH2:54])[C@H:49]1[NH2:55].C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1>[NH2:55][C@H:49]1[C:48]([F:56])([F:47])[CH2:53][CH2:52][CH2:51][C@H:50]1[NH:54][C:3]1[N:4]=[N:5][C:6]([C:22]([NH2:24])=[O:23])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:11]=2)[N:8]=1
Reactant: CSc1nnc(C(N)=O)c(Nc2cccc(-c3ncccn3)c2)n1
Reactant: N[C@@H]1CCCC(F)(F)[C@@H]1N
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1nnc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1cccc(-c2ncccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
3-(Methylthio)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide (40 mg, 0.12 mmol) was dissolved in 4 mL NMP. To it was added mCPBA (77%) (108 mg, 0.48 mmol). The mixture was stirred at RT for 1 h. To it was added DIEA (0.21 mL, 1.20 mmol) and (1R,2R)-3,3-difluorocyclohexane-1,2-diamine dihydrochloride (53 mg, 0.24 mmol). The mixture was stirred at 80° C. for 1 h. It was cooled to RT, acidified with TFA (0.3 mL) and subjected to reverse phase preparative HPLC to isolate the title compound (35 mg) as HCl salt. MS found for C20H21F2N9O as (M+H)+ 442.5. UV: λ=240 nm. Proton NMR: (CD3OD) δ 8.94-8.92 (3H, m), 8.41 (1H, d, J=8.0 Hz), 7.79 (1H, d, J=8.0 Hz), 7.64 (1H, t, J=8.0 Hz), 7.45 (1H, t, J=4.8 Hz), 4.90 (1H, m), 4.13 (1H, m), 2.24-1.82 (6H, m) ppm.
Reaction SMILES: [CH2:1]([C:8]1([CH2:11]O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:20][CH2:11][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1
Reactant: OCC1(Cc2ccccc2)CC1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: BrCC1(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a solution of the title C compound, (1-benzyl-cyclopropyl)-methanol (0.8 g, 4.93 mmol), pyridine (994 uL, 12.3 mmol) and CBr4 (1.8 g, 5.42 mmol) in methylene chloride (25 mL) is added triphenylphosphine (1.8 g, 6.9 mmol), with stirring at 0° C. After completion of the reaction, the mixture is poured into a saturated aqueous solution of NaHCO3. The aqueous layer is extracted twice with methylene chloride and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is taken up into ether and the triphenylphosphine oxide precipitate is filtered off. The filtrate is concentrated under reduced pressure and purified by flash column chromatography on silica gel (hexane/EtOAc 9/1) to afford the title compound: TLC, Rf (hexane/AcOEt 99/1)=0.54. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.41 min.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][CH2:14][CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18].CCN(CC)CC.N#N>O1CCOCC1>[Cl:12][C:11]1[C:2]([NH:13][CH2:14][CH:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CC(C)CC(O)CN
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)CC(O)CNc1nc2ccccc2nc1Cl
Temperature: 25 °C
Yield: 47.8 %

Procedure:
2,3-Dichloroquinoxaline (18.05 g, 90.7 mmol) is added to a solution of crude 1a (11.7 g, 99.8 mmol) and Et3N (19 ml, 13.8 g, 136 mmol) in dioxane (210 ml). The solution obtained is heated at reflux (under N2) for 6 h, it is then cooled to room temperature. Et3N, HCl is eliminated by filtration and the filtrate is concentrated under reduced pressure. The dark orange residue is purified by chromatography on a silica column, eluent: CH2Cl2/MeOH (100:0→99:1), to obtain a yellow solid (12.14 g, 48%); 1H NMR (100 MHz, CDCl3) δ: 0.72 (d, 3H), 0.78 (d, 3H), 1.60 (m, 3H), 3.68 (m, 4H), 5.82 (t, 1H), 7.58 (m, 4H); 13C NMR (25 MHz, CDCl3) δ: 22.17, 23.35, 24.60, 44.32, 48.62, 69.67, 125.30, 125.62, 127.91, 130.36, 136.52, 137.92, 140.59, 148.62. Analysis calculated for C14H18N3OCl: C, 60.10; H, 6.49; N, 15.02. Experimental: C, 59.87; H, 6.62; N, 15.25.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH:30](O)[CH3:31])=[C:25]([CH:27]([CH3:29])[CH3:28])[N:26]=2)=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:30]([C:24]2[O:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=3)=[N:26][C:25]=2[CH:27]([CH3:28])[CH3:29])[CH3:31])=[CH:8][C:7]=1[CH3:13]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: CC(C)c1nc(-c2ccc(Br)cc2)oc1C(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(Br)cc3)nc2C(C)C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A solution of 3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (6.30 g, 32.1 mmol) and 1-[2-(4-bromo-phenyl)-4-isopropyl-oxazol-5-yl]-ethanol (9.05 g, 29.2 mmol) in toluene (300 mL) is degassed and filled with nitrogen for 3 times. Tributylphosphine (7.70 g, 38.1 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of of 1,1′-(azodicarbonyl)-dipiperidine (8.84 g, 35.0 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight, the mixture is loaded directly on silica gel column chromatography with 10–15% EtOAc/Hexanes to afford the title compound (11.8 g, 79%).