Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH3:2].[OH-].[Na+].[CH2:14](O)[CH3:15].BrCC>ClCCl>[CH2:14]([O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[O:3][CH2:1][CH3:2])[CH3:15]
Reactant: CCOc1c(O)cccc1F
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCBr
Solvent: ClCCl
Product: CCOc1cccc(F)c1OCC
Temperature: 10 °C
Yield: 75 %

Procedure:
To a 250 ml reactor were added 12.5 (0.08 mol) of 2-ethoxy-3 -fluorophenol [F1], 3.2 g (0.08 mol) of sodium hydroxide and 20 ml of ethanol. After cooling to around 10° C., 20 ml of an ethanol solution of 9.6 g (0.088 ml) of bromoethane was slowly added. After the termination of the addition, they were reacted under a reflux temperature for 3 hours and, after the termination of the reaction, dichloromethane was added, followed by extraction. The extraction liquid was washed with water and dried, and the solvent was removed by distillation to obtain 11.0 g of an oily product [G1]. The process yield was 75%.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=5)[C:33]([CH3:41])=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:43].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:43].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([F:40])[CH:38]=5)[C:33]([CH3:41])=[CH:32][C:31]4=[O:42])[CH2:24][CH2:23]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(F)ccc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(F)ccc12
Reaction time: 4 h

Procedure:
To 1.5 mL of methanol solution containing 0.17 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-fluoro-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1.5 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 4 hours. Ethyl acetate was added, and the resulting solid was filtered to give 0.15 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.FC(F)(F)C([NH:16][CH2:17][CH:18]1[C:24]2=[CH:25][NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[C:22]([C:23]=32)[C:21](=[O:31])[N:20]([CH2:32][OH:33])[CH2:19]1)=O>CO>[NH2:16][CH2:17][CH:18]1[C:24]2=[CH:25][NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[C:22]([C:23]=32)[C:21](=[O:31])[N:20]([CH2:32][O:33][CH3:1])[CH2:19]1
Reactant: O=C1c2cccc3[nH]cc(c23)C(CNC(=O)C(F)(F)F)CN1CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COCN1CC(CN)c2c[nH]c3cccc(c23)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 332 %

Procedure:
0.1 g of p-toluenesulfonic acid was added to a solution of 1.5 g of 3-trifluoroacetamidomethyl-5-hydroxymethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole (see Example 11C for preparation) in 25 ml of methanol, and the solution was heated under reflux for 2 hours. The reaction mixture was then concentrated, and saturated aqueous potassium carbonate solution was added to the residue until a pH of 11 was reached, and the mixture was stirred at room temperature for 4 hours. The treatment with the saturated aqueous potassium carbonate solution eliminated the trifluoroacetyl protective group and neutralized the p-toluenesulfonic acid. To work up the reaction mixture it was subsequently evaporated to dryness, the residue was taken up in methanol, insoluble components were removed by filtration, and the residue on the filter was washed twice more with 30 ml portions of methanol. The combined methanol phases were evaporated and the residue was purified by chromatography under moderately elevated pressure (=low-pressure chromatography under 3 to 6 bar) on silica gel using methanol/25% strength aqueous ammonia solution 97:3 as eluent. The title compound which remained after concentration of the eluate was crystallized from ethanol/ether 9:1. 0.5 g of 3-aminomethyl-5-methoxymethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole was obtained with a melting point of 160° to 163° C.
Reaction SMILES: [I-].[K+].FC(F)(F)S([O:8][CH2:9][C:10]([C:13]#[N:14])([CH3:12])[CH3:11])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:23][C:24]1[O:25][CH2:26][C@@:27]2([N:44]=1)[C:40]1[CH:39]=[C:38](O)[CH:37]=[C:36]([F:42])[C:35]=1[O:34][C:33]1[C:28]2=[CH:29][C:30]([Br:43])=[CH:31][CH:32]=1>CN(C=O)C>[NH2:23][C:24]1[O:25][CH2:26][C@:27]2([N:44]=1)[C:28]1[CH:29]=[C:30]([Br:43])[CH:31]=[CH:32][C:33]=1[O:34][C:35]1[C:40]2=[CH:39][C:38]([O:8][CH2:9][C:10]([CH3:11])([CH3:12])[C:13]#[N:14])=[CH:37][C:36]=1[F:42]
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: CC(C)(C#N)COS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C#N)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 60 °C

Procedure:
To a flask charged with potassium iodide (273 mg, 1.643 mmol), 2-cyano-2-methylpropyl trifluoromethanesulfonate (1140 mg, 4.93 mmol), cesium carbonate (3212 mg, 9.86 mmol), and (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (1200 mg, 3.29 mmol) was added 10 ml of DMF. The resulting slurry was heated for 1 hour at 60° C. The solution was quenched with water (20 mL). The aqueous layer was extracted with CH2Cl2 (3×25 mL) and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After being filtered and concentrated, the derived residue was purified via silica gel column chromatography using 15-70% 90/10/1 (CH2Cl2/MeOH/ammonia) in CH2Cl2 to afford (S)-3-(2-amino-2′-bromo-5′-fluoro-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile as a brown solid. MS m/z=446.0 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH2:18][O:19][CH:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)[CH:15]=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH2:18][O:19][CH:20]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)[CH:15]=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(COC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(COC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1

Procedure:
Methyl 2-(4-fluorophenyl)-4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxymethyl]benzoate (0.635 g; 1.41 mmol) in methanol (15 ml) was treated with 2N aqueous sodium hydroxide solution (1.77 ml; 3.54 mmol) at ambient temperature for 8 hours. After evaporation of the methanol, the residue was taken up in water, the pH adjusted to 4.8 with 2N HCl and extracted with dichloromethane to give 2-(4-fluorophenyl)-4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxymethyl]benzoic acid after evaporation as a foam (0.522 g; 85%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>O1CCCC1.C(O)(=O)C.CO>[Br:13][C:9]1[N:8]=[C:7]([CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(Br)n1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCc1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
n-BuLi (2.5M, 20.0 mL, 50.0 mmol) in tetrahydrofuran (40 mL) was cooled to −78° C. 2,6-Dibromopyridine (11.85 g, 50.0 mmol) in 70 mL tetrahydrofuran was added dropwise while keeping the internal temperature of the reaction below −70° C. The resulting dark green solution stirred for 15 min at this temperature upon which N,N-dimethylformamide (6.0 mL, 78 mmol) was added over a period of 30 seconds. The reaction stirred at −78° C. for 15 min and methanol (50 mL) and acetic acid (3.2 mL) were added. Sodium borohydride (1.89 g, 50.0 mmol) was added last. The reaction was allowed to warm to room temperature. The solution was carefully quenched with sat. ammonium chloride and then extracted with ethyl acetate (2 times). The organic layers were combined and washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography (25% ethyl acetate/hexanes) gave 2.57 g (27% yield) of the alcohol as a pale yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[Cl:18][C:19]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[Cl:18][C:19]1[CH:26]=[C:25]([CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[O:27][CH:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1)[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: O=Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: COC(=O)C(Oc1ccc(C=O)c(Cl)c1)c1ccccc1
Yield: 76.3 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.41 mmol) of 2-chloro-4-hydroxybenzaldehyde was alkylated with 1.61 g (7.05 mmol) of methyl 2-bromophenylacetate to afford 1.49 g (76%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([C:15]#[C:16][CH2:17][NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[BrH:29].C(O)(=O)C>C(Cl)Cl>[Br:29][C:16]1[CH:15]=[C:13]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=2)[N:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:17]=1
Reactant: COc1cc(C(=O)C#CCNS(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cc(Br)cn2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(p-toluenesulfonylamino)-1-propinyl 3,4,5-trimethoxyphenyl ketone (4.03 g, 10.0 mmol) in CH2Cl2 (40 ml), a 33% HBr/acetic acid solution (2.63 ml, 15.0 mmol) is added dropwise at 4° C. within 10 min. The reaction mixture is stirred for 1 h at 40° C. and extracted with CH2Cl2 and aqueous 1 N HCl solution. The organic layer is dried over MgSO4, the solvents evaporated, and the residue chromatographed on SiO2 with gradients of hexane/ethyl acetate (4:1 to 3:1) to yield the title compound as a greyish solid. 1H-NMR (300 MHz, CDCl3): 7.49 (d, J=2.0 Hz, 1H); 7.3-7.2; 7.2-7.1 (2m, 4H); 6.38 (s, 2H); 6.17 (d, J=2.0 Hz, 1H); 3.92 (s, 3H); 3.77 (s, 6H); 2.38 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:15][C:12]2([CH2:14][CH2:13]2)[N:11]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[N:20]=[C:19]3[N:30](C4CCCCO4)[N:31]=[C:32]([CH3:33])[C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl>[CH2:13]1[C:12]2([CH2:15][NH:8][CH2:9][CH2:10][N:11]2[CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)[N:20]=[C:19]3[NH:30][N:31]=[C:32]([CH3:33])[C:18]=23)[CH2:14]1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(CN3CCN(C(=O)OC(C)(C)C)CC34CC4)c12
Agent: Cl
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CCNCC34CC4)c12
Yield: 109.8 %

Procedure:
160 mg 4-[6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl]-4,7-diaza-spiro[2.5]octane-7-carboxylic acid tert-butyl ester were dissolved in 6 ml HCl (4N in 1,4-dioxane). After stirring the reaction at r.t. for 15 min the precipitated residue was isolated by filtration and washed with 1,4-dioxane and THF. It was taken up in water and freeze dried in vacuo. 115 mg (100%) of the title compound were obtained.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[C:6](=[O:17])[NH:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=1.Br[CH2:19][CH3:20]>CN(C=O)C.CO.O>[Br:4][C:5]1[C:6](=[O:17])[N:7]([CH2:19][CH3:20])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[CH:10]=1
Reactant: O=c1[nH]cc(-c2ccncn2)cc1Br
Reactant: CCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCn1cc(-c2ccncn2)cc(Br)c1=O
Temperature: 70 °C

Procedure:
A solution of 1.9 g of sodium methoxide in 100 ml of DMF and 30 ml MeOH is added to a suspension of 8.0 g of 3-bromo-5-(4-pyrimidinyl)-2(1H)-pyridone in 100 ml of DMF. Bromoethane (2.7 ml) is added to the mixture, and the mixture is heated to 70° C. for 2 hours. After cooling the mixture to RT, the solvent is evaporated leaving a solid residue which is suspended in 500 ml of distilled H2O, filtered through charcoal and dried. The dried residue is recrystallized from isopropanol with hot filtration to yield 3-bromo-1-ethyl-5-(4-pyrimidinyl)-2-pyridone, M.P. 195°-197° C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH2:23]OC)=[N:18][CH:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.C(OCC)(=O)C>CS(C)=O.CO>[CH2:1]([C:8]1[S:12][C:11]([CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[N:18][CH:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCNc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CNc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)cn1
Temperature: 140 °C
Reaction time: 5 h
Yield: 38.8 %

Procedure:
To a solution of N-(5-benzyl-thiophen-2-ylmethyl)-6-(methoxymethyl-amino)-nicotinamide described in Example A-159 (183 mg, 0.52 mmol) in dimethylsulfoxide (3 mL) was added sodium borohydride (120 mg, 3.12 mmol), and the solution was stirred at 140° C. for 5 hours. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed with water twice. Silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by silica gel column chromatography (ethyl acetate, then ethyl acetate:methanol=10:1), and the title compound (68 mg, 0.20 mmol, 38.8%) was obtained as a green solid.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](O)([CH3:10])[C:8]#[CH:9].[Br-:18].[NH4+].O>Br>[Br:18][CH:9]=[C:8]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: [Br-]
Reactant: C#CC(C)(O)c1ccccc1-c1ccccc1
Agent: Br
Agent: [NH4+]
Solvent: O
Product: CC(=C=CBr)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 1.1 g of 3-(p-biphenylyl)-but-1-yn-3-ol (obtainable analogously to Steps A and B, Example 10), 1.8 g of ammonium bromide and 0.2 g cuprous chloride in 10 ml of 48% hydrobromic acid is stirred for 4 hours at room temperature. The reaction mixture is then poured into water and extracted 3 times with 8 ml portions of methylene chloride. The combined organic extracts are washed 3 times with water, dried over anh. S.S., filtered and evaporated (i.v.) to dryness to obtain a residue. The residue is chromatographed on silica gel using chloroform/pentane (1:1) as eluent. The solvent is removed by evaporation to obtain a residue, from which 1-bromo-3-(p-biphenylyl)-1,2-butadiene is crystallized from pentane.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][C:5]1[N:6]([CH3:21])[C:7]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:8]([S:10][CH3:11])[CH:9]=1.[OH-].[Na+]>C(O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]([C:7]2[N:6]([CH3:21])[C:5]([CH2:4][C:3]([OH:22])=[O:2])=[CH:9][C:8]=2[S:10][CH3:11])=[O:20])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc(SC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Methyl-5-(p-chlorobenzoyl)-4-methylthio-1-methylpyrrole-2-acetate (19 mg) is dissolved in 0.5 ml of absolute ethanol. Aqueous sodium hydroxide (1 ml of 2.5 N solution) is added dropwise at a rate such that the reaction stayed homogeneous. Upon completion of the addition, the reaction is allowed to stand for about 30 minutes followed by precipitation with 1.5 ml of 2.5 N aqueous hydrochloride. The resulting precipitate is filtered, and dried in vacuo to afford 15 mg of 5-(p-chlorobenzoyl)-4-methylthio-1-methylpyrrole-2-acetic acid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:14][NH:13][C:12]2[N:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Br:23]Br>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:14][NH:13][C:12]2[N:15]=[CH:16][C:17]([Br:23])=[CH:18][C:11]=2[CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: c1ccc(C[C@H]2CNc3ncccc3CN2)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cnc2c(c1)CN[C@@H](Cc1ccccc1)CN2
Reaction time: 8 h

Procedure:
(S)-3-Benzyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine (60 mg, 0.25 mmol) was dissolved into acetic acid (1 mL). Bromine (15 μL, 0.3 mmol) was added and the reaction was stirred overnight. Methylene chloride (10 mL) was added and the solution was washed with 1 N NaOH (1 mL) and brine (1 mL), dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (3 mL) and precipitated with diethyl ether. The title compound was collected as an orange solid (80 mg, 100%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.42 (s, 1H), 7.37-7.17 (m, 5H), 5.42-5.00 (bs, 2H), 3.96-3.75 (m, 2H), 3.45-3.40 (m, 1H), 3.30-3.20 (m, 1H), 2.98-2.91 (m, 1H), 2.87-2.73 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:20](=[CH:21][CH:22]=1)[C@@H:19]1[C@H:10]([C@H:11]3[C@@:15]([CH2:17][CH2:18]1)([CH3:16])[C:14](=[O:23])[CH2:13][C@H:12]3[CH2:24][CH2:25][C:26]([NH:28][C:29]1[S:30][C:31]([CH3:34])=[CH:32][N:33]=1)=[O:27])[CH2:9][CH2:8]2)=[O:4].[Li+].[OH-].CO>O>[CH3:34][C:31]1[S:30][C:29]([NH:28][C:26](=[O:27])[CH2:25][CH2:24][C@H:12]2[C@H:11]3[C@H:10]4[C@H:19]([CH2:18][CH2:17][C@:15]3([CH3:16])[C:14](=[O:23])[CH2:13]2)[C:20]2[C:7](=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:22][CH:21]=2)[CH2:8][CH2:9]4)=[N:33][CH:32]=1
Reactant: COC(=O)c1ccc2c(c1)CC[C@H]1[C@@H]3[C@H](CCC(=O)Nc4ncc(C)s4)CC(=O)[C@@]3(C)CC[C@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cnc(NC(=O)CC[C@@H]2CC(=O)[C@@]3(C)CC[C@@H]4c5ccc(C(=O)O)cc5CC[C@H]4[C@H]23)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
350 mg 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxylic acid methyl ester and 5 eq LiOH are mixed with 30 ml MeOH and 10 ml H2O and stirred at 50° C. (water bath) for about 4 h. Then a few mg LiOH, 30 ml MeOH and 10 ml H2O were added and the reaction mixture was stirred for another 2 h at 50° C. After reducing the solvents, H2O is added, the reaction mixture is extracted with EtOAc. The combined aquatic layers are acidified with KHSO4aq to pH 2-3, and extracted twice with EtOAc. The latter organic layers are combined, washed with brine, dried (Na2SO4) and the solvent removed. Purifying by column chromatography (CH2Cl2: MeOH:AcOH 37:3:0.1) give 150 mg pure 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxylic acid (=EXAMPLE 4, NMR data see below). 15β-{3-[(5-methyl-1,3-thiazol-2-yl)amino]-3-oxopropyl}-17-oxoestra-1(10),2,4-triene-3-carboxamide
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1.C[Sn](C)(C)[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:7][C:5]1[N:4]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=[C:2]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:6]=1
Reactant: Cc1cc(Br)nn1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccsc1[Sn](C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2sccc2NC(=O)OC(C)(C)C)nn1COCC[Si](C)(C)C
Temperature: 80 °C

Procedure:
A microwave vial charge with 3-bromo-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (2.99 g, 10.3 mmol), tert-butyl [2-(trimethylstannyl)-3-thienyl]carbamate (4.40 g, 11.3 mmol), cesium fluoride (3.4 g, 23 mmol) and pre-milled palladium acetate and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (190 mg, 0.20 mmol) was purged with nitrogen three times. 1,2-Dimethoxyethane (10 mL) was added and resulting suspension was heated at 80° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate and filtered through a pad of silica gel. The silica gel pad was washed with ethyl acetate. The solvent was removed in vacuo and the residue was purified with flash chromatography (eluting with a gradient of 0-20% ethyl acetate in hexanes) to give the desired product. LCMS calculated for C19H32N3O3SSi (M+H)+: m/z=410.2. Found: 410.2.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:19])=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH2:12][N:11]3[C:17]=2[CH3:18])[CH:5]=[CH:4][N:3]=1.N[C:21]1C=CC=CC=1>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([CH3:19])=[C:10]3[C:15](=[O:16])[N:14]([CH3:21])[CH2:13][CH2:12][N:11]3[C:17]=2[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(-c2ccnc(F)n2)c(C)n2c1C(=O)NCC2
Reactant: Nc1ccccc1
Product: Cc1c(-c2ccnc(F)n2)c(C)n2c1C(=O)N(C)CC2

Procedure:
The following compounds were prepared by reaction of 7-(2-fluoropyrimidin-4-yl)-6,8-dimethyl-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one with an the appropriate aniline
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:19]([O-:21])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2[nH]c3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1

Procedure:
A solution of 10.2 g of the above carboxylic acid in 135 ml of chloroform containing 0.4 ml of N,N-dimethylaniline and 20.0 ml of phosphorus oxychloride was heated at reflux for three hours, cooled, and reddish-orange crystals of the title compound, mp 239°-241° C., were collected.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH4+:27]>C(O)C>[N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:27])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cccc2nc(-c3cccc(CN4CCCC4)c3)oc12
Reactant: [NH4+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1cccc2nc(-c3cccc(CN4CCCC4)c3)oc12
Temperature: 30 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
Methyl 2-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxylate (56 mg, 0.18 mmol) and ammonium water (50.4 mg, 1.44 mmol) were added to ethanol (30 mL) and the mixture was stirred at 30° C. for 1 hr. The resulting mixture was evaporated under reduced pressure and purified with Pre-HPLC to obtain 2-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide (14 mg, yield 22%). 1H-NMR (400 MHz, DMSO-d6) δ 1.92 (s, 4H), 3.19 (s, 4H), 4.42 (s, 2H), 7.49 (s, 1H), 7.70-7.94 (m, 6H), 8.35-8.43 (d, J=32 Hz, 2H); LC-MS (ESI) m/z 322 [M+1]+.