Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][CH2:14][CH2:15][OH:16]>C(#N)C>[CH3:8][S:9]([CH2:8][S:9]([O:16][CH2:15][CH2:14][Cl:13])(=[O:11])=[O:10])(=[O:11])=[O:10]
Reactant: OCCCl
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CS(=O)(=O)OCCCl
Reaction time: 1 h

Procedure:
A solution of 133 g (1.32 mol.) of triethylamine in 400 ml of anhydrous acetonitrile was cooled to -30° to -40° C., and a solution of 100 g (0.88 mol.) of methanesulfonyl chloride in anhydrous acetonitrile (67 ml) was added dropwise at a rate that prevented the temperature from rising above -30° C. The mixture was stirred at -30° to -40° C. for 1 hour, and a solution of 35.4 g of 2-chloroethanol in anhydrous acetonitrile (30 ml) was added. The resulting mixture was stirred for 2 hours at -30° to -40° C. and then was filtered to separate triethylamine hydrochloride. The latter material was washed with ethyl acetate, the washings were combined with the filtrate, and the organic solution was concentrated in vacuo to an oil. A solution of the residual oil in ethyl acetate (1200 ml) was washed quickly with two portions (2×200 ml) of dilute sodium chloride solution and then with two portions (2×200 ml) of saturated sodium chloride solution, dried with magnesium sulfate, filtered, and concentrated in vacuo. The residual solid (70 g) was dissolved in methylene chloride (450 ml), the solution was filtered and diluted slowly with cyclohexane (450 ml). The mixture, protected from atmospheric moisture, was allowed to stand at room temperature for about an hour and was then stored at low temperatures (about 5° C.) overnight. The precipitate was collected by filtration, washed with cyclohexane, and dried in vacuo over phosphorus pentoxide: yield, 58.7 g (56%); m.p. 60°-62° C.; IR (cm-1, medium and strong bands) 3040, 3025, 2990 s, 2930, 2935 sh, 1465, 1430, 1415, 1390, 1370 s, 1320 s, 1240, 1200, 1185 s, 1175 s, 1165 s, 1125, 1070, 990 s, 955 s, 915 s, 870 s, 790 s, 765, 755, 665, 605 sh, 600, 525 s, 505, 465 s, 420; 1H NMR (300.6 MHz, CDCl3, Me4Si as internal reference), δ 3.26 (s, CH3), 3.80 (t, CH2Cl), 4.65 (t, OCH2), 4.67 (s, SCH2S). Anal. Calcd. for C4H9ClO5S2 : C, 20.30; H, 3.83. Found: C, 20.26; H, 4.00.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:12]1([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].Cl>C1(C)C=CC=CC=1>[CH3:7][N:6]1[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=[C:2]1[C:12]1([C:16]#[N:17])[CH2:15][CH2:14][CH2:13]1
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: N#CC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1c(C2(C#N)CCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
To a solution of Example 275A (1.90 g, 11.4 mmol) in toluene (30 mL) was added cyclobutanecarbonitrile (1.01 g, 12.5 mmol) and potassium hexamethyldisilazide (34.2 mL, 17.1 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was poured into 1N HCl solution (50 mL) and the aqueous layer was extracted with EtOAc (3×20 mL). The combined layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by prep. TLC on silicagel (eluted with EtOAc:petroleum ether=1:10) to give the title compound (1.0 g, 4.69 mmol, 41.1% yield) as a white solid. MS: MS (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.80-7.78 (m, 1H), 7.36-7.30 (m, 3H), 3.83 (s, 3H), 3.13-3.05 (m, 2H), 2.99-2.92 (m, 2H), 2.48-2.41 (m, 1H), 2.24-2.18 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+:19]>C(O)C>[Na+:19].[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(=O)CCCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1ccc(C(=O)CCCC(=O)[O-])cc1
Reaction time: 8 h

Procedure:
5-(4-Isopropyl-phenyl)-5-oxo-pentanoic acid (5 g, 21.3 mmol) was dissolved in 75 mL ethanol in a 250 mL flask. Sodium hydroxide (0.85 g, 21.3 mmol) was added and the reaction was stirred overnight under reduced pressure on a rotary evaporator. The solid was dried under vacuum and used without further purification. Found: C, 60.24; H, 6.66; Na, 9.21%; C14H17O3Na requires C, 61.28; H, 6.98; Na, 8.38%;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[C:23]1([CH2:29][C:30](O)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][C:4]=1[C:30](=[O:31])[CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Reactant: O=C(O)Cc1ccccc1
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(=O)Cc1ccccc1

Procedure:
The title compound was prepared in a similar manner to those described in Reference Example 56 using 4-(4-methoxyphenoxy)-5-methyl-7-nitroindane instead of ethyl N-[7-(4-methoxyphenoxy)-6-methylindan-4-yl]malonamate and using phenylacetic acid instead of 4-fluorophenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C[C:16]1[CH:17]=[C:18]([N:23]2CC[NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:20][C:21]=1[CH3:22]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:22][C:21]3[CH:20]=[C:19]4[C:18](=[CH:17][CH:16]=3)[NH:23][CH2:24][CH2:25][NH:26]4)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: Clc1ccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)cc1Cl

Procedure:
Example 7 was prepared according to Example 2 except that in Step A 1-(3,4-dichlorophenyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 139°-141° C.
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20](O)[CH2:21][OH:22].C1C=CC=CC=1>O>[C:1]([N:11]1[CH2:18][C:17]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: OCCO
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCO2
Reaction time: 8 h
Yield: 97 %

Procedure:
A stirred mixture of 12.8 g (0.049 mole) of N-carbobenzyloxy-4-keto-L-proline, 53 ml (0.095 mole) of ethylene glycol, and 0.35 g of p-toluenesulfonic acid H2O in 1.31 l. of benzene is heated and the resulting solution is refluxed for 7 hours (water formed is collected in a Dean-Stark apparatus). After standing overnight at room temperature, the lower glycol layer is separated and the benzene solution is washed with 150 ml of saturated sodium chloride, dried (MgSO4), and the solvent evaporated to give 14.6 g of N-carbobenzyloxy-4,4-ethylenedioxy-L-proline as a syrupy residue. The latter is dissolved in 60 ml of ethanol, filtered, treated with 5 g of cyclohexylamine, and diluted with ether. On seeding and rubbing, the crystalline cyclohexylamine salt separates; weight after cooling overnight, 9.0 g., m.p. 179°-180° (s. 173°). The material is recrystallized from acetonitrile, m.p. 182°-184° (s. 179°), [α]D26 -21° (c, 1 % in EtOh).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4](O)[N:3]=1.P(Cl)(Cl)([Cl:12])=O>N>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: Cc1nc(N)cc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: Cc1nc(N)cc(Cl)n1
Temperature: 20 °C

Procedure:
150 g (1.2 mol) of anhydrous 2-methyl-4-amino6-hydroxypyrimidine are added little by little, with good stirring, to 720 ml of phosphorus oxychloride. The mixture is refluxed gently for 5 hours. A yellow solution is obtained. After cooling to 20° C., the precipitate formed is drained. An oily residue is recovered by evaporating the filtrate almost to dryness. This oily residue is poured, little by little, onto 500 g of ice, with stirring and while cooling the vessel in ice. The precipitate is introduced little by little into the solution obtained after some time. The addition is exothermic and the mixture must be cooled well in an ice bath. All of the solid dissolves. The solution is cooled to 0° C. and is rendered alkaline to pH 8 by the addition of 20% ammonia (850 ml). The formation becomes very thick. The solid is drained and washed on the filter with 100 ml of 10% aqueous sodium chloride solution and then with 200 ml of water. 144.2 g of crude product are obtained, which are recrystallised from acetonitrile. 97 g (0.676 mol) of pure product having a melting point of 191° C. are recovered. The yield of recrystallised product is 56.3%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH2:18])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:28]12([C:38](Cl)=[O:39])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:38]([C:28]34[CH2:37][CH:32]5[CH2:31][CH:30]([CH2:36][CH:34]([CH2:33]5)[CH2:35]3)[CH2:29]4)=[O:39])=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1ncnc2c1CCN(Cc1ccccc1)C2
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncnc2c1CCN(Cc1ccccc1)C2)C12CC3CC(CC(C3)C1)C2
Temperature: 160 °C
Yield: 41.8 %

Procedure:
In a 20 ml microwave vessel was added 7-benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-ylamine (1.5 g, 6.3 mmole) in 7.0 ml of chloroform, diisopropylethylarnine (2.2 ml, 12.6 mmole) and 1-adamantane carbonylchloride (2.51 g, 12.6 mmole). The reaction was heated at 160° C. for 7.0 minutes in a microwave. After completion the solvent was evaporated and the residue was dissolved in EtOAc and washed with sat. NaHCO3, washed with brine and dried over sodium sulphate. The solvents were removed under reduced pressure and the residue was chromatographed using chloroform (100%) to give the desired product as a white solid (1.06 g).
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:5]=2[S:6][C:7]=1[C:8](Cl)=[O:9]>O1CCOCC1>[Cl:2][C:3]1[C:4]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:5]=2[S:6][C:7]=1[C:8]([OH:1])=[O:9]
Reactant: COc1cc2sc(C(=O)Cl)c(Cl)c2cc1OC
Reactant: O
Solvent: C1COCCO1
Product: COc1cc2sc(C(=O)O)c(Cl)c2cc1OC

Procedure:
40 ml of water are added to a solution of 70 mmol of the compound of Step A in 250 ml of dioxane. After 20 hours' reflux and then return to room temperature, a precipitate forms. After filtration and rinsing with water until neutral, the precipitate is dried over P2O5 under reduced pressure. 18.6 g of the expected product are thus isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:33])([C:31]#[CH:32])[CH3:30])=[N:27][CH:28]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([C:32]#[C:31][C:29]([C:26]4[CH:25]=[CH:24][C:23]([F:22])=[CH:28][N:27]=4)([OH:33])[CH3:30])[CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[O:18][CH2:19][CH2:20][OH:21])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(-n2c(OCCO)nc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ccc(F)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(O)(C#Cc1ccc2nc(OCCO)n(-c3ccnc(N)n3)c2c1)c1ccc(F)cn1
Temperature: 25 °C
Yield: 1.5 %

Procedure:
A mixture of 2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol (200 mg, 0.57 mmol), 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol (940 mg, 5.69 mmol), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) and triethylamine (0.5 mL) in dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen for 1 hr at 120° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was concentrated under vacuum and the crude product (80 mg) was purified by preparative HPLC to give 3.7 mg (1%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-fluoropyridin-2-yl)but-3-yn-2-ol as a light yellow solid: 1H NMR (300 MHz, DMSO) delta 8.54 (d, J=2.7 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.15 (d, J=1.2, 1H), 7.84 (q, 1H), 7.78-7.72 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.24 (q, 1H), 7.10-7.04 (m, 3H), 6.37 (s, 1H), 5.03 (s, 1H), 4.60 (t, J=4.5 Hz, 2H), 3.81 (d, J=4.5 Hz, 2H), 1.82 (s, 3H); LC-MS: m/z=+435 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].Cl[CH2:19][C:20]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[O:22][N:21]=1>>[CH2:1]([C:3]1[N:4]([CH2:19][C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[O:22][N:21]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2]
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole. MS (ESI): m/z 465 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[C:7]([CH3:15])=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH2:16]1[CH2:20]OC[CH2:17]1>C(Cl)Cl>[CH:16]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[C:6]([Br:5])[C:7]=1[CH3:15])([CH3:20])[CH3:17]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: C1CCOC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1c(Br)cccc1C(=O)OC(C)C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (6 mL) was addend over 1 min to a 0° C. suspension of 3-bromo-2-methyl benzoic acid (2.15 g, 10 mmol) in DCM (10 mL). After 30 min of stirring, THF (5 mL) was added to induce dissolution. The now homogeneous solution was stirred for 24 h at rt and the volatile component were removed in vacuo. A portion of the crude acid chloride was dissolved in dry isopropyl alcohol (10 mL) and pyridine (2 mL) was added. After stirring for 4 h at rt, the volatile components were removed in vacuo. The residue was partitioned between EtOAc (70 mL) and HCl (1M, 30 mL) and the layers were separated. The organic layer was washed with HCl (1M, 10 mL), NaHCO3 (3×20 mL), water (30 mL), brine (30 mL), and was dried over sodium sulfate. Removal of solvent in vacuo yielded the title compound as a light-yellow oil which was used without further purification. 1H-NMR (CDCl3): δ 7.69 (d, 2H, J=7.7 Hz), 7.11 (t, 1H, J=7.9 Hz), 5.26 (heptet, 1H, J=6.3 Hz), 2.63 (s, 3H), 1.39 (d, 6H, J=6.3 Hz).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.CC(O)=O>CO.[OH-].[OH-].[Pd+2]>[N:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH2:19][CH2:18]2)=[CH:21][CH:22]=1
Reactant: CC(=O)NCC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NCC1(N2CCN(c3ccncc3)CC2)CCNCC1
Reaction time: 16 h
Yield: 5 %

Procedure:
A degassed solution containing N-((1-benzyl-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)acetamide AM14 (1.96 mmol), AcOH (0.3 ml) and Pd(OH)2 in methanol was hydrogenated for 16 h to yield N-((4-(4-(pyridin-4-yl)-piperazin-1-yl)piperidin-4-yl)methyl)acetamide AM2, which was obtained after passage through a celite pad and solvent removed under reduced pressure. N-((4-(4-(pyridin-4-yl)piperazin-1-yl)piperidin-4-yl)methyl)acetamide AM2 was re-dissolved in dichloromethane and added to a solution containing 2-(2-(N-cyclopropyl-4-methoxy-2,6-dimethylphenylsulfonamido)ethoxy)acetic acid AC7 (0.8 equiv.), EDCI (1.5 equiv.), HOBT (1 equiv.) and DIPEA (4 equiv.) in dichloromethane at 0° C. The reaction mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane and was given aq. NH4Cl and aq. NaHCO3 washes. The organic layer was dried over sodium sulfate and the solvent removed. The crude product was purified by alumina column chromatography. Yield: 5%. MS, Rt=2.5 min, m/z=657.5 [MH]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C:17]([C@@H:18]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)[CH2:19][C@:3]12[CH3:4])=[C:16]1[C:11](=[CH:12][C:13](=[O:28])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.C1C(=O)N([Br:36])C(=O)C1>C1COCC1>[Br:36][C:12]1[C:13](=[O:28])[CH2:14][CH2:15][C:16]2[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C:17]=2[C@@H:18]([C:20]2[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=2)[CH2:19][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C@@H:2]2[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@]12C[C@H](c3ccc(C=O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@H]2O
Solvent: C1CCOC1
Product: C[C@]12C[C@H](c3ccc(C=O)cc3)C3=C4CCC(=O)C(Br)=C4CC[C@H]3[C@@H]1CC[C@@H]2O

Procedure:
4-(17β-Hydroxy-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is reacted according to Example 5 in THF with NBS to form 4-(4′-bromo-17β-hydroxy-3-oxoestra-4,9-dien-11β-yl)benzaldehyde and purified by chromatography. The purified product is incorporated directly into the oximization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].Cl.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([B:20]([OH:22])[OH:21])=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([B:20]([OH:22])[OH:21])=[CH:18][CH:19]=1
Reactant: O=C=Nc1ccccc1F
Reactant: NCc1ccc(B(O)O)cc1
Agent: Cl
Product: O=C(NCc1ccc(B(O)O)cc1)Nc1ccccc1F

Procedure:
4-[3-(2-Fluoro-phenyl)-ureidomethyl]-phenylboronic acid was prepared from 2-fluorophenyl isocyanate and 4-aminomethylphenylboronic acid HCL salt according to the procedure of Example 65.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH2:5][N:6]1[C:14]([O:15][CH2:16][CH3:17])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([Cl:18])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[S:27])=[CH:24][CH:23]=1>>[Cl:18][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([O:15][CH2:16][CH3:17])[N:6]([CH2:5][C:2]([NH:1][C:26](=[S:27])[C:25]3[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:30][CH:29]=3)([C:3]#[N:4])[CH3:19])[N:7]=2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CCOc1c2cc(Cl)ccc2nn1CC(C)(N)C#N
Product: CCOc1c2cc(Cl)ccc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-3-ethoxy-2H-indazol-2-yl)-2-methylpropionitrile (52 mg, described in Example 109) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (83 mg, 93%). MS (ES): M/Z [M+H]=483. 1H NMR: (400 MHz, DMSO-d6): 1.26 (t, J=7.0 Hz, 3H), 1.71 (s, 3H), 4.52 (q, J=7.0 Hz, 2H), 4.78 (d, 1H), 4.93 (d, 1H), 7.16 (dd, J=9.3, 1.9 Hz, 1H), 7.47 (d, J=9.3 Hz, 1H), 7.85-7.89 (m, 3H), 7.96 (d, J=8.8 Hz, 2H) and 8.99 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH:58]1[CH2:63][CH2:62][CH:61]([N:64]2[CH2:70][CH2:69][C:68]3[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=3[NH:66][C:65]2=[O:75])[CH2:60][CH2:59]1>CN(C)C=O>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:19])[N:58]4[CH2:59][CH2:60][CH:61]([N:64]5[CH2:70][CH2:69][C:68]6[CH:71]=[CH:72][CH:73]=[CH:74][C:67]=6[NH:66][C:65]5=[O:75])[CH2:62][CH2:63]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Br:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
(S)-2-(1,4-Dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl)acetic acid (52 mg, 0.104 mmol) was dissolved in N,N-dimethylformamide (1.5 mL). N,N-Diisopropylethylamine (70 μl, 0.402 mmol) was added to the mixture followed by TBTU (34.8 mg, 0.108 mmol). 3-(Piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (35.4 mg, 0.144 mmol) was then added to the mixture. Reaction stirred at room temperature for 1 hour. Reaction was quenched with 50% acetonitrile-water. Material was purified by reverse phase prep HPLC (acetonitrile-water-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 67% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.92 (s, 1H) 8.51 (s, 1H) 7.48 (s, 1H) 6.98-7.08 (m, 3H) 6.76-6.86 (m, 1H) 5.58 (d, J=17.40 Hz, 1H) 5.39 (d, J=17.09 Hz, 1H) 4.49 (d, J=13.12 Hz, 1H) 4.26-4.42 (m, 2H) 4.10-4.24 (m, 1H) 3.90-4.09 (m, 2H) 3.33-3.41 (m, 2H) 3.19 (d, J=16.79 Hz, 1H) 3.05-3.15 (m, 1 H) 2.95-3.02 (m, 1H) 2.83-2.94 (m, 3H) 2.53-2.65 (m, 1H) 2.33-2.46 (m, 1H) 1.58-1.85 (m, 3H) 1.40-1.57 (m, 1H). High resolution MS m/e (M+H)+=725.0720.
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1.[O:14]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=O)C1C=CC=CC=1.O>C1COCC1>[CH3:3][N:4]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:14])[CH2:5][C:6]1[N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[S:9][CH:10]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 50 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
To a stirred slurry of 95% NaH (560 mg, 23.2 mmol) at -10° C. in 20 mL of THF was slowly added N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.76 g, 22.1 mmol) keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. A solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 20 mL of THF was added slowly keeping the temperature not more than 0° C. THF (5 mL) was added as a rinse. After 4 hours, water (100 mL) was added, and the THF was removed under reduced pressure. The pH was adjusted to 9 with concentrated HCl, and the phenol by-product was removed with methyl tert-butyl ether washes (3×60 mL). The aqueous phase was stirred with 70 mL of toluene and adjusted to pH 3 with 4 N HCl. The aqueous phase was separated and extracted twice more with toluene (2×70 mL). The combined toluene extracts were concentrated under reduced pressure, and the residue was redissolved in toluene and heptane (50 mLs of a 1:1 v/v solution), warmed to 50° C. and allowed to cool to ambient temperature. The product was collected by filtration, washed with heptane and dried under vacuum to afford the title compound as a white powder in 83% yield.