Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([C:8]3[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)c1cccnc1-c1cccc(Cl)n1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccnc1-c1cccc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.21 g (0.30 mmol) of (Ph3P)2PdCl2 is added under argan to a solution of 2.5 g (10.05 mmol) of methyl 6′-chloro-2,2′-bipyridine-3-carboxylate (1) in 70 ml of dioxane and the mixture is stirred for 30 min at room temperature. Thereafter, 1.98 g (12.08 mmol) of para-chlorophenylboronic acid, 4.17 g (30.17 mmol) of K2CO3 and 7 ml of H2O are added in succession to the mixture, and the mixture is stirred for 6 hours under reflux and subsequently left to stand overnight at RT. For work-up, the reaction mixture is poured into 100 ml of H2O and extracted repeatedly with CH2Cl2. The combined organic phases are dried over Na2SO4 and concentrated. The residue is purified by column chromatography over silica gel using heptane/ethyl acetate (7:3) as the mobile phase. This gives 2.7 g (82.7%) of product as a solid. M.p.: 120.5° C.; 1H NMR (CDCl3) δ 8.75 (dd, 1H), 8.17 (dd, 1H), 8.00 (m, 2H, C6H4Cl), 7.95 (dd, 1H), 7.92 (dd, 1H), 7.28 (dd, 1H), 7.45 (m, 2H, C6H4Cl), 7.40 (dd, 1H), 3.60 (s, 3H, COOMe).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.[OH-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CI
Solvent: O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 5-fluoro-2-nitrophenol (10.0 g) in dry acetone (40 ml) under nitrogen was treated with potassium carbonate (8.9 g). The mixture formed a deep red coloured thick precipitate. Methyl iodide (5 ml, 11.4 g) was added slowly and the mixture stirred overnight and then at 60° C. for 3 hours. Further methyl iodide (3 ml, 6.84 g) was added and the mixture stirred at 60° C. for a further 3 hours. After this time the deep red colour had disappeared, and the mixture (now orange) was added to water (50 ml) and sodium hydroxide (2N, 40 ml), and extracted with dichloromethane (3×100 ml). The combined, dried extracts were concentrated in vacuo to give a yellow oil which upon cooling crystallised giving a pale yellow crystalline solid (4-fluoro-2-methoxy-1-nitrobenzene 10.88 g). A solution of this solid in ethanol:water (200 ml, 6:2) was added under vacuum to a prehydrogenated suspension of palladium (10% on carbon, 50% paste, 2.5 g) in ethanol:water (80 ml, 6:2). The suspension was stirred under an atmosphere of hydrogen for 2 hours, the suspension was filtered through Hyflo and the filtercake washed thoroughly with ethanol and water. The combined filtrates were concentrated in vacuo and the moist residue re-evaporated with ethanol. The purple oily residue was dissolved in dichloromethane (200 ml), dried and concentrated in vacuo to give the title compound as a dark purple liquid. (7.73 g).
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:32]12[N:39]([C:40](=[O:42])[CH3:41])[CH:36]([CH2:37][CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[C:40]([N:39]1[CH:36]2[CH2:37][CH2:38][CH:32]1[CH2:33][N:34]([C:22]([C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:14]3[N:15]=[CH:16][C:11]4[CH:10]=[C:9]([C:27]([N:28]([CH3:29])[CH3:30])=[O:31])[N:8]([CH:1]5[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:12]=4[N:13]=3)=[N:19][CH:20]=1)=[O:23])[CH2:35]2)(=[O:42])[CH3:41]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Reactant: CC(=O)N1C2CCC1CNC2
Product: CC(=O)N1C2CCC1CN(C(=O)c1ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCCCC5)c4n3)nc1)C2
Yield: 88 %

Procedure:
Following general amide formation method 3, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with 1-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanone which gave 2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (63 mg) in 88% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.69 (s, 1H) 8.90 (s, 1H) 8.72 (d, J=8.59 Hz, 1H) 8.51 (d, J=2.02 Hz, 1H) 7.78 (dd, J=8.84, 2.27 Hz, 1H) 6.46 (s, 1H) 4.71 (br. s., 1H) 4.51 (tt, J=11.12, 4.04 Hz, 1H) 4.16 (br. s., 1H) 3.24-3.10 (m, 7H) 2.70-2.55 (m, 2H) 2.18-2.06 (m, 4H) 2.01 (ddd, J=13.64, 7.07, 4.04 Hz, 4H) 1.95-1.79 (m, 5H) 1.79-1.62 (m, 5H) 1.62-1.49 (m, 2H). HR-MS (m/z MH+) 559.31 RT 3.89 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([CH:24]([OH:25])[C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([NH2:20])[CH:22]=1)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(O)c1cccc(N)c1

Procedure:
N-t-butyloxycarbonylphenylalanine (1.00 g, 3.8 mmole) is dissolved in 4 ml of dichloromethane, in which is then suspended m-aminobenzyl alcohol. The cooled mixture is treated with 0.78 g (3.8 mmole) of dicyclohexylcarbodiimide for 12 to 24 hours. Dicyclohexylurea is removed by filtration, using an ethyl acetate wash. The filtrate is extracted three times with saturated aqueous potassium bisulfate, three times with aqueous potassium bicarbonate, and once with brine. The organic layer is dried over magnesium sulfate, filtered, and blown dry under flowing nitrogen. Column chromatography using silica gel and chloroform eluent produces, after removal of solvent, 1.19 g (3.2 mmole) of pure product. Structure assignment is supported by elemental analysis (C,H,N).
Reaction SMILES: [N+:1]([C:4]1C=C(N)C=[CH:8][C:9]=1NCC=C)([O-])=O.F[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[CH:18][C:17]=1[N+:29]([O-:31])=[O:30]>>[N+:29]([C:17]1[CH:18]=[C:19]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])[CH:20]=[CH:21][C:16]=1[NH:1][CH2:4][CH:9]=[CH2:8])([O-:31])=[O:30]
Reactant: C=CCNc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc(N(CCO)CCO)ccc1F
Product: C=CCNc1ccc(N(CCO)CCO)cc1[N+](=O)[O-]

Procedure:
Synthesis and working up same as for compound 1, but with 4-fluoro-3-nitro-N,N-bis-(2-hydroxyethyl)-aminobenzene instead of 4-fluoro-3-nitroaminobenzene. Black crystals, melting point 73°-75° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15].[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=1>C1COCC1.C(O)(=O)C.O>[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:25])[CH2:12][P:13](=[O:18])([O:16][CH3:17])[O:14][CH3:15])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1ccc(Cl)cc1)OC
Temperature: -78 °C
Yield: 76.1 %

Procedure:
A solution of n-butyl lithium in hexane (1.63N, 43 ml, 70 mmol) was added dropwise to a solution of dimethyl methylphosphonate (8.68 g, 70 mmol) in 100 ml of anhydrous THF with stirring at -78° C. under argon atmosphere. After the mixture was stirred for 30 minutes, a solution of methyl p-chlorobenzoate (4.8 g, 28 mmol) in 10 ml of anhydrous THF was added dropwise and the mixture was stirred for 30 minutes. This reaction mixture was allowed to warm to 0° C., diluted with 4.2 ml of acetic acid and 10 ml of water, and concentrated. The residue was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give a colorless transparent oil of dimethyl 2-p-chlorophenyl-2-oxoethylphosphonate (5.6 g, 21.3 mmol, yield 76.2%, b.p. 146°-149° C./0.07 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C@H:24]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:25][C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][C:32](O)=[O:33])=[CH:28][CH:27]=1)[CH3:22].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:32](=[O:33])[CH2:31][O:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][C@H:24]([O:23][CH2:21][CH3:22])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][CH:35]=2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCNCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(Cc1ccc(OCc2ccccc2)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
To a solution of N-[4-(benzyloxy)benzyl]-N-butylamine (3.59 g, 12.0 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (2.96 g, 10.0 mmol) in methylene chloride (100 mL) were added N,N-diisopropylethylamine (4.00 mL, 23.0 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (3.85 g, 12.0 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (100 mL) and the organic phase was washed with 5% HCl (3×75 mL), saturated aqueous NaHCO3 (2×75 mL), and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with methanol (0-1% gradient) in methylene chloride as the eluent and collection of pure fractions yielded 1.80 g (33%) of a whitish oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1>>[F:25][C:24]([F:26])([F:27])[C@@H:23]([C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1)[OH:28]
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Product: O=C1N(c2ccc([C@@H](O)C(F)(F)F)cc2)CCC12CCC1(CC2)OCCO1

Procedure:
The title compound was prepared in analogy to example 133, step 4 from 1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (5.01 g) (described in example 133, step 3) and (1R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (9.07 g) (synthesis described in J. Org. Chem. 2009, 74, 1605-1610) as a white solid (4.9 g). MS (m/e): 386.1[MH+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([O:1][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)=[CH:10][CH:9]=1)[C:11]([O:13][CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=1)=[O:12]
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1cccc(F)c1)c1ccc(OCc2cccc(F)c2)cc1C(=O)OCc1cccc(F)c1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A mixture of 4-hydroxyphthalic acid (5.0 g, 27.5 mmol), 3-fluorobenzylbromide (31.14 g, 164.7 mmol) and potassium carbonate (15.18 g, 109.8 mmol) in THF:water (1:1, 200 mL) was heated under reflux for 72 h. After cooling to RT, the mixture was then half evaporated and the residue extracted with ethyl acetate (100 mL). The organic layer was then washed with brine, dried over sodium sulfate, filtered and evaporated. The mixture was then heated in a Kugelrohr apparatus (160° C. at 15 mmHg) to remove the excess 3-fluorobenzylbromide to leave the title compound (13.1 g, 94%) as a light yellow liquid. MS m/e=506.1 (M).
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][N:31]([C:34](=[O:36])[CH3:35])[CH2:30][CH2:29]3)=[CH:24][N:23]=2)=[CH:18][CH:19]=1)=[O:11])[NH:2]C(OC(C)(C)C)=O.O1CCOCC1.Cl.Cl>CC(O)C.C(O)C>[NH:1]([C:10]([O:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:34](=[O:36])[CH3:35])[CH2:32][CH2:33]3)=[CH:24][N:23]=2)=[CH:18][CH:19]=1)=[O:11])[NH2:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOC(=O)NNC(=O)OC(C)(C)C)s3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CCOC(=O)NN)s3)nc2)CC1
Yield: 86.1 %

Procedure:
By a method similar to Production Example 108, step 8, 2-(5-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}thiophen-2-yl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (corresponding to 0.974 mmol) was treated with 4M hydrogen chloride dioxane solution. The obtained hydrochloride was dissolved in 2-propanol-ethanol (9:1) mixture, and filtered through aminopropylated silica gel. The aminopropylated silica gel was washed with 2-propanol-dichloromethane (1:9), the filtrate and the washing solution were combined and concentrated under reduced pressure to about 20 ml. Hexane (200 ml) was added, and the mixture was concentrated again under reduced pressure to about 40 ml. Hexane (200 ml) was added to the residue and the mixture was stirred. The resulting solid was collected by filtration, washed with hexane and dried under reduced pressure to give the title compound (350.1 mg, yield 86.1%) as a white solid.
Reaction SMILES: C[C:2]1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH:21]([CH3:23])[CH3:22])[O:11][CH3:12])=[O:9])[C:4](=[O:24])[O:3]1>CO>[CH3:2][O:3][C:4](=[O:24])[C:5]([OH:6])=[CH:7][C:8](=[O:9])[N:10]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH:21]([CH3:22])[CH3:23])[O:11][CH3:12]
Reactant: CON(Cc1ccccc1OC(C)C)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccccc1OC(C)C)OC
Yield: 62 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(2-isopropoxybenzyl)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as a white syrup (62% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.33 (6H, d, J=6 Hz, CH3), 3.68 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.59 (1H, m, CH), 4.9 (2H, s, NCH2), 6.50 (1H, s, CH), 6.88 (2H, m, aromatics), 7.24 (2H, m, aromatics). HRMS (MAB N2) calculated for C16H21NO6, [M]+: 323.136888. found: 323.136700.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]1([CH2:36][O:37][NH2:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:38][O:37][CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:12]([N:14]2[C@H:18]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[N:23]=3)=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)O)CC2CCCC2)n1
Reactant: NOCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCc1cccc(NC(=O)[C@@H]2CC=NN2C(=O)[C@@H](CC(=O)NOCc2ccccc2)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoic acid (323 mg, 0.81 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (129 mg, 1.05 mmol), 4-methylmorpholine (0.23 ml, 2.1 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (110 mg, 0.81 mmol), and EDC (186 mg, 0.97 mmol) at 0° C. The reaction was left to warm to room temperature and stirred overnight. The reaction was then washed with water (15 mL) and NaHCO3 solution (15 mL×3), then concentrated to provide the crude product as a mixture of diastereomers, which was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN: H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N-(6-ethyl-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxamide (119 mg, 29% yield). MS: 506 ([M+H]+).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:41][CH3:42])[C@H:3]([NH:33]C(=O)OC(C)(C)C)[C:4]([NH:6][CH2:7][C@@H:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH:28]([CH3:32])[CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1)[NH:9][C:10](=[O:19])[C@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:5].C(O)(C(F)(F)F)=O>ClCCl>[NH2:33][C@@H:3]([C@@H:2]([CH3:1])[CH2:41][CH3:42])[C:4]([NH:6][CH2:7][C@@H:8]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:28]([CH3:32])[CH2:29][CH2:30][CH3:31])=[CH:24][CH:25]=1)[NH:9][C:10](=[O:19])[C@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:12])=[O:5]
Reactant: CCCC(C)COc1ccc([C@H](CNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)NC(=O)[C@@H](C)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)COc1ccc([C@H](CNC(=O)[C@@H](N)[C@@H](C)CC)NC(=O)[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of t-butyl (2S,3S)-3-methyl-1-((2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethylamino)-1-oxopentan-2-ylcarbamate (80 mg, 0.138 mmol) in dichloromethane (2 mL) was added TFA (1 mL, 12.98 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated and the residue was transferred to a separatory funnel containing saturated aqueous K2CO3 solution. The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. 1H NMR indicated that the product was still a TFA salt. The product was dissolved in methanol and passed through a cation exchange resin (washed with methanol and water to remove the acid followed by 2M ammonia in methanol to elute the product) to afford (2S,3S)-2-amino-3-methyl-N-((2R)-2-(4-(2-methylpentyloxy)phenyl)-2-((S)-2-phenylpropanamido)ethyl)pentanamide (51 mg, 77% yield) as a colorless solid as the free base: 1H NMR (400 MHz, CDCl3) δ 7.70 (t, J=6.2 Hz, 1H), 7.26-7.33 (m, 2H), 7.19-7.26 (m, 3H), 6.93 (d, J=6.5 Hz, 1H), 6.87 (d, 2H), 6.70 (d, J=8.6 Hz, 2H), 4.89 (ddd, J=9.5, 6.4, 3.5 Hz, 1H), 3.72 (dd, J=8.8, 5.8 Hz, 1H), 3.62 (dd, J=8.8, 6.8 Hz, 1H), 3.45-3.57 (m, 2H), 3.35 (ddd, J=14.0, 5.7, 3.9 Hz, 1H), 3.23 (d, J=3.5 Hz, 1H), 1.93-2.04 (m, 1H), 1.83-1.93 (m, 1H), 1.42 (d, J=7.1 Hz, 3H), 1.23-1.54 (m, 6H), 1.01-1.21 (m, 2H), 0.96 (d, J=6.8 Hz, 3H), 0.94 (d, J=7.3 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H), 0.89 (t, J=7.1 Hz, 3H); LRMS (ESI) m/e 482.5 [(M+H)+, calcd for C29H44N3O3 482.3].
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=[O:28])[CH:17]=[C:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C(O[C@H]1CC[C@@]2(C)C(CC(=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2=O)C1)(=O)C>CCOC(C)=O>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=[O:28])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C[C@]12CCCCC1=CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Agent: CC(=O)O[C@H]1CC[C@@]2(C)C(CC(=O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Solvent: CCOC(C)=O
Product: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 82 %

Procedure:
17,17-Bis(ethylendioxy)androstane-7-one was prepared in 82% yield from 3,3:17,17-bis(ethylendioxy)-5-androsten-7-one by the procedure described above for the preparation of 3β-acetoxyandrostane-7,17-dione (Prepn. 29) using EtOAc instead of EtOH. The crude product was purified by flash chromatography (SiO2, n-hexane/EtOAc 6/4). 1H-NMR (300 MHz, acetone-d6, ppm from TMS: δ 3.96-3.75 (8H, m), 2.54-1.10 (20H, m), 1.13 (3H, s), 0.83 (3H, s).
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)(=[O:17])[CH3:16]
Reactant: O=C1C=CC(O)OC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1C=CC(=O)CO1
Temperature: 0 °C

Procedure:
24.0 g of 6-hydroxy-2H-pyran-3(6H)-one was dissolved in 80 ml of acetic anhydride. After cooling the solution to 0° C., 30 ml of pyridine was dropwise added thereto.
Reaction SMILES: Cl.Cl[C:3]1[N:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[C:10]3([CH2:16][CH2:15]3)[CH2:9][N:8]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:7]=2[N:24]=1.[NH2:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])=[CH:28][C:27]=1[O:38][CH3:39]>C(O)C.O>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:36]=[CH:37][C:26]([NH:25][C:3]3[N:4]=[CH:5][C:6]4[N:12]([CH3:13])[C:11](=[O:14])[C:10]5([CH2:15][CH2:16]5)[CH2:9][N:8]([C@@H:17]5[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]5)[C:7]=4[N:24]=3)=[C:27]([O:38][CH3:39])[CH:28]=2)[CH2:34][CH2:35]1
Reactant: CN1C(=O)C2(CC2)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CC2)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N([C@@H]1CCC(F)(F)C1)CC1(CC1)C(=O)N2C
Temperature: 85 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Concentrated hydrochloric acid (45 μl) was added to a mixture of (R)-2′-chloro-9′-(3,3-difluorocyclopentyl)-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (100 mg, 0.29 mmol) and 4-amino-N-cyclopropyl-3-methoxybenzamide (90 mg, 0.44 mmol) in ethanol (1.4 mL) and water (5.2 mL). The reaction mixture was heated to 85° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (49 mg, 33% yield).
Reaction SMILES: [C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16](Cl)[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2].[F:22][C:23]([F:28])([F:27])[C@@H:24]([OH:26])[CH3:25]>>[C:1]([CH2:4][C:5]1([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:26][C@@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[C:15]([CH:19]3[CH2:21][CH2:20]3)=[CH:14][N:13]=2)=[O:11])[CH2:8][O:7][CH2:6]1)(=[O:3])[NH2:2]
Reactant: C[C@H](O)C(F)(F)F
Reactant: NC(=O)CC1(NC(=O)c2cc(Cl)c(C3CC3)cn2)COC1
Product: C[C@H](Oc1cc(C(=O)NC2(CC(N)=O)COC2)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 63c, using 4-Chloro-5-cyclopropyl-pyridine-2-carboxylic acid (3-carbamoylmethyl-oxetan-3-yl)-amide (Example 63b) and (S)-1,1,1-trifluoropropan-2-ol (CAN 3539-97-7) as starting materials and isolated (9 mg, 18%) as light brown solid; MS (ESI, m/z): 388.0 (M+H+).