Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:7])=[CH:3][C:4](=O)[CH3:5].[C:8]1(=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=O)[CH2:9]1.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:7][C:2]1[N:1]=[C:10]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8](=[O:18])[C:9]2=[C:4]([CH3:5])[CH:3]=1
Reactant: CC(=O)C=C(C)N
Reactant: O=C1CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(n1)-c1ccccc1C2=O
Yield: 24.4 %

Procedure:
A solution of 23.6 g (0.24 mol) of 4-amino-3-penten-2-one, 29.2 g (0.2 mol) of indene-1,3-(2H)dione and 7.7 g (0.1 mol) of ammonium acetate in 500 ml of acetic acid was stirred at 115° C. for 3 hours and concentrated under reduced pressure, and the residue was treated with 500 ml of water and rendered alkaline with solid potassium carbonate. The mixture was extracted three times with methylene chloride, and the combined extracts were washed with 100 ml of water and concentrated under reduced pressure. The residue was crystallized at +5° C. using 20 ml of diethyl ether. 10.2 g of 2,4-dimethyl-5H-indeno[3,2-b]pyridin-5- one were obtained as slightly yellow crystals of m.p. 102°-104° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)=[CH:4][C:3]=1/[CH:17]=[CH:18]/[C:19]([O:21]CC)=O.Cl>>[F:9][C:8]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([N:12]2[CH:16]=[N:15][N:14]=[CH:13]2)[CH:4]=[C:3]2[C:2]=1[NH:1][C:19](=[O:21])[CH:18]=[CH:17]2
Reactant: CCOC(=O)/C=C/c1cc(-n2cnnc2)cc(C(F)(F)F)c1N
Agent: Cl
Product: O=c1ccc2cc(-n3cnnc3)cc(C(F)(F)F)c2[nH]1

Procedure:
The following compound, m.p. >320°, was prepared similarly to the previous Example, starting from trans-ethyl 3-(2-amino-3-trifluoromethyl-5-[1,2,4-triazol-4-yl]phenyl)prop-2-enoate and 5M HCl. ##STR62##
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:16](=[O:17])[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH2:4][CH2:3]1.C1COCC1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1.CCOCC>[NH4+].[Cl-]>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:16]2([OH:17])[C:6]3[CH:7]=[C:8]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)[S:9][C:5]=3[CH2:4][CH2:3][C:2]2([CH3:18])[CH3:1])=[CH:27][CH:26]=1
Reactant: CC1(C)CCc2sc(-c3ccncc3)cc2C1=O
Reactant: Clc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 100 mL round bottomed flask were placed 5,5-dimethyl-2-pyridin-4-yl-6,7-dihydro-1-benzothiophen-4(5H)-one (380 mg, 1.5 mmol) and THF (30 mL). To the mixture was added a solution of 4-chlorophenylmagnesium bromide in ether (1.0 M, 3.5 mL, 3.5 mmol) then the reaction was stirred for 3 hr at rt. LCMS indicated that starting material still remained, so additional 4-chlorophenylmagnesium bromide in ether (1.0M, 2.5 mL, 2.5 mmol) was added and the reaction was stirred for 16 hr at rt then for 10 hr at 70° C. The mixture was allowed to cool to rt then additional 4-chlorophenylmagnesium bromide in ether (1.0M, 5 mL, 5 mmol) was added and the mixture was stirred for 16 hr at rt. The mixture was then diluted with a saturated aqueous solution of NH4Cl (50 mL) and was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. The insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified using column chromatography on silica gel (24 g RediSep column, gradient 30% EA in hexane to 100% EA in hexane) to give the product (530 mg; 97%) as a colorless foam: 1H NMR (400 MHz, DMSO-d6) δ: 8.48 (dd, 2H), 7.45 (dd, 2H), 7.32-7.35 (m, 2H), 7.23-7.25 (m, 3H), 5.55 (s, 1H), 2.87-2.91 (m, 2H), 1.84-1.90 (m, 1H), 1.57-1.63 (m, 1H), 0.91 (s, 3H), 0.63 (s, 3H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:35]#[N:36])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:34]=[CH:33][C:23]3[N:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[S:26][C:22]=3[CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+].CO>>[C:35]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:34]=[CH:33][C:23]4[N:24]=[C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[S:26][C:22]=4[CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:7])[N:9]=1)#[N:36]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4nc(N5CCOCC5)sc4c3)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccc4nc(N5CCOCC5)sc4c3)ccc12
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-(2-morpholin-4-yl-benzothiazol-6-yloxy)-isoquinoline-3-carboxylic acid butyl ester (137 mg, 0.27 mmol), glycine (408 mg, 5.43 mmol) and 0.5 M sodium methoxide/methanol (10.3 mL) was refluxed for twenty-six hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (40 mL) and extracted with dichloromethane (2×35 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (7.5 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (119 mg): MS: (+) m/z 506.26 (M+1); (−) m/z 504.24 (M−1).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)=[O:16].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH:10]1[C:11]2[N:12]([C:20]3[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH3:14])=[CH:18][CH:19]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
To carbazole (5.02 g) in DMSO (50 mL) is added 4-fluoroacetophenone (3.45 g) and K2CO3 (10.4 g), and the mixture is stirred at 135° C. overnight. The mixture is poured into water to afford a precipitate, which is isolated by filtration and washed with water. The crude product thus obtained is further purified by recrystallization from TBME (tert-butyl methyl ether), giving the product as a light brown solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.71 (s, 3H), 7.32 (ddd, 2H), 7.41-7.50 (m, 4H), 7.72 (d, 2H), 8.15 (d, 2H), 8.21 (d, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:5]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:4]=1[C:33]([O:35]C)=[O:34])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>ClC(Cl)C.C(OCC)(=O)C>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:3]([CH2:1][N:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1)=[C:4]([C:33]([OH:35])=[O:34])[N:5]2[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: C1COCCN1
Reactant: COC(=O)c1c(C=O)c2c(-c3ccccc3C)cccc2n1CCCOc1cccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cccc2c1c(CN1CCOCC1)c(C(=O)O)n2CCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 107C (50 mg) in dichloroethane (3 ml) was added sodium triacetoxyborohydride (35 mg) and morpholine (15 mg). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water, brine, and dried over Na2SO4. The residue was dissolved in tetrahydrofuran (4 ml), methanol (2 mL) and water (2 ml) and LiOH (100 mg) was added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue neutralized with aqueous NH4Cl and extracted with ethyl acetate (100 mL×3). The combined extracts were dried and concentrated to give crude product, which was purified by RPHPLC. 1H NMR (300 MHz, dimethyl sulfoxide-d6) δ 8.25 (m, 1H), 7.86 (m, 2H), 7.45 (m, 9H), 6.93 (m, 2H), 4.99 (m, 2H), 4.47 (m, 1H), 4.25 (t, 2H), 3.60 (m, 10H), 2.43 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: [Br:1]Br.[CH2:3]([C:10]1[CH:31]=[C:30]([O:32][CH3:33])[C:13]2[N:14]([CH2:26][CH2:27][O:28][CH3:29])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[N:16][C:12]=2[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CCOC(C)=O>C(O)(=O)C>[CH2:3]([C:10]1[CH:31]=[C:30]([O:32][CH3:33])[C:13]2[N:14]([CH2:26][CH2:27][O:28][CH3:29])[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[N:16][C:12]=2[C:11]=1[Br:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3)cc(OC)c21
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(Cc3ccccc3)cc(OC)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.9 %

Procedure:
6 μl (0.122 mmol) bromine are added to a solution of 48 mg (0.116 mmol) 5-benzyl-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole in 6 ml glacial acetic acid. The reaction mixture is stirred at room temperature for 10 min. 25 ml EtOAc are added and this solution is washed 4N NaOH (2×), water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is recrystallized from dichloromethane/diethyl ether/hexane to afford 40 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10]3[CH2:12][CH2:13][CH2:14][C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[Cl:20]C1C=CC=C(Cl)C=1S[S:29][C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37].Cl>>[ClH:20].[C:1]1([CH:7]2[CH2:11][N:10]3[CH2:12][CH2:13][CH:14]([S:29][C:30]4[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=4[Cl:36])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2CN3CCCC3=N2)cc1
Reactant: Clc1cccc(Cl)c1SSc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Li]CCCC
Product: Clc1cccc(Cl)c1SC1CCN2CC(c3ccccc3)N=C12
Yield: 40.7 %

Procedure:
2,5,6,7-Tetrahydro-2-phenyl-3H-pyrrolo[1,2-a]imidazole was reacted with 2 equivalents of n-BuLi and 1 equivalent of 2,6-dichlorophenyldisulfide according to the general procedure A above except that when the reaction mixture was poured into the aq HCl solution, the HCl salt of the desired product precipitated. It was collected, washed well with cold H2O, then Et2O and dried in vacuo; yield 40.7%; m.p. 96°-99°. Neutralization of the acidic filtrate with NaHCO3, followed by extraction with Et2O, yielded an additional amount of the desired product as the free base (39.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)=[CH:9]\[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27]C(=O)C)=[C:21]([O:31][CH3:32])[CH:20]=2)[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[K+].[K+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](/[C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)=[CH:9]\[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([OH:27])=[C:21]([O:31][CH3:32])[CH:20]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: COc1ccc(/C(=C/C(=O)N2CCN(C(=O)c3cc(OC)c(OC(C)=O)c(OC)c3)CC2)c2ccccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COc1ccc(/C(=C/C(=O)N2CCN(C(=O)c3cc(OC)c(O)c(OC)c3)CC2)c2ccccc2Cl)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of a compound of Example 91 (0.500 g) in methanol (20 ml) was added an aqueous solution saturated with potassium carbonate (10 ml), and the resulting mixture was stirred at room temperature for an hour. The reaction mixture was poured into water and extracted thrice with methylenechloride. The combined extract was washed with water, dried and concentrated. The residue was purified by liquid chromatography under medium pressure through two Lobar B columns. Fractions eluted with a 19:1 mixture of ethyl acetate and methanol were collected and worked up to afford the title compound (0.464 g) as a powder.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.O>[C:31]([O:30][C:28](=[O:29])[CH2:27][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[C:3]([CH2:1][CH3:2])[N:4]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCc1cc2c(O)cccc2n1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
2-Ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole (5.82 g, 20 mmol) is added to 7.82 g (24 mmol) cesium carbonate in 25 mL DMF and the mixture is stirred at 35° C. for 30 minutes. After cooling to 20° C., a solution of tert-butyl bromoacetate (4.65 g, 23.8 mmol) in 5 mL DMF is added and stirring maintained until the reaction is judged complete by TLC analysis (several hours). The mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried (MgSO4) and concentrated at reduced pressure to give 6.8 g of solid. Mass spectrum: 365
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:24]=[CH:23][C:22]3[CH:21]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:20][CH2:19][C:18]([CH3:31])([CH3:30])[C:17]=3[CH:16]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[OH-].[Na+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:21]2[CH2:20][CH2:19][C:18]([CH3:30])([CH3:31])[C:17]3[CH:16]=[C:15]([C:14]#[C:13][C:10]4[CH:9]=[CH:8][C:7]([C:4]([CH3:6])([CH3:5])[C:3]([OH:32])=[O:2])=[CH:12][CH:11]=4)[CH:24]=[CH:23][C:22]2=3)[CH2:28][CH2:29]1
Reactant: COC(=O)C(C)(C)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(C(C)(C)C(=O)O)cc3)ccc21
Yield: 88.7 %

Procedure:
A solution of 2-{4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-2-methyl-propionic acid methyl ester (Intermediate 170, 0.08 g, 0.19 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of sodium hydroxide (2 mL, 4 mmol) and the resulting reaction mixture was refluxed overnight. The volatiles were evaporated in vacuo and the residue was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product (0.07 g,˜100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:10][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[NH:8][C:9]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[N:10][C:6]=2[CH:5]=[C:4]([O:17][C:23]2[CH:24]=[C:19]([Cl:18])[N:20]=[CH:21][N:22]=2)[CH:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Oc1cc(Cl)c2[nH]c(C3CCOCC3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2cc(Cl)c3[nH]c(C4CCOCC4)nc3c2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.10 g (0.40 mmol) 7-chloro-2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-5-ol and 60 mg (0.40 mmol) 4,6-dichloropyrimidine were placed in 2.0 mL DMF. 61 mg (0.40 mmol) potassium carbonate were added and the mixture was stirred overnight at RT. The reaction mixture was filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac.
Reaction SMILES: [CH3:1][N:2]([CH3:4])[NH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([C:13]2([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[C:20]([CH3:27])[CH:19]=3)[CH2:14]2)[CH:9]=[C:10]([Cl:12])[CH:11]=1.O.[OH-].[Na+]>CCOCC>[CH3:1][N:2]([CH3:4])[NH:3][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:15]2[CH2:14][C:13]([C:8]3[CH:9]=[C:10]([Cl:12])[CH:11]=[C:6]([Cl:5])[CH:7]=3)([C:28]([F:31])([F:30])[F:29])[O:17][N:16]=2)=[CH:19][C:20]=1[CH3:27]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: CN(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NN(C)C
Yield: 71.1 %

Procedure:
To a solution of N,N-dimethyl hydrazine (0.55 g) in ether (46 mL) was added 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoyl chloride (2.00 g) in small portions at 0° C. After 50 min at this temperature, water was added and the pH was adjusted to 7 by addition of NaOH (2 M). The organic layer was separated and the aqueous layer was extracted with ether. Combined organic layers were washed with NaHCO3 solution, dried over Na2SO4 and evaporated to give the title compound (1.50 g, 71%).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=1.[NH2:18][C@H:19]([C:44](O)=[O:45])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:43])[NH:25][S:26]([C:29]1[C:41]([CH3:42])=[C:40]2[C:34]([O:35][C:36]([CH2:39]2)([CH3:38])[CH3:37])=[C:32]([CH3:33])[C:30]=1[CH3:31])(=[O:28])=[O:27]>CN(C=O)C>[NH2:18][C@H:19]([C:44]([NH:1][C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:8][CH:9]=1)=[O:45])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:43])[NH:25][S:26]([C:29]1[C:41]([CH3:42])=[C:40]2[C:34]([O:35][C:36]([CH2:39]2)([CH3:38])[CH3:37])=[C:32]([CH3:33])[C:30]=1[CH3:31])(=[O:27])=[O:28]
Reactant: CC(C)(C)Oc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)O)c(C)c2c1OC(C)(C)C2
Solvent: CN(C)C=O
Product: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)c(C)c2c1OC(C)(C)C2

Procedure:
Commercially available Rink Amide MBHA resin (1 g, 0.45 mmol) was measured and placed in a reaction vessel and swollen with DMF. By a manual solid phase synthesis operation, Tyr(But), Arg(Pbf) were successively condensed, and Fmoc was removed. The resin was washed with DMF, MeOH, and dried to give H-Arg(Pbf)-Tyr(But)-Rink Amide MBHA resin (1.162 g). From the obtained resin, 65.6 mg, 0.025 mmol was measured and placed in a reaction vessel. Gln(Trt), Lys(Mtt) were introduced thereto by manual solid phase synthesis process to give Fmoc-Lys(Mtt)-Gln(Trt)-Arg(Pbf)-Tyr(But)-Rink Amide MBHA resin (SEQ ID NO:175) (Mtt: methyltrityl). The obtained resin was washed with toluene, then TFA-TIS-TFE-toluene (1:5:47:47) was added and the mixture was shaken in the reaction vessel for 10 min. The processing was repeated until the solution was no longer colored with free trityl group to remove Mtt group. The resin was neutralized with 5% DIEA/toluene solution, suspended in toluene:TFE (4:1), N,N-bis-Boc-1-guanylpyrazole (31.0 mg, 0.1 mmol) was added, and the mixture was adjusted to pH 10 with DIEA, and treated overnight at room temperature. After removal of Fmoc from the obtained Fmoc-Har(Boc2)-Gln(Trt)-Arg(Pbf)-Tyr(But)-Rink Amide MBHA resin (SEQ ID NO:157), the resin was treated with Fmoc-Ambz(4)-Arg(Pbf)-Ala-Tyr(But)-Ile-Asn (Trt)-Leu-Ile-Thr (γMe,MePro)-OH (28.4 mg, 0.015 mmol) obtained in Example 3, PyAOP (27.1 mg, 0.05 mmol), 0.5 M HOAt/DMF (0.2 mL, 0.1 mmol), DIEA (34.8 μL, 0.2 mmol) at room temperature overnight. The obtained resin (92.0 mg) was treated with TFA:thioanisole:m-cresol:H2O:EDT:TIS (80:5:5:5:2.5:2.5) (0.6 mL) for 90 min, and diethyl ether was added to the reaction solution to allow precipitation of a white powder. An operation to remove ether by decantation after centrifugation was repeated twice to remove acid and scavenger. The residue was extracted with aqueous acetic acid solution, and purified by preparative HPLC using Daisopak-SP100-5-ODS-P 2×25 cm to give 2.2 mg of a white powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[CH:7]=[C:2]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[CH:4][C:5]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: C1COCCN1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCOCC3)ccc2[N+](=O)[O-])CC1

Procedure:
A suspension of cis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (300 mg, 0.883 mmol) in morpholine (2 mL, 22.93 mmol) was irradiated in a microwave reactor for 1 hour at 150° C. The reaction mixture was partitioned between water and DCM. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to a yellow oil. The residue was concentrated, adsorbed onto a plug of silica gel, and purified by column chromatography, eluting with 0-100% EtOAc in DCM, to provide cis-N-isopropyl-4-(5-morpholino-2-nitrophenylamino)cyclohexanecarboxamide as a yellow powder (0.38 g, 110% yield). MS, m/z (C20H30N4O4): calcd, 390.2. found, 390.9 [M+H].
Reaction SMILES: C(O[C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:9]([O:8][CH2:7][C:6](=[O:12])[C:5]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH:13]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Yield: 80.9 %

Procedure:
One gram of 17α,21-diacetoxy-11β-hydroxy-1,4- pregnadiene-3,20-dione is treated analogously to Example 1 in "Dowtherm" for 50 minutes at 250° C. and worked up. Recrystallization from isopropyl ether yields 700 mg of 21-acetoxy-11β-hydroxy-1,4,16-pregnatriene-3,20-dione (81% of theory).
Reaction SMILES: [C:1](=[O:7])([O:3][CH:4]([CH3:6])[CH3:5])[NH2:2].[C:8](Cl)(=[O:12])/[CH:9]=[CH:10]/[CH3:11].CC(C)([O-])C.[Li+].Cl>C(OCC)C.O1CCCC1>[C:8]([NH:2][C:1](=[O:7])[O:3][CH:4]([CH3:6])[CH3:5])(=[O:12])/[CH:9]=[CH:10]/[CH3:11]
Reactant: CC(C)OC(N)=O
Reactant: C/C=C/C(=O)Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C/C=C/C(=O)NC(=O)OC(C)C
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Isopropyl carbamate (30 g, 291 mmol, available from TCI) was charged to a 3 L Lara vessel and dry Tetrahydrofuran (THF) (150 ml) added. (2E)-2-butenoyl chloride (31.2 ml, 326 mmol, available from Aldrich) was added under nitrogen and the jacket cooled to −30° C. When the solution temperature reached −17° C. 1M Lithium tert-butoxide (655 ml, 655 mmol) was added by peristaltic pump over 2 hours, keeping the reaction temperature between −10° C. and −18° C. Once the addition was complete the mixture was complete the mixture was stirred for 30 mins and brought to 0° C. Diethyl ether (450 ml) and 1M HCl (375 ml) were added and the mixture brought to 20° C. with vigorous stirring. The stirring was stopped, the layers allowed to separate and the aqueous layer run off. Brine (375 ml) was added and the mixture stirred vigorously. The stirring was stopped, the layers allowed to separate and the aqueous layer run off. The organic layer was dried (magnesium sulfate), filtered and evaporated to a brown oil (60 g). The mixture was loaded on to a 40+M Biotage silica column and eluted with DCM:ethyl acetate (1:1 to 0:1, 10 CV). The product containing fractions were evaporated to dryness and loaded on to a 1500 g Redisep Isco silica column and eluted with a gradient of 0 to 40% ethyl acetate in cyclohexane. The clean, product containing fractions were evaporated to an off white solid (15.41 g). LCMS (Method C): Rt=0.68, MH+=172