Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([S:16](Cl)(=[O:18])=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH2:24].O>C(Cl)Cl>[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23][NH:24][S:16]([CH:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:18])=[O:17]
Reactant: CN(C)CCN
Reactant: O=C(OCc1ccccc1)N1CCC(S(=O)(=O)Cl)C1
Solvent: O
Solvent: ClCCl
Product: CN(C)CCNS(=O)(=O)C1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
A solution of 3-chlorosulfonyl-pyrrolidine-1-carboxylic acid benzyl ester (110 mg, 0.362 mmol) in CH2Cl2 (1.5 mL) was added to a solution of N,N-dimethylethylenediamine (0.20 mL, 1.83 mmol) in CH2Cl2 (1 mL) at 0° C. The mixture was stirred at 0° C. for 10 min, and then warmed to room temperature and stirred for 1 hr. Water was added and the phases were separated. The aqueous phase was extracted with CH2Cl2 (2×), the combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum to give benzyl 3-({[2-(dimethylamino)ethyl]amino}sulfonyl)-1-pyrrolidinecarboxylate (102 mg, 88%), which was used in the next step without further purification: 1H NMR (CDCl3) δ 7.36-7.29 (m, 5H), 5.14 (d, J=1.8 Hz, 2H), 3.80-3.72 (m, 4H), 3.50 (m, 1H), 3.16 (br s, 2H), 2.42 (t, J=5.7 Hz, 2H), 2.31 (m, 2H), 2.21 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(O)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.[Fe]>[CH3:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1c([N+](=O)[O-])cc(C)c2ncccc12
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(N)cc(C)c2ncccc12

Procedure:
5,8-Dimethyl-6-aminoguinoline. To a solution of 5,8-dimethyl-6-nitroquinoline (1.41 g) in ethanol (17.4 mL) under argon is added iron (Fe) (1.21 g) and glacial acetic acid (2.56 g). The mixture is refluxed for two hours. More Fe (1.23 g) and glacial acetic acid (2.49 g) are added to the reaction, which is allowed to reflux for an additional hour. The reaction is poured into a beaker of ice and adjusted to pH 10 by careful addition of a saturated solution of potassium carbonate. The product is extracted with methylene chloride and the organic layer is dried over sodium sulfate, filtered, and rotary evaporated to give 5,8-dimethyl-6-aminoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:16][CH:17]=2)[C:12]1=[O:30].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:42][C:43]1[CH:47]=[CH:46][O:45][N:44]=1>C(Cl)Cl.CO.C(OCC)(=O)C>[O:45]1[CH:46]=[CH:47][C:43]([NH:42][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][C:15]([CH2:21][CH2:22][CH2:23][N:24]5[CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)=[CH:16][CH:17]=4)[C:12]3=[O:30])[CH:4]=2)=[N:44]1
Reactant: Cc1ccc(C(=O)O)cc1-n1ccc2ccc(CCCN3CCOCC3)cc2c1=O
Reactant: Nc1ccon1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccon2)cc1-n1ccc2ccc(CCCN3CCOCC3)cc2c1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-methyl-3-[7-(3-morpholin-4-ylpropyl)-1-oxoisoquinolin-2(1H)-yl]benzoic acid (140 mg) in methylene chloride (3 ml) was cooled to 0° C. and oxalyl chloride (59 μl) was added. After the addition of DMF (25 μl), the reaction mixture was stirred at room temperature for 2 hours, 3-aminoisoxazole (126 μl) was added and stirring continued at room temperature for 3.5 hours. The reaction mixture was dissolved in methanol and water and purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give a brown oil. The oil was dissolved in ethyl acetate and the insoluble material was removed by filteration. The filtrate was washed with water, brine, dried (magnesium sulfate) and concentrated to a brown oil. Purification by column chromatography on a silica column eluting using a gradient of ethyl acetate to 10% methanol/ethyl acetate gave N-isoxazol-3-yl-4-methyl-3-[7-(3-morpholin-4-ylpropyl)-1-oxoisoquinolin-2(1H)-yl]benzamide as a yellow foam (55 mg); NMR Spectrum: (DMSOd6) 1.80 (m, 2H), 2.15 (s, 3H), 2.28-2.36 (m, 6H), 2.78 (t, 2H), 3.58 (t, 4H), 6.75 (d, 1H), 7.05 (s, 1H), 7.33 (d, 1H), 7.59 (d, 1H), 7.68 (m, 2H), 8.01 (s, 1H), 8.06 (d, 1H), 8.10 (s, 1H), 8.85 (s, 1H), 11.47 (s, 1H); Mass Spectrum: M+H+ 473.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH2:18]2)[CH:8]=1)[CH2:3][OH:4].C([O-])(=O)C.[K+].O.[N:34]#[C:35]Br>CO>[CH2:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[CH2:21][CH2:22][CH2:23][N:17]1[C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C@H:2]2[CH2:3][O:4][C:35]([NH2:34])=[N:1]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: N[C@H](CO)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: NC1=N[C@@H](CCc2cc(N3CCCc4ccccc4C3)nc3ccccc23)CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.5 %

Procedure:
To the stirred mixture of (2S)-2-amino-4-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]butan-1-ol (110 mg, 0.3 mmol), potassium acetate (90 mg, 0.91 mmol), methanol (8 mL) and water (2 mL) was added a solution of cyanogen bromide (32.3 mg, 0.3 mmol) in cold methanol (2 mL) at 0° C. After the addition, the resulting mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure to give a residue which was purified by preparative HPLC to give 40 mg of product as a white solid (yield was 34.5%). MS obsd. (ESI+) [(M+H)+] 387. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J=7.2 Hz, 1 H), 7.56-7.43 (m, 3 H), 7.17-7.04 (m, 4 H), 5.91 (brs, 1 H), 4.84 (s, 2 H), 4.21 (t, J=8.0 Hz, 2 H), 4.13 (brs, 2 H), 3.87 (t, J=7.2 Hz, 1 H), 3.77 (t, J=7.2 Hz, 1 H), 3.01 (brs, 2 H), 2.94-2.89 (m, 1 H), 1.78 (brs, 2 H), 1.72-1.67 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccncc23)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2cn(S(=O)(=O)c3ccccc3)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-4-piperidinyl)-5-azaindole (20 mg, 0.094 mmol), benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.C1COCC1.[N:42]1[CH:47]=[CH:46][CH:45]=[N:44][C:43]=1[NH2:48].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:48][C:43]4[N:44]=[CH:45][CH:46]=[CH:47][N:42]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: Nc1ncccn1
Reactant: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(C)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ncccn3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (5.00 g, 8.47 mmol), and THF (85 ml). To this, was added pyrimidin-2-amine (1.208 g, 12.71 mmol) and the reaction was cooled to 0° C. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (18.63 ml, 18.63 mmol) was added dropwise and allowed to stir at 0° C. After 1 hour, the mixture was diluted with 1N aq. HCl (10 mL) and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40 g Redi-Sep Gold column, 10-50% of a 3:1 EtOAc/EtOH solution in heptane) to give 1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide (3.54 g, 7.06 mmol, 83% yield) as an off white solid. m/z (ESI) 502.8 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)(=[O:4])=[O:3]>CCOC(C)=O.[Pt]=O>[CH3:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=1[NH2:12]
Reactant: Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(C)(=O)=O)cc1N
Reaction time: 1.25 h
Yield: 99 %

Procedure:
A mixture of 4-methylsulfonyl-2-nitrotoluene (Alfa; 4.00 g; 18.6 mmol) and platinum oxide (120 mg; 0.53 mmol) in EtOAc (200 mL) was hydrogenated in a PARR apparatus at 5 atm for 75 minutes. The mixture was filtered through a pad of celite and the solvent was evaporated to afford the title compound as a colorless oil (3.41 g, 99%).
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[N:11]3[CH:18]=[N:17][CH:16]=[C:12]3[S:13][C:14]=2[CH3:15])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][C:10]1[N:11]2[CH:18]=[N:17][CH:16]=[C:12]2[S:13][C:14]=1[CH3:15]
Reactant: Cc1sc2cncn2c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1sc2cncn2c1CN
Yield: 85.8 %

Procedure:
A 0.42 ml portion of hydrazine hydrate was added to 30 ml of a dry ethanol solution containing 1.7 g of 3-phthalimidomethyl-2-methylimidazo[5,1-b]thiazole, and the mixture was then heated under reflux for 2 hours. The reaction solution was cooled on ice, and the resulting crystal was filtered and then washed with a small amount of cold methanol. The filtrate was concentrated under reduced pressure, and to the resulting residue, dichloromethane was added. The solution was extracted with 1N hydrochloric acid, and the extract was then alkalified with a 1N aqueous potassium hydroxide solution. The organic layer extracted from the aqueous layer with dichloromethane was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was evaporated under reduced pressure to obtain 820 mg of 3-aminomethyl-2-methylimidazo[5,1-b]thiazole as a green powder.
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18](O)=[O:19])[CH2:15][N:16]=1)=[CH:8]2.C[N:31](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[CH3:1][N:2]([S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)(=[O:22])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([NH2:31])=[O:19])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(C)C=O
Reactant: CN(c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(c1cccc2cc(C3=NCC(CC(N)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a mixture of (2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (92 mg) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 4 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (166 mg, yield: 83%) as pale-yellow prism crystals. MS: 430 (MH+). melting point 206-207° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][C@@H:18]([CH2:20][CH2:21][OH:22])[CH3:19])[CH3:14]>C(Cl)Cl>[CH3:19][C@@H:18]1[CH2:20][C:21](=[O:22])[C:15](=[C:13]([CH3:14])[CH3:12])[CH2:16][CH2:17]1
Reactant: CC(C)=CCC[C@H](C)CCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)=C1CC[C@H](C)CC1=O
Yield: 53.1 %

Procedure:
10 l of CH2Cl2 and 1704 g (7.89M) of pyridinium chlorochromate were introduced in a four neck reaction vessel equipped with a mechanical stirrer, a thermometer, a condenser and an inlet tube for nitrogen. To this mixture and under nitrogen, 400 g (2.56M) of (-)-(S)-β-citronellol were added while the temperature was kept at 15°-20°. Stirring was then carried on for 60 h at room temperature. After filtration, the mixture was extracted with CH2Cl2 and the combined organic extracts were washed with 15% HCl, saturated NaHCO3, then with water until neutrality. Evaporation and distillation on residue at 7.8 mmHg gave 206.9 g of (-)-pulegone and (-)-isopulegone (40:60) (yield 37%). B.p. 62°/7.8 mmHg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH:37]=2)=[O:34])=[C:4]([F:50])[CH:3]=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)[CH:37]=2)=[O:34])=[C:4]([F:50])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(CN4CCN(C)CC4)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3cccc(CN4CCN(C)CC4)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Yield: 77.2 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (78 mg, 0.112 mmol) and anisole (60 mg, 0.559 mmol) was stirred in TFA (2 mL) at RT for 2 h. The mixture was concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure and the aqueous residue was treated with satd. NaHCO3. The mixture was extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (50 mg, 76% yield). MS (ESI) m/z: 578.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.[CH3:53][C:54]1[O:58][N:57]=[C:56]([C:59](Cl)=[O:60])[CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:52]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH:46]1[CH2:51][CH2:50][N:49]([C:59]([C:56]2[CH:55]=[C:54]([CH3:53])[O:58][N:57]=2)=[O:60])[CH2:48][CH2:47]1
Reactant: Clc1cnc2nc1Nc1ccc(OCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N2CCC(COc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)no1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(piperidin-4-ylmethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 60% yield. LCMS for C28H29ClN7O3 (M+H)+: m/z=546.2.
Reaction SMILES: [CH:1]([OH:3])=O.Cl.CN(C)CCCN=C=NCC.[C:16]([NH:19][C:20]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:25][CH2:24][N:23]([CH:26]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)[CH2:27][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:29][NH2:30])[CH2:22][CH2:21]1)(=[O:18])[CH3:17].CN1CCOCC1>ClCCl.Cl.O>[C:16]([NH:19][C:20]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH2:21][CH2:22][N:23]([CH:26]([CH2:39][C:40]2[CH:41]=[C:42]([C:50]([F:51])([F:53])[F:52])[CH:43]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:45]=2)[CH2:27][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)[CH2:29][NH:30][CH:1]=[O:3])[CH2:24][CH2:25]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CN)c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: CC(=O)NC1(c2ccccc2)CCN(C(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC(CNC=O)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of formic acid (0.09 mL) in dichloromethane (3 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.23 g) and the mixture stirred for 15 minutes. To this mixture was added a solution of 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butyl amine (0.40) and N-methylmorpholine (0.13 mL) in dichloromethane (5 mL). The mixture was allowed to warm to room temperature overnight, and was diluted with 1N hydrochloric acid (5 mL), dichloromethane, and water (5 mL). The layers were separated and the the aqueous phase was extracted with dichloromethane (10 mL). The combined organic layers were washed (brine), dried, and evaporated to afford material which was purified by chromatography with dichloromethane:methanol (20:1) as eluent, to give a hydrate of the title compound (0.206 g); mp 108-110° C.; NMR: 8.1-7.5 (m,6), 7.3 (m,6), 4.75-4.40 (m,2), 3.75-3.3 (m,4), 3.3-3.0 (m,4), 2.85 (m,1), 1.95 (s,3), 2.25-1.80 (m,4); MS: m/z=688(M+l,100%); TLC: Rf=0.46 (10:1 dichloromethane:methanol). Analysis for C33H33C2F6N3O2.1.50 H2O: Calculated: C, 55.39; H, 5.07; N, 5.87; Found: C, 55.38; H, 4.77; N, 5.84.
Reaction SMILES: C([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])(OC(C)(C)C)=O.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH2:14]([NH:18][C:11](=[O:13])[C@H:9]([CH3:10])[NH2:8])[CH:15]([CH3:17])[CH3:16]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)CNC(=O)[C@H](C)N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Boc-L-alanine (5.0 g, 26.4 mmol), isobutylamine (2.9 mL, 29.1 mmol), diisopropylethylamine (11.5 mL, 66 mmol), and HOBt (3.6 g, 26.4 mmol) in anhydrous DMF (15 mL) is stirred 15 min. EDC is added, and the reaction is stirred at room temperature 16 h. The reaction is diluted in ethyl acetate and washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. The residue is redissolved in 4N hydrochloric acid in dioxane (30 mL) and stirred for 2 h. The solution is concentrated under reduced pressure, dissolved in chloroform and washed with 1 N NaOH (aq). The aqueous layer is extracted with chloroform, and the pooled organics are dried (sodium sulfate), filtered, and concentrated under reduced pressure to give the title compound. ESI MS m/z 145.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([NH2:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:28][CH:27]=1>>[OH:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:31]=1
Reactant: NC(c1ccccc1)c1ccc(O)cc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(c4ccccc4)c4ccc(O)cc4)[C@@]3(C)CC[C@@H]12
Yield: 25 %

Procedure:
The title compound was prepared in a yield of 25% in a similar manner to that described in Example 37 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and α-(4-hydroxyphenyl)benzylamine.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=O)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>O1CCCC1>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][N:39]2[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: CN1CCNCC1
Reactant: NC(=O)Nc1sc(-c2ccccc2C=O)cc1C(N)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccccc2-c2cc(C(N)=O)c(NC(N)=O)s2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
2-[(Aminocarbonyl)amino]-5-[2-formylphenyl]-3-thiophenecarboxamide (0.1 g) and sodium tri-acetoxy borohydride (0.1 g) were mixed with tetrahydrofuran (10 ml). N-Methylpiperazine (0.04 g) was added and the mixture stirred at room temperature for 18 h. Separation was achieved using cation exchange chromatography eluting with ammonia/methanol/dichloromethane mixtures. This gave the title compound (0.07 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[OH:9])=[N:6][CH:7]=1>CCOC(C)=O.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1
Reactant: COc1ccc(C(O)c2ccc(Br)cn2)cc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2ccc(Br)cn2)cc1
Reaction time: 1 h

Procedure:
To a solution of (5-bromo-pyridin-2-yl)-(4-methoxy-phenyl)-methanol (1.0 eq.) in EtOAc (0.2M) was added MnO2 (3.0 eq.). The mixture was stirred for 1 h, filtered on celite and concentrated to afford the title compound as a white solid.