Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH2:32])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:34]1[CH:39]=CC=C[CH:35]=1>>[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH:32][C:14](=[O:16])[C@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[NH:8][CH2:6][C:34]([CH3:39])([CH3:35])[CH3:33])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21

Procedure:
The title compound was prepared by substituting (S)-4-methyl-2-(neopentylamino)pentanoic acid from Step A of Example 244 for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine of Step E from Example 16 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.07-8.09 (m, 1H), 7.43-7.45 (m, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.28 (t, J=7.3 Hz, 1H), 4.43 (p, J=6.2 Hz, 1H), 3.60 (d, J=13.1 Hz, 1H), 3.45 (d, J=13.1 Hz, 1H), 3.26 (dd, J=8.6, 5.6 Hz, 1H), 2.86 (dd, J=8.9, 2.6 Hz, 1H), 2.47-2.60 (m, 2H), 2.42-2.47 (m, 2H), 2.36 (dd, J=9.1, 3.0 Hz, 1H), 2.29-2.35 (m, 1H), 2.29 (dd, J=8.7, 7.3 Hz, 1H), 2.14 (dq, J=12.1, 6.0 Hz, 1H), 1.81-1.95 (m, 2H), 1.52-1.76 (m, 4H), 1.44 (dq, J=13.2, 6.6 Hz, 1H), 0.94 (s, 9H), 0.93 (d, J=6.6 Hz, 3H), 0.87 (d, J=6.5 Hz, 3H); MS (ESI+) m/z 400 (M+H)+.
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[NH2:12])(=O)C.[CH3:13][Mg+].[Br-].[CH2:16]1[CH2:20][O:19]CC1>>[NH2:12][C:6]1[CH:7]=[C:8]([Br:11])[CH:9]=[CH:10][C:5]=1[C:20]([OH:19])([CH3:16])[CH3:13]
Reactant: C1CCOC1
Reactant: CC(=O)Oc1ccc(Br)cc1N
Reactant: C[Mg+]
Agent: [Br-]
Product: CC(C)(O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into the solution of 2-amino-4-bromophenyl acetate (2.3 g) in THF (50 mL) was added 1M solution of MeMgBr in THF (50 mL) at 0° C. Then the reaction mixture was warmed to rt., and stirred for another 2 h. The reaction was quenched by saturated NH4Cl water solution, and extracted with ethyl acetate and washed with brine, after being dried, the solvent was removed to provide 2.3 g crude of 2-(2-amino-4-bromophenyl)propan-2-ol. This product was used in the next step reaction without any purification. LCMS [M+H]+: 231.86. 1H NMR (400 MHz, Chloroform-d) δ 7.26 (s, 1H), 6.95 (d, J=8.1 Hz, 2H), 6.81-6.73 (m, 3H), 1.64 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J19) (210 mg, 0.68 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (220 mg, 0.68 mmol) according to the general procedure M. Obtained as a white foam (260 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[NH:33][CH:34]=[N:35]2>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH:20][C:31]1[N:39]=[CH:38][N:37]=[C:36]3[C:32]=1[N:33]=[CH:34][NH:35]3)[CH3:19])=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)Nc2ncnc3[nH]cnc23)s1
Temperature: 130 °C

Procedure:
To a stirred solution of (1S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)-quinolin-3-yl)ethanamine (9 mg, 30 μmol) in 1-butanol (1.5 mL) was added huenig's base (6 μl, 35 μmol) and 6-chloropurine (5 mg, 30 μmol). The reaction was heated to 130° C. for 16 hours and then cooled to room temperature. The crude reaction mixture was purified by reverse phase HPLC (gradient: 20% water in acetonitrile to 85% water in acetonitrile) to give N-((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.62 (1H, s), 8.05 (1H, s), 7.83-7.89 (2H, m), 7.53-7.57 (1H, m), 2.89 (3H, s), 1.83 (3H, d, J=6.6 Hz). Mass Spectrum (ESI) m/e=423.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:10])[CH3:9].Cl.[N:26]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[CH2:35]([O:37][C:38](=[O:51])[NH:39][C:40](=[O:50])[CH2:41][C:42]([NH:44][C:45](=[O:49])[O:46][CH2:47][CH3:48])=[O:43])[CH3:36]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:24][N:26]=[C:41]([C:42]([NH:44][C:45](=[O:49])[O:46][CH2:47][CH3:48])=[O:43])[C:40]([NH:39][C:38](=[O:51])[O:37][CH2:35][CH3:36])=[O:50])[CH:5]=[C:6]([Cl:23])[C:7]=1[C:8]([C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[O:13][N:12]=1)([CH3:10])[CH3:9]
Reactant: Cc1ccccc1-c1nc(C(C)(C)c2c(Cl)cc(N)cc2Cl)no1
Reactant: CCOC(=O)NC(=O)CC(=O)NC(=O)OCC
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)NC(=O)C(=NNc1cc(Cl)c(C(C)(C)c2noc(-c3ccccc3C)n2)c(Cl)c1)C(=O)NC(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of intermediate (19) (0.0302 mole) and concentrated HCl (0.0906 mole) in acetic acid (100 ml) was stirred at 0° C. A solution of NaNO2 (0.032 mole) in water (10 ml) was added dropwise at 0° C. The reaction mixture was stirred for 1 hour at 0° C. A powdered mixture of sodium acetate (0.0906 mole) and diethyl(1,3-dioxo-1,3-propanediyl)biscarbamate (0.0332 mole) was added portionwise. The mixture was allowed to warm to RT and stirred for 1 hour. Water was added and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated, yielding diethyl N,N′-[2-[[3,5-dichloro-4-[1-[5-(2-methylphenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl]phenyl]hydrazono]-1,3-dioxo-1,3-propanediyl]dicarbamate (intermediate 20).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:7][O:6][C:5]([CH3:8])=[N:4]1.C([O-])([O-])=O.[Cs+].[Cs+].[O:24]([CH2:31][CH2:32]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOC(C)=O>CN(C=O)C.O>[CH3:8][C:5]1[O:6][CH2:7][C:3]([CH2:2][OH:1])([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:32][CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][CH:16]=2)[N:4]=1
Reactant: CC1=NC(CO)(CCc2ccc(O)cc2)CO1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1=NC(CO)(CCc2ccc(OCCOc3ccccc3)cc2)CO1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (300 mg, 1.27 mmol) in DMF (5 ml) was added Cs2CO3 (1.2 g, 3.83 mmol) and 2-phenoxyethyl bromide (770 mg, 1.27 mmol). The reaction mixture was stirred at 85° C. for 4 hours. AcOEt and water were then added, the organic layer was separated and the aqueous phase was extracted with AcOEt (3×50 ml). The combined organic extracts were washed with brine, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (AcOEt/Hx 9:1) afforded (2-Methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil. To a solution of (2-methyl-4-{2-[4-(2-phenoxy-ethoxy)phenyl]-ethyl}-4,5-dihydro-oxazol-4-yl)-methanol (50 mg, 0.14 mmol) in ethanol (2 ml) was added conc. HCl (2 ml). The reaction mixture was stirred at 85° C. for 2 hours, then concentrated to dryness. The residue was re-dissolved in AcOEt and precipitated with hexanes. The solid was filtered off, washed with dry ether and dried in vacuo to afford 2-amino-4-{4-[2-phenoxy-ethoxy]-phenyl}-2-ethoxy-butan-1-ol hydrochloride as a colorless powder. ESI+MS: m/z=332.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][O:6][C:7]([C:9]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8].C(O)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2cccc(Cl)c2)C1c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1cccc(Cl)c1
Yield: 70 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 3-chlorobenzyl ester in 120 ml of pyridine gave 2,6 dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3-chlorobenzyl ester of melting point 142° C (from ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]1)[N:6]=[CH:5]2.[OH-].[Na+].Cl>CO.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]1)[N:6]=[CH:5]2
Reactant: COC(=O)C1CCN(c2ncc3cc(O)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)C1CCN(c2ncc3cc(O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
To a solution of methyl 1-(6-hydroxyquinazolin-2-yl)piperidine-4-carboxylate (330 mg, crude from above) in MeOH (10 mL) was added aqueous NaOH (10 mL, 2M). The mixture was stirred at 25° C. for 16 hours. The reaction mixture was acidified with 1N HCl to pH=1-2, then concentrated to give a residue, which was diluted with EtOAc (100 mL), filtered and concentrated to give the crude product which was purified by prep-HPLC (0.1% TFA as additive). Most of the solvent was removed in vacuo followed by lyophilization to give the product (70 mg, 2-step yield: 19%) as a solid. 1H NMR (DMSO-d6 400 MHz): δ 9.15 (s, 1H), 7.51 (d, J=9.2 Hz, 1H), 7.37 (dd, J=9.2, 2.8 Hz, 1H), 7.13 (d, J=2.8 Hz, 1H), 4.59 (d, J=13.2 Hz, 2H), 3.16 (t, J=11.4 Hz, 2H), 2.68-2.52 (m, 1H), 1.93 (dd, J=13.2, 3.2 Hz, 2H), 1.62-1.48 (m, 2H). MS (ESI): m/z 274.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](Cl)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.[C:18]([O-:21])([O-])=O.[K+].[K+].O.C[N:26]([CH:28]=O)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:26][CH2:28][C:2]4[CH:7]=[CH:6][C:5]([O:21][CH3:18])=[CH:4][CH:3]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: N#Cc1cnc(Cl)c2c1sc1cc(Br)ccc12
Agent: [K+]
Solvent: O
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-bromo-1-chloro[1]benzothieno[3,2-c]pyridine-4-carbonitrile, 4-methoxybenzyamine (1 equiv) and K2CO3 (1 equiv) in DMF (0.3 M) was heated to 100° C. for 1 h. The mixture was poured into H2O, stirred for 15 min and filtered. The crude product was air dried over night and then heated to reflux in EtOH for 1 h, filtered and washed with EtOH to give the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(Cl)(=O)C1C=CC=CC=1.[NH2:14][C:15]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2>CC(C)=O>[CH3:26][O:25][C:24]1[C:15]([NH:14][C:2]([NH2:3])=[S:1])=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][CH:18]=[CH:17]2
Reactant: COc1ccc2ncccc2c1N
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc2ncccc2c1NC(N)=S

Procedure:
1.7 g or ammonium thiocyanate are dissolved in 50 ml of acetone, 2.5 ml of benzoyl chloride are then added and the reaction mixture is heated at reflux for 15 minutes. 2.9 g of amine (Compound 14), dissolved in 20 ml of acetone, are added and the reaction mixture is then heated to reflux for 30 minutes. Evaporation is carried out to dryness and the residue is taken up in water and then extracted with ethyl acetate. The residue is deprotected by treatment with 5 ml of 33% ammonia in 10 ml of ethanol at reflux for 2 hours. The precipitate formed is separated off by filtration, the filtrate is evaporated and the residue is triturated with a 75/25 (v/v) ethyl acetate/hexane mixture, to obtain 3.5 g of white powder. 1H NMR (CDCl3): 3.93 (s, 3H, --OCH3), 7.50-7.53 (m, 1H, H3), 7.70 (d, 1H, J=9.5, 1H, H7), 8.00 (d, J=9.5, 1H, H4), 8.08 (d, 1H, H8), 8.75 (d, J=2.5, 1H, H2).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:15]2[C@@H:6]([CH2:7][CH2:8][C:9]3[C@:14]2([CH3:16])[CH2:13][CH:12]([CH:17]=O)[C:11](=O)[CH:10]=3)[C@@H:5]2[CH2:20][CH2:21][C@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@@:4]2([CH3:31])[CH2:3]1.[NH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=[O:38])[NH2:33].C([O-])(=O)C.[K+].Cl>C(O)C.O>[OH:1][C@H:2]1[C@@H:15]2[C@H:6]([CH2:7][CH2:8][C:9]3[C@@:14]2([CH3:16])[CH2:13][C:12]2[CH:17]=[N:33][N:32]([C:34]4[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=4)[C:37]([OH:39])=[O:38])[C:11]=2[CH:10]=3)[C@H:5]2[CH2:20][CH2:21][C@@:22]3([C:26]4([CH2:30][O:29][CH2:28][O:27]4)[O:25][CH2:24][O:23]3)[C@:4]2([CH3:31])[CH2:3]1
Reactant: NNc1cccc(C(=O)O)c1
Reactant: C[C@]12CC(C=O)C(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@@]21OCOC12COCO2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@@]12Cc3cnn(-c4cccc(C(=O)O)c4)c3C=C1CC[C@H]1[C@H]2[C@H](O)C[C@]2(C)[C@@H]1CC[C@]21OCOC12COCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
(8S,9S,10R,11S,13S,14S,17R)-11-hydroxy-10,13-dimethyl-3-oxo-1,2,3,6,7,8,9,10,11,12,13,14,15,16-tetradecahydrodispiro[cyclopenta[a]phenanthrene-17,4′-[1,3]dioxolane-5′,4″-[1,3]dioxolane]-2-carbaldehyde (Steroids 2003, (68), 177-191) (1.4 g, 3.24 mmol) was dissolved in ethanol (10 ml) and water (1 ml). 3-hydrazinobenzoic acid (0.493 g, 3.24 mmol) and potassium acetate (0.491 g, 5 mmol) were added to give a brown solution which was stirred for 1 hour at room temperature. The mixture was poured into a separation funnel containing 1M HCl (200 ml) and was extracted with DCM (3 times 150 ml). The combined organic phases were washed with water (2 times 100 ml) and 1M NaOH. The organic phase was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to give 1.9 g of a brownish foam. The crude product was purified on a silica gel column (Heptane:EtOAc=1:1) and the product containing fractions were evaporated under reduced pressure to yield 1.5 g of the desired compound. APCI-MS m/z: 549 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:3]=1.[CH2:17]1[O:26][C:25]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=2[O:18]1>>[O:26]1[C:25]2[CH:24]=[CH:23][C:21]([NH:22][C:2]3[N:3]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=4)[N:5]=[C:6]([Cl:8])[N:7]=3)=[CH:20][C:19]=2[O:18][CH2:17]1
Reactant: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: Nc1ccc2c(c1)OCO2
Product: Clc1ccc(Nc2nc(Cl)nc(Nc3ccc4c(c3)OCO4)n2)cc1
Yield: 65 %

Procedure:
The reaction of 4,6-dichloro-N-(4-chlorophenyl)-[1,3,5]triazine-2-amine with 3,4-methylenedioxyaniline using the method described for the synthesis of CT-116433 provided CT-31978 (56 mg, 65% yield). 1H NMR (d6-DMSO) δ 10.08–10.37 (m, 2 H), 7.58–7.87 (m, 2 H), 7.21–7.40 (m, 3 H), 6.85–7.03 (m, 2 H), 6.00 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[C:10]1[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].N1C2C(=CC=CC=2)C=CC=1.Cl>O.N1C=CC=CC=1>[O:20]=[C:19]1[C:17]2[CH:18]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][C:16]=2[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: Nc1ccccc1S
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 180 °C
Yield: 117 %

Procedure:
A mixture of 2-amino-benzenethiol (1.34 mL, 12.5 mmol), 2-bromo-terephthalic acid (1.54 g, 6.3 mmol), cuprous oxide (0.50 g, 3.5 mmol), quinoline (6.3 mL), and pyridine (0.63 mL) was heated in a 180° C. oil bath under nitrogen for 20 hours, then cooled to room temperature. Concentrated hydrochloric acid (20 mL) was added slowly while cooling in cold water, with stirring. The resulting precipitate was filtered, washed with water, and dried to give crude title compound (2 g). LC-MS: m/z 270 (M−1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[CH:14]([CH2:15][C:16](=[O:24])[CH:17]=[CH:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH2:25]1COC[CH2:26]1.C([Al](CC)CC)C.C[Si](Cl)(C)C>C1(C)C=CC=CC=1>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[CH:14]([CH2:15][C:16](=[O:24])[CH2:17][C@@H:18]1[CH2:25][CH3:26])[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: CC[Al](CC)CC
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Product: CC[C@H]1CC(=O)CC2CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@]21C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.31 g (10 mmol) of 17β-acetoxy-androst-1-en-3-one and 143 mg (1 mmol) of CuBr are introduced into 15 ml of dry THF. 5.79 ml (11 mmol) of a 1.9 molar solution of triethylaluminum in toluene as well as 2.16 g (20 mmol) of trimethylsilyl chloride are added at 0° C. It is stirred for 1 hour at room temperature, then hydrolyzed with 10 ml of 2N hydrochloric acid and the product is extracted with methyl tert-butyl ether. After evaporation of the solvent and recrystallization from acetone, 3.2 g of 17β-acetoxy-1α-ethylandrostan-3-one (90% of theory) of melting point 159° C. is obtained.
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH:5]([CH2:24][O:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=[O:22])[CH2:10][S:9]1=[O:23]>CCOCC>[OH:4][CH:5]([CH2:24][O:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:3])=[O:20])[C:11](=[O:22])[CH2:10][S:9]1=[O:23]
Reactant: CCCOCC(O)CCC1N(CCCCCCC(=O)O)C(=O)CS1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: CCCOCC(O)CCC1N(CCCCCCC(=O)OC)C(=O)CS1=O
Reaction time: 4 h

Procedure:
A solution of diazomethane (approximately 2.5 g., 0.06 mole) in ether (100 ml.) is slowly added to a solution of 7-[2-(3-hydroxy-4-propoxybutyl)-1,4-dioxo-3-thiazolidinyl]heptanoic acid (11.3 g., 0.03 mole) in ether (50 ml.) with stirring and cooling (0° to 5° C.). The resulting solution is allowed to warm to and stand at room temperature for 4 hours. After destroying excess diazomethane with acetic acid, the reaction solution is washed with 5% sodium bicarbonate solution and water, dried over sodium sulfate, and filtered. In vacuo evaporation of the filtrate leaves the title compound as an essentially colorless, viscous oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][C:35]1([CH3:38])[CH2:37][O:36]1>CC#N>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH2:34][C:35]([CH3:38])([OH:36])[CH3:37])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC1(C)CO1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Solvent: CC#N
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(CC(C)(C)O)C3)n(C)c2n1
Temperature: 80 °C
Reaction time: 20 h
Yield: 27.1 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in MeCN (2 mL) was added 2,2-dimethyloxirane (198 μL, 2.23 mmol) and the resulting mixture stirred at 80° C. for 3 h before the addition of further 2,2-dimethyloxirane (1.0 mL, 11.15 mmol). The reaction mixture was stirred at 80° C. for a further 20 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with Et2O and the resulting solid dried in vacuo affording 833 (31 mg, 27%). LCMS (method I): RT 2.59 min, [M+H]+ 521.3. 1H NMR (DMSO, 400 MHz): δ 8.04-8.04 (1 H, m), 7.66-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.29 (4 H, brd s), 4.07 (1 H, s), 3.99 (2 H, d, J=8.32 Hz), 3.80 (4 H, t, J=4.57 Hz), 3.70 (3 H, s), 3.52 (2 H, d, J=8.34 Hz), 3.34-3.19 (2 H, m), 3.02 (3 H, s), 2.43 (2 H, s), 1.34 (3 H, t, J=7.43 Hz), 1.05 (6 H, s)
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[N:8]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[C@:7]2([C:22]3[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=3)[N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]2=[O:32])[C@@H:6]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=2)[CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:41].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH2:59].C(Cl)(Cl)(Cl)Cl.CC#N>O.[Ru](Cl)(Cl)Cl>[Cl:23][C:19]1[CH:18]=[C:17]2[N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:15](=[O:32])[C@:7]3([C@@H:6]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[CH2:5][C@H:4]([CH2:1][C:2]([OH:41])=[O:59])[C:9](=[O:10])[N:8]3[CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:22]2=[CH:21][CH:20]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(COCC[Si](C)(C)C)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)C[C@H](CC(=O)O)C(=O)N2CC1CC1
Reaction time: 19 h

Procedure:
To a rapidly stirred solution of (rac) (2′S,3′R,5′S)-5′-allyl-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step J) (46 mg, 0.079 mmol) in H2O/CCl4/MeCN (0.75 ml/0.5 mL/0.5 mL) was added sodium periodate (67.2 mg, 0.314 mmol) and ruthenium(III) chloride hydrate (1.771 mg, 7.85 μmol). The reaction mixture was stirred vigorously for 19 h and then acidified (10% citric acid) and filtered through a plug of celite and washed with EtOAc. The filtrate was transferred to a separatory funnel and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide the title compound.