Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].O([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N+:33]([O-:44])=[CH:32][N:31]=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:19]([NH:18][C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:41])[F:42])[CH:38]=3)[N+:33]([O-:44])=[CH:32][N:31]=2)[C:3]1=[O:22])(=[O:21])[CH3:20]
Reactant: [O-][n+]1cnc(Oc2ccccc2)c2cc(C(F)(F)F)ccc21
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2nc[n+]([O-])c3ccc(C(F)(F)F)cc23)C1=O
Temperature: 120 °C
Yield: 110.5 %

Procedure:
Example 5, Alternative Preparation, Step 3: To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide (50 mg, 0.161 mmol; see Example 1, Step 10) and 4-phenoxy-6-(trifluoromethyl)quinazoline 1-oxide (99 mg, 0.161 mmol) in i-PrOH (2 ml) was added N,N-diisopropylethylamine (0.056 ml, 0.322 mmol). The vessel was sealed under argon and heated in a microwave for 1 hr at 120° C. LC/MS found: (M+H)+=523.3 as the major product peak. The mixture was concentrated and purified by automated flash chromatography (40 g silica gel, eluting with 8:92 10% cNH4OH/MeOH). The fractions containing the desired product were pooled and concentrated in vacuo. The residue was crystallized from CH2Cl2 and hexane. The two crops were combined and dried under vacuum to afford the title compound, 4-((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylamino)-6-(trifluoromethyl)quinazoline 1-oxide (93 mg). Analysis by 1H-NMR showed that this material contained ˜0.75 molar equivalents of CH2Cl2. 1H-NMR (400 MHz, d4-MeOH): δ 8.99 (s, 1H), 8.81 (s, 1H), 8.62 (d, J=8.9 Hz, 1H), 8.32 (dd, J=9.0, 1.5 Hz, 1H), 5.28 (t, J=8.4 Hz, 1H), 4.59 (br s, 1H), 4.05 (m, 1H), 3.55-3.65 (m, 2H), 3.43 (m, 1H), 2.75 (br s, 1H), 2.55 (m, 1H), 2.27 (s, 3H), 2.1-2.3 (m, 3H), 2.02 (s, 3H), 2.0 (m, 1H), 1.65-1.7 (m, 3H), 1.12 (d, J=6.0 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H). LC/MS found: [M+H]+=523.33.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH2:3][C:2]1=O.F[B-](F)(F)F.C[O+](C)C.[NH:20]([C:22](OC)=[O:23])[NH2:21]>C(Cl)Cl>[CH3:9][O:8][C:6]([CH:5]1[N:1]2[C:2](=[N:21][NH:20][C:22]2=[O:23])[CH2:3][CH2:4]1)=[O:7]
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: COC(=O)NN
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCc2n[nH]c(=O)n21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A portion of (S)-methyl 2-pyrrolidone-5-carboylate (3.00 g, 0.021 mol) was dissolved in DCM (105 mL) and treated with trimethyloxonium tetrafluoroborate (3.10 g, 0.021 mol). The mixture was stirred at room temperature for 24 h. The mixture was concentrated in vacuo. The oil was dissolved in DMF (100 mL). Methyl hydrazinocarboxylate (2.00 g, 0.022 mol) was added and the solution was heated to reflux using a Dean-Stark trap for 24 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography (silica gel, using a gradient of DCM:MeOH 95:5 to 90:10) to provide 3-Oxo-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazole-5-carboxylic acid methyl ester. 1H NMR (300 MHz, CDCl3) δ 4.68-4.72 (m, 1H), 3.82 (s, 3H), 2.75-2.99 (m, 4H); MS (ES+) 184.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16]
Reactant: COc1c(Cl)ccc2oc(C(=O)O)c(C)c12
Agent: B
Solvent: C1CCOC1
Product: COc1c(Cl)ccc2oc(CO)c(C)c12
Reaction time: 8 h
Yield: 99 %

Procedure:
To 0.31 g (1.3 mmol) 5-chloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid (Example 116, Step 3) in 10 mL of THF under nitrogen was added 1.0M BH3/THF solution (1.8 mL; 1.8 mmol; 1.4 eq). The reaction was stirred overnight and then quenched cautiously with water and extracted twice with ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide and then brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give (5-chloro-4-methoxy-3-methyl benzofuran-2-yl)-methanol as a white crystalline solid (0.29 g; 99% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14](Cl)([Cl:16])=[O:15].CN(C)C1C=CC=CC=1.O>C1(C)C=CC=CC=1.C(OCC)C.C1(C)C=CC=CC=1>[Cl:16][C:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:15]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Solvent: O
Product: O=C(Cl)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Hydroxybiphenyl (2.62 g, 15.4 mmol) in absolute toluene/diethyl ether (60/30 mL) was added dropwise in the space of 30 minutes, with ice cooling, to a solution of phosgene (1.98 g, 20 mmol) in absolute toluene (20 mL). Then, at −3° C., N,N-dimethylaniline (1.86 g, 1.95 mL, 15.4 mmol) in absolute toluene (10 mL) was added dropwise and it was stirred overnight, while slowly warming to room temperature. After cooling to 0° C. again, water (30 mL) was slowly added dropwise, then the organic phase was washed with 0.1N HCl, 0.1N NaOH and water (each 2×100 mL), dried over sodium sulphate and concentrated under vacuum.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([NH:23][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Brc1ccc(OC2CN3CCC2CC3)cc1
Reactant: NC1CCCCC1
Product: c1cc(OC2CN3CCC2CC3)ccc1NC1CCCCC1

Procedure:
The product of Example 21A (281 mg, 1.0 mmol) was treated with cyclohexylamine (Aldrich, 150 mg, 1.5 mmol) according to the procedure of Example 17A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:2, Rf. 0.10) as oil (130 mg, yield, 43%). 1H NMR (MeOH-d4, 300 MHz) δ 1.06–1.45 (m, 6H), 1.60–1.90 (m, 5H), 1.93–2.05 (m, 3H), 2.18–2.37 (m, 2H), 3.05–3.28 (m, 5H), 4.30–4.40 (m, 1H), 6.65 (d, J=8.8 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH3) m/z 301 (M+H)+.
Reaction SMILES: [C:1]([C:7]1[N:8]=C(N)C2N=CN(C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[I:26][C:27]1[N:28]=[C:29]([NH2:45])[C:30]2[N:31]=[CH:32][N:33]([C:43]=2[N:44]=1)[C@@H:34]1[O:42][C@H:39]([CH2:40][OH:41])[C@@H:37]([OH:38])[C@H:35]1[OH:36].C#CCCCC>>[I:26][C:27]1[N:28]=[C:29]([NH2:45])[C:30]2[N:31]=[C:32]([NH:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:33]([C:43]=2[N:44]=1)[C@@H:34]1[O:42][C@H:39]([CH2:40][OH:41])[C@@H:37]([OH:38])[C@H:35]1[OH:36]
Reactant: CCCCC#Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: C#CCCCC
Product: Nc1nc(I)nc2c1nc(NCc1ccccc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
2-(1-hexynyl)adenosine (Compound 3).8 The reaction was performed with 2-iodoadenosine (1, 255 mg, 0.65 mmol) and 1-hexyn (3.15 mmol). The mixture was purified by column chromatography (5% MeOH in CH2Cl2). Yield 192 mg (0.55 mmol, 85%), mp 106–109÷C; Rƒ 0.10 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 8.37 (s, 1H, H-8), 7.41 (bs, 2H, NH2), 5.84 (d, J=6.18 Hz, 1H, H-1′), 5.45 (d, J=6.18 Hz, 1H, OH-2′), 5.22–5.16 (m, 1H, OH-5′), 5.22–5.16 (m, 1H, OH-3′), 4.52 (q, J=5.15 Hz, 1H, H-2′), 4.11 (q, J=3.43 Hz, 1H, H-3′), 3.93 (pd, J=3.43 Hz, 1H, H4′), 3.65–3.48 (m, 2H, H-5′), 2.39 (t, J=6.86 Hz, 2H, ≡CCH2), 1.51–1.39 (m, 4H, CH2CH2), 0.90 (t, J=6.87 Hz, 3H, CH3); MS m/z 348 (M+H)+; Anal. (C16H21N5O4 0.22 CH2Cl2) C, H, N.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]([OH:22])[CH2:20][OH:21])=[C:16]([Cl:23])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:21][CH2:20][CH:19]([OH:22])[CH2:18][C:17]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]3[C:14](=[CH:15][C:16]=2[Cl:23])[CH2:13][CH2:12][CH2:11]3)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)Cc1c(Cl)cc2c(c1OCc1ccccc1)CCC2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)Cc2c(Cl)cc3c(c2OCc2ccccc2)CCC3)cc1
Yield: 77 %

Procedure:
Treatment of (±)-3-[4-(benzyloxy)-6-chloro-2,3-dihydro-1H-inden-5-yl]propane-1,2-diol (5.60 g, 0.0168 mol) with p-toluenesulfonyl chloride (3.70 g, 0.0194 mol) in pyridine (200 mL) generally according to the procedure described for Intermediate 18 provided 6.30 g (77%) of (±)-3-[4-(benzyloxy)-6-chloro-2,3-dihydro-1H-inden-5-yl]-2-hydroxypropyl 4-methylbenzenesulfonate as a light yellow oil. 1H NMR (DMSO-d6) 8H 7.65(d, 2H); 7.40(m, 7H); 7.05(s, 1H); 5.25(s, 1H); 4.90(s, 2H); 3.80(m, 3H); 2.90(m, 2H); 2.80(m, 3H); 2.65(dd, 1H); 2.40(s, 3H); 2.00(m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[C:33]=2[F:39])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:40]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=4)[NH:23][C:22]3=[O:31])[CH:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[C:33]=2[F:39])=[O:11])=[CH:7][CH:8]=1)(=[O:40])[NH2:2]
Reactant: OO
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.16 g, 0.26 mmol) prepared in Example 98 in DMSO (1 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.45 g, 3.9 mmol), then aqueous solution (1N) of NaOH (1.3 mL, 1.3 mmol) was added dropwise. The reaction mixture was stirred at 10° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.14 g, 85%)
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23].Cl.[OH-].[Na+]>C1COCC1>[CH:1]1([NH:4][C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: COC(=O)CCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCCCCC(=O)NC1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
All reactions reported in this invention were carried in oven-dried three-necked, round-bottomed flasks equipped with a Teflon-coated magnetic stirring bar. The reaction flask was purged with nitrogen, and during the entire operation, the reaction was under nitrogen. To a stirred solution of cyclopropanamine (0.615 g, 10.78 mmol) in 25 mL of dried THF, triethylamine (1.20 g, 11.90 mmol) was added in one portion. After the reaction had been cooled to about 0° C., methyl 10-chloro-10-oxodecanoate (2.53 g, 10.78 mmol) in 5 mL of THF was added dropwise via an addition funnel. After the addition, the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was subjected to roto-vap distillation to remove the majority of solvent, and the residue was poured with stirring into a mixture of ice-water containing 10 mL of HCl aqueous 2N solution (20 mmol) leading to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min, and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was washed with two 50-mL portions of water. The NMR analysis of a dried sample of the material confirmed the structure of the desired ester. The GC retention time of the ester is 12.79 min. The ester was saponified with 20 mL of NaOH aqueous 2N solution (40 mmol) at room temperature overnight. Ice was added to the reaction and acidification with a 30 mL of HCl aqueous 2N solution (60 mmol) led to the immediate precipitation of a white solid. Stirring was continued for an additional 30 min, and then the precipitation was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with three 50-mL portions of water, and two 25-mL portions of hexane. The collected solid was dried in vacuo for two days at ambient temperature to afford 1.81 g (70%) of 10-(cyclopropylamino)-10-oxodecanoic acid as a white solid. HPLC: Rt: 3.52 min. 1H NMR (400 MHz DMSO-d6) δ: 0.25 (m, 2H), 0.48 (m, 2H), 1.14 (m, 9H), 1.37 (m, 4H), 1.89 (m, 2H), 2.09 (m, 2H), 7.70 (br. s, 1H), 1.850 (s, 1H). 13C NMR (100 MHz DMSO-d6) δ: 5.60(C2 & C3), 22.0(C8), 24.46(C13), 25.18(C1), 28.63(C9, C10, C11 & C12), 33.64(C14), 35.0(C7), 173.2(C5), 174.45(C15). LC/MS m/z: 242 [(M+1)+].
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH2:17].CC(O)=O.[BH3-]C#N.[Na+]>ClCCCl>[CH2:2]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:17][NH:16][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NNC1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A mixture of 1-benzylpiperidin-3-one hydrochloride (1.00 g, 4.10 mmol), tert-butyl hydrazinecarboxylate (0.596 g, 4.51 mmol), and AcOH (0.470 mL, 8.21 mmol) in DCE (20 mL) was stirred at ambient temperature for about 1 h then NaCNBH3 (0.258 g, 4.10 mmol) was added. The reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (50 mL). The organic layer was separated, concd under reduced pressure and purified by RP-HPLC (Table 1, Method h) to afford tert-butyl 2-(1-benzylpiperidin-3-yl)hydrazinecarboxylate (1.25 g, 100%) as a clear oil: LC/MS (Table 1, Method b) Rt=1.66 min; MS m/z: 306 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>FC(F)(F)C(O)=O>[F:12][C:11]1[C:10]([N+:15]([O-:17])=[O:16])=[C:9]2[C:4](=[CH:3][C:2]=1[F:1])[NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2
Reactant: O=c1[nH]c2cc(F)c(F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 55 °C
Reaction time: 20 h
Yield: 68.1 %

Procedure:
To a suspension of 6,7-difluoro-1,4-dihydro-2,3-quinoxalinedione (837 mg, 4.23 mmol) in trifluoracetic acid (30 mL) was added KNO3 (5 12 mg, 5.07 mmol). The mixture was stirred at 55 ° C. for 20 h at the end of this time, 256 mg (2.50 mmol) of KNO3 was added and the reaction mixture was stirred at 55° C. for 20 h, then another 256 mg (2.50 mmol) of KNO3 was added and the mixture was stirred at 55° C. for 20 h. The reaction mixture was then rotaevaporated to dryness. To the residual solid was added ice-cold water (about 15 mL), the solid was collected by vacuum filtration, washed with ice-cold water (5×5 mL), and dried at 40° C. under 1 mm Hg for 14 h, giving 700 mg (68%) of the title compound as a yellow powder. Mp 288°-90° C. (dec.). IR (KBr) 3424, 3226, 1752, 1717, 1554, 1356, 1304 cm-1. 1H NMR (DMSO-d6): 12.249 (s, 1H), 11.864 (bs, 1H), 7.330 (dd, 1H, J=10.5, 7.8 Hz). Analysis for C8H3F2N3O4, calcd: C, 39.50, H, 1.24, N, 17.29; found: C, 39.42, H, 1.26, N, 17.08.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:13]([CH3:32])[C:14]([N:16]([CH3:31])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][Si](C)(C)[N-][Si](C)(C)C.[K+].CI.C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]([F:33])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([CH3:35])([CH3:32])[C:14]([N:16]([CH3:31])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]([CH3:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(C(=O)N(C)c1ccccc1N(C)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1N(C)c1ccccc1

Procedure:
To a solution of 52 mg (0.11 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[2-(methyl-phenyl-amino)-phenyl]-propionamide in 0.5 ml N,N-dimethylformamide at 0° C. were added 32 mg (0.16 mmol) potassium hexamethyldisilazide. Stirring was continued for 1 h at this temperature and 30 mg (0.16 mmol) methyl iodide were added. After stirring for 3 h at room temperature, ethyl acetate was added. The mixture was washed with brine, dried (magnesium sulfate) and evaporated. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 54 mg (quantitative) of the title compound as colourless oil.
Reaction SMILES: [Cl-].[Li+].BrCCBr.Cl[Si](C)(C)C.II.I[C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]1.Br[C:25]1[C:26]([CH3:37])=[N:27][N:28]2[C:33]=1[C:32]1[S:34][CH:35]=[CH:36][C:31]=1[N:30]=[CH:29]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1COCC1.C1(C)C=CC=CC=1.[Zn]>[CH3:37][C:26]1[C:25]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]2)=[C:33]2[N:28]([CH:29]=[N:30][C:31]3[CH:36]=[CH:35][S:34][C:32]=32)[N:27]=1
Reactant: Cc1nn2cnc3ccsc3c2c1Br
Reactant: N#CC[C@H]1CC[C@H](I)CC1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)Cl
Agent: II
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: BrCCBr
Product: Cc1nn2cnc3ccsc3c2c1[C@H]1CC[C@H](CC#N)CC1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A microwave tube equipped with a magnetic stir bar and a rubber septum was charged with lithium chloride (44.9 mg, 1.06 mmol). The vial was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen after cooling to room temperature. Zinc (69.3 mg, 1.06 mmol) was added and the vial was heated at 140° C. for 10 min under high vacuum and backfilled with nitrogen. After cooling to room temperature, THF (0.6 mL) and 1,2-dibromoethane (3.4 μL, 0.040 mmol) was added via syringe. The mixture was heated at 60° C. for 10 min and then cooled to room temperature. Chlorotrimethylsilane (0.99 μL, 0.0078 mmol) and iodine (1.0 mg, 0.0039 mmol) in THF (0.2 mL) was added and stirred at 60° C. for 10 min and cooled to room temperature. (trans-4-Iodocyclohexyl)acetonitrile (132 mg, 0.53 mmol) in THF (0.2 mL) was then added, and the mixture stirred at 50° C. overnight. 9-Bromo-8-methylpyrazolo[1,5-c]thieno[2,3-e]pyrimidine (80.2 mg, 0.299 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (29 mg, 0.072 mmol) in toluene (0.2 mL) were added to a microwave vial. The vial was evacuated under high vacuum and backfilled with nitrogen. The mixture was cooled to 0° C. and the zinc reagent was added slowly via syringe. After addition, the reaction was heated to 60° C. overnight and partitioned between EtOAc and saturated NH4Cl solution. The layers were separated and the aqueous extracted further with ethyl acetate (2×). The combined organics were washed with water and brine, dried over MgSO4, and concentrated. The residue was dissolved in methanol and purified with preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give a colorless solid (5.3 mg, 5.7%). LCMS calculated for C17H19N4S (M+H)+: m/z=311.1. Found: 311.1. 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.59 (m, 1H), 7.49 (m, 1H), 2.90 (m, 1H), 2.51 (s, 3H), 2.36 (d, J=6.5 Hz, 2H), 2.06 (m, 2H), 1.97-1.88 (m, 5H), 1.37 (m, 2H). ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7](=O)[C:8]2[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=2)C1=O.[Na].[BH4-].[Na+].O>Cl>[N:10]1[CH:9]=[C:8]([CH:7]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])[CH:13]=[CH:12][CH:11]=1
Reactant: CN1CCC(C(=O)c2cccnc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CN1CCCC1c1cccnc1
Temperature: 135 °C
Yield: 87.4 %

Procedure:
1-methyl-3-nicotinoyl-2-pyrrolidone (11.3 g, 0.055 mol) was dissolved in a 6N hydrochloric acid (125 mL) The solution was heated at 135° C. in an oil bath for 40 h and then cooled to room temperature. The pH of the mixture was adjusted to 8 by using 4 mol/L sodium hydroxideunder an ice-water bath, and then sodium borohydride (2.4 g) was added therein under ice-water bath. The mixture was stirred for 1.5 h after the ice-water bath was removed. The reaction solution was extracted with dichloromethane, dried and concentrated to obtain a crude product as a yellowish oil. 100 mL water was added and the mixture was stream-distilled directly. After the water was extracted with petroleum ether, the extract was dried and concentrated to obtain an oily product (7.8 g, yield 71%). HPLC purity 98.2%. 1H NMR (CDCl3, 300 MHz) δ: 8.52 (d, 1H), 8.48 (dd, 1H), 7.69 (dt, 1H), 7.25 (dd, 1H), 3.23 (t, 1H), 3.07 (t, 1H), 2.29 (m, 1H), 2.16 (s, 3H), 1.90-2.04 (m, 2H), 1.65-1.88 (m, 2H); ESI-MS 163.4 (M+H).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[O:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C@@H:17]([OH:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C@H:10]1[CH2:9][C@@H:8]([OH:24])[CH2:7][CH2:6]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:25][Si:2]([CH3:1])([CH3:26])[O:3][CH2:4][C@@:5]12[C@@H:22]3[C@H:13]([C@H:14]4[C@@:18]([CH2:20][CH2:21]3)([CH3:19])[C:17](=[O:23])[CH2:16][CH2:15]4)[CH2:12][CH2:11][C@H:10]1[CH2:9][C:8](=[O:24])[CH2:7][CH2:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4C[C@@H](O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)CC[C@@]43CO[Si](C)(C)C)[C@@H]1CCC2=O
Temperature: 10 °C
Reaction time: 0.08 h

Procedure:
19-Trimethylsiloxy-5α-androstane-3β,17β-diol is dissolved in acetone and chilled to 10° C. Jones reagent is added with stirring over a period of 5 minutes and the mixture left standing for an additional 20 minutes. The acetone layer is poured onto water with vigorous stirring. The solid which forms is collected by filtration, air dried and crystallized from an acetone-hexane solution to yield 19-trimethylsiloxy-5α-androstane-3,17-dione.