Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][C@@H:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CO1
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 40.2 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]oxazin-3-one (commercial; 6.49 g, 39.5 mmol) and tert-butyl-dimethyl-[(R)-2-oxiranyl-ethoxy]-silane (first eluting compound in step H.i; 8.0 g, 39.5 mmol) in EtOH/H2O (9:1; 240 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure. Residual starting aniline could be removed by addition of Et2O/MeOH followed by filtration. The filtrate containing the product was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (5.82 g, 40% yield).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:2][CH3:3].C1(C)C(C)=CC=CC=1.[CH2:20]([SH:23])[CH2:21][CH3:22]>ClC1C=CC=CC=1Cl.C1(C)C=CC=CC=1>[CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH2:2][CH3:3].[CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:23][CH2:20][CH2:21][CH3:22])[CH2:2][CH3:3]
Reactant: CCCS
Agent: CCCSc1ccccc1Cl
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CCCSc1ccccc1SCCC
Reaction time: 64 h
Yield: 56.4 %

Procedure:
A solution of 215 g of 61.5 weight % of o-chlorophenyl propyl sulfide in o-dichlorobenzene (ODCB) was combined with 222.8 g of 85% potassium propyl mercaptide, 200 ml of xylene, 45 g of Carbowax® 350, polyethyleneglycol (Union Carbide), and 20 ml of propyl mercaptan, and heated at reflux for 96 hours. The liquid temperature of the refluxing mixture, initially at 137° C., rose to 168° after 64 hours, and to 198° C. after 86 hours. The dark solution was cooled, diluted with 300 ml of toluene, and washed with water to remove inorganic salts. The organic phase was dried (MgSO4) and fractionally distilled to give 48.6 g of recovered o-chlorophenyl propyl sulfide and 129.6 g (56.4%) of ortho-bis-propylthiobenzene, b.p. 100°-105° C. (0.06 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15].[H-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:12]([O:13][CH2:14][CH3:15])=[O:16]
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
To a solution of 2′,4′-Dichloroacetophenone (1.50 g, 7.93 mmol) in diethyl carbonate (24.0 mL, 198 mmol) at 0° C. was slowly added NaH (60% suspension in mineral oil, 0.657 g, 16.4 mmol). The mixture was then stirred at 80° C. for 90 minutes. The mixture was cooled to room temperature and then poured into an ice cold solution of 2.0 mL acetic acid in 56 mL water. The layers were separated and the aqueous phase was extracted with ether 3 times. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (1.16 g, 56%). LCMS: (FA) ES+, 262. 1H NMR (400 MHz, d1-chloroform) δ (2 sets of signals, keto and enol): 12.49 (s, 1H), 7.61-7.29 (m, 2 sets of 3H), 5.57 (s, 1H), 4.28 (q, J=7.28 Hz, 2H), 4.19 (q, J=7.28 Hz, 2H), 4.02 (s, 2H), 1.34 (t, J=7.03 Hz, 3H), 1.25 (t, J=7.03 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[C:20](I)[C:12]=3[C:11](=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.C(OCC1C2CCC3C=CC=CC=3C(=O)C=2C(I)=CC=1)(=O)C.O.O.[NH2:47][NH2:48]>N1C=CC=CC=1.CO>[N:47]1[NH:48][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[C:16]3[CH2:15][CH2:14][C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[C:11]=1[C:10]=23
Reactant: CC(=O)OCc1cccc2c1CCc1cccc(I)c1C2=O
Reactant: NN
Agent: CC(=O)OCc1ccc(I)c2c1CCc1ccccc1C2=O
Solvent: CO
Solvent: O
Solvent: c1ccncc1
Product: OCc1ccc2[nH]nc3c2c1CCc1ccccc1-3

Procedure:
2.1 g of the mixture of (6-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate and (4-iodo-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate prepared in Example 1-g was dissolved in a mixed solvent of 5 ml of pyridine and 5 ml of methanol, and 5 ml of hydrazine monohydrate was added, followed by heating under reflux for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 330 mg and 130 mg of the title compounds as a colorless powder, respectively.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]=[N:9]O)=[CH:6][CH:5]=1)([O-])=O.[H][H].[OH-].[Na+]>[Pt].CO>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C=NO)cc1
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NCc1ccc(N)cc1
Reaction time: 13.5 h
Yield: 92.1 %

Procedure:
33.2 g (0.2 mol) of this p-nitrobenzaldoxime, 18.3 g (0.25 mol) of boric anhydride, 1 g of a 5% Pt-C catalyst and 100 ml of methanol were charged into a hermetically sealed glass container and vigorously stirred while charging hydrogen. Reaction was continued at temperatures of 25° C. to 30° C. for 13.5 hours and 22.2 l of hydrogen was absorbed. Next, this reaction mixture was filtered to remove the catalyst and methanol was distilled off by concentration under reduced pressure. A yellow viscous liquid thus obtained was neutralized by adding 57 g (0.5 mol) of a 35% aqueous solution of sodium hydroxide and then, the liquid was separated to two layers. The lower layer, a colorless and transparent aqueous solution of sodium borate was removed and then, a brown and oily crude p-aminobenzylamine was obtained. This crude p-aminobenzylamine was subject to vacuum distillation at pressure of 5 to 6 mmHg and 22.5 g of fractions between 129.5° C. and 130° C. was obtained (yield 92.1%). The purity by means of gas chromatography was 99.93%.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>O1CCOCC1.C(Cl)Cl>[CH2:14]([O:13][C:11]1[C:6]([C:7](=[O:8])[NH:9][CH3:10])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:34]([NH:33][C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])=[S:35])[CH:12]=1)[CH3:15]
Reactant: CCOc1cc(CN)ncc1C(=O)NC
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1cc(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)ncc1C(=O)NC
Reaction time: 1 h
Yield: 74.6 %

Procedure:
500 mg (2.39 mmol) of 6-aminomethyl-4-ethoxy-N-methylnicotinamide (Example 12f) were dissolved in 25 ml of dioxane and treated at RT with 672.4 mg (2.39 mmol) of fluoren-9-ylmethyloxycarbonyl isothiocyanate. After one hour, the mixture was freed from the solvent and the residue was taken up in DCM. It was washed three times with aqueous LiCl solution and once with water. After drying with MgSO4, the mixture was concentrated and the crude product (875 mg) thus obtained was reacted further without further purification.
Reaction SMILES: N[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]([O-])=O.[Na+].C1(S(O)(=O)=O)C=CC=CC=1.C=CC1C=CC=CC=1>C(O)C.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH2:2])=[CH:5][CH:6]=1
Reactant: NC=Cc1ccccc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C=Cc1ccccc1
Product: C=Cc1ccc(N)cc1

Procedure:
The diazonium salt of 4-aminostyrene is prepared as described above from 3.6 g aminostyrene, 2.1 g sodium nitrite, and 150 g water. Ethanol, 10 g, is added to completely dissolve the diazonium salt. A solution of SA-treated MMC is added to the diazonium salt solution, and it is allowed to react for 18 hours under mixing. The solution is filtered to provide MMC solution at about 11 wt %. This MMC contains both benzenesulfonic acid and styrene functionalities covalently attached to the MMC particle.
Reaction SMILES: C([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:17][CH:16]=2)[CH:7]=[N:6]1)(C)(C)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([CH:14]([O:13][C:8]1[CH:7]=[N:6][NH:5][C:10](=[O:11])[C:9]=1[Cl:12])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH:23]([O:25][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH3:24])=[CH:19][CH:20]=1)([CH3:20])([CH3:16])[CH3:14]
Reactant: CC(O)CCc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)CCc2ccc(C(Oc3cn[nH]c(=O)c3Cl)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of the product of Example 7B (200 mg, 0.548 mmol) in pyridine (10 mL) was added p-toluenesulfonyl chloride (209 mg, 1.096 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Monitoring by LC-MS showed a 1:1 mixture of starting material and product. The reaction was diluted with ethyl acetate and washed with 5% CuSO4 until a light blue aqueous solution was maintained. The organic layer was then dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash column chromatography (3:1 hexane:ethyl acetate to 100% ethyl acetate) to recover the starting material (90 mg) and the product as a clear oil (74 mg, 47% yield based on recovered starting material). 1H NMR (600 MHz, CDCl3): 7.80 (d, 2H, J=8.3 Hz), 7.72 (s, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.1 Hz), 7.13 (d, 2H, J=8.1 Hz), 5.27 (s, 2H), 4.66 (m, 1H), 2.65 (m, 1H), 2.54 (m, 1H), 2.45 (s, 3H), 1.94 (m, 1H), 1.81 (m, 1H), 1.63 (s, 9H), 1.26 (s, 3H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]#[CH:38])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>C1COCC1.C(Cl)Cl.CO>[CH2:13]([N:20]1[CH2:21][CH2:22][C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]#[C:38][C:40]([O:42][CH2:43][CH3:44])=[O:41])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:25]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccccc1C1(C(=O)OCC)CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#Cc1ccccc1C1(C(=O)OCC)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
n-Butyllithium (0.76 mL, 1.9 mmol) was added to a stirred solution of diisopropylamine (0.28 mL, 2.0 mmol) in THF (20 mL, 244 mmol) at −78° C. The reaction mixture was then allowed to warm to ambient temperature for 5 minutes before it was cooled down to −78° C. Ethyl 1-benzyl-4-(2-ethynylphenyl)piperidine-4-carboxylate (0.22 g, 0.63 mmol) was then added dropwise as a solution in THF (20 mL, 244 mmol). After 15 minutes, ethyl chloroformate (0.19 mL, 2.0 mmol) in 5 mL of THF was added to the reaction. The resulting solution was allowed to warm to ambient temperature and then stirred for 30 minutes. MeOH (3 mL) was added, and the resulting mixture was concentrated in vacuo to give a bright-yellow oil. The residue was dissolved in DCM and purified by Isco HPLC (0-80% EtOAc/hexane) to give the title compound as a yellow oil (0.15 g). MS m/e=420 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:20]=[C:19]2[CH2:36]Br>>[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH:20]=[C:19]2[CH2:36][N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1
Reactant: O=c1c2ccc(Br)cc2c(CBr)cn1S(=O)(=O)c1ccccc1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: C[C@H]1CN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)CCN1C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared by the method of Example 11e using (S)-tert-butyl 2-methylpiperazine-1-carboxylate and 6-bromo-4-(bromomethyl)-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11d)
Reaction SMILES: NSOO[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)=[CH:7][CH:6]=1.[NH2:32][S:33](NC1C=C(NN)C=CC=1)(=[O:35])=[O:34]>>[NH2:32][S:33]([C:10]1[CH:9]=[C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)[CH:7]=[CH:6][CH:5]=1)(=[O:35])=[O:34]
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Reactant: NNc1cccc(NS(N)(=O)=O)c1
Product: CCOC(=O)c1nn(-c2cccc(S(N)(=O)=O)c2)c2c1CCc1ccc([N+](=O)[O-])cc1-2

Procedure:
This compound was prepared using the same procedures for Ethyl 1-{4-[(aminothio)peroxy]phenyl}-8-nitro-4,5-dihydro-1H-benzo[g]indazole-3-carboxylate of Example 2, where 3-(aminosulfonamido)-phenylhydrazine was used in place of 4-(aminosulfonamido)-phenylhydrazine. Its structure was confirmed by 1H NMR and MS (443, M+1). C20H18N4O6S, Calc.: C: 54.29; H: 4.10; N: 12.66; Found, C: 54.27; H: 4.09; N: 12.55.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:16][CH2:12][CH2:13][C:14]#[CH:15])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C#CCCO
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCOc1ccc(Br)cc1[N+](=O)[O-]
Yield: 71.4 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (20.0 g, 90 mmol), 3-butyn-1-ol (7.0 g, 99.8 mmol) and potassium carbonate (13.8 g, 99.8 mmol) in dry DMF (20 mL) was heated with 4 Å molecular sieves for 43 h. The mixture was cooled, diluted with water to approximately 500 mL and extracted three times with ethyl acetate. The combined organic extracts were washed with water and then brine, dried and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 5 to 10% ethyl acetate in cyclohexane) to give 4-Bromo-1-but-3-ynyloxy-2-nitro-benzene as a yellow solid (17.35 g, 71%). NMR showed an impurity (19%) which was not removed at this stage. LCMS: RT=4.41 min, [M+Na]+=292/294.
Reaction SMILES: [CH3:1]P(=O)(OCCCC)OCCCC.C(COC)OC.C([Li])CCC.[C:25]([O:28][C@H:29]1[CH2:34][CH2:33][C@H:32]2[C@H:35]3[C@H:45]([CH2:46][CH2:47][C@:30]12[CH3:31])[C@:43]1([CH3:44])[C:38](O[C:40](=[O:48])[CH2:41][CH2:42]1)=[CH:37][CH2:36]3)(=[O:27])[CH3:26]>CCCCCC.O.O1CCCC1>[CH3:26][C:25]([O:28][C@@H:29]1[C@@:30]2([CH3:31])[CH2:47][CH2:46][C@@H:45]3[C@:43]4([CH3:44])[C:38](=[CH:1][C:40]([CH2:41][CH2:42]4)=[O:48])[CH2:37][CH2:36][C@H:35]3[C@@H:32]2[CH2:33][CH2:34]1)=[O:27]
Reactant: CCCCOP(C)(=O)OCCCC
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC=C4OC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]CCCC
Solvent: O
Solvent: COCCOC
Solvent: CCCCCC
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4 g. of dibutyl methylphosphonate in 75 ml. of dry monoglyme at about -78° under nitrogen, there is added with stirring one equivalent of n-butyl lithium in hexane. After about 10 minutes, there is added one equivalent of 17β-acetoxy-4-oxa-androst-5-en-3-one in 75 ml. of dry tetrahydrofuran while maintaining the temperature at about -78°. The reaction mixture is allowed to warm to room temperature and then left to stand for about four hours. The reaction mixture is diluted with water and extracted with ether. The ether extracts are combined, washed, dried and evaporated to give testosterone acetate (17β-acetoxyandrost-4-en-3-one) which can be purified by chromatography.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH2:25][OH:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][CH:25]=[O:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCC1CCCCN1Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCC1CCCCN1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
To a stirred solution of DMSO (5.84 mL, 82.2 mmol) in dry DCM (220 mL) was added (COCl)2 (3.55 mL, 41.1 mmol) at −78° C. and the mixture stirred at same temperature for 20 minutes. A solution of compound 49 (6 g, 27.4 mmol) in DCM (30 mL) was then added slowly and the reaction mixture was stirred at −78° C. for 1 hour. TEA (13.8 mL, 137 mmol) was added at −78° C. and the reaction mixture was stirred and allowed to come to rt. The reaction mixture was diluted with DCM and the organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to provide sticky compound 50.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([C@H:10]2[CH2:14][O:13]C(C)(C)[N:11]2C(OC(C)(C)C)=O)[CH:6]=[C:7]([F:9])[CH:8]=1.Cl.O1CCOCC1>C(Cl)Cl>[NH2:11][C@@H:10]([C:5]1[CH:6]=[C:7]([F:9])[CH:8]=[C:3]([CH2:2][Cl:1])[CH:4]=1)[CH2:14][OH:13]
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(CCl)c2)COC1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N[C@H](CO)c1cc(F)cc(CCl)c1
Temperature: 80 °C
Yield: 84.5 %

Procedure:
To a solution of (S)-tert-butyl 4-(3-(chloromethyl)-5-fluorophenyl)-2,2-dimethyloxazolidine-3-carboxylate (140 mg, 0.407 mmol) in anhyd DCM (1.357 mL) was added 4 N HCl in Dioxane (1.018 mL, 4.07 mmol) portionwise. The mixture was refluxed at 80° C. overnight. The reaction was not completed. More 4N HCl in dioxane (1. 018 mL, 4.07 mmol) was added, and refluxed for another 24 h. Solvent was removed under reduced vacuum to provide (S)-2-amino-2-(3-(chloromethyl)-5-fluorophenyl)ethanol (70 mg, 84%). LCMS (m/z): 204 (MH+), 0.41 min.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[OH:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][NH2:26])[CH:20]=[CH:21][C:22]=1[OH:23].C(N(C(C)C)C(C)C)C.C(=O)(O)[O-]>CN(C)C(=O)C>[OH:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][NH:26][CH2:3][C:4]2[N:5]=[C:6]3[C:11](=[N:12][CH:13]=2)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]3[NH2:15])[CH:20]=[CH:21][C:22]=1[OH:23]
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Br
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CNCCc3ccc(O)c(O)c3)cnc2n1
Temperature: 50 °C
Reaction time: 4 h
Yield: 22.6 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (67.3 mg, 0.2003 mmol) in anhydrous N,N dimethylacetamide was added 2-(3,4-dihydroxyphenyl) ethylamine (43.6 mg, 0.23 mmol). Under positive pressure of Argon, iPr2EtN (32.63 ul) was added. The reaction mixture was stirred at 50° C. for 4 hrs and then at Room temperature overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 14.8 mg product was obtained. Yield: 22.6%; 1H NMR (500 MHz, DMSO-d6): δ 2.69242 (b, 4H), 4.03353 (s, 2H), 6.37542–6.39065 (d, J=7.615 Hz, 1H), 6.4851(s, 1H), 6.56632–6.58226 (d, J=7.97 Hz, 1H), 8.80972 (s, 1H); ESI-MS: m/z 328 (M++1)
Reaction SMILES: O=S(Cl)Cl.C(OC([N:12]1[CH2:17][CH2:16][C:15]2([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:19][CH2:18]2)[CH2:14][CH2:13]1)=O)(C)(C)C.[CH3:27]O>>[CH2:16]1[C:15]2([CH2:18][CH2:19][CH:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:21][CH2:22]2)[CH2:14][CH2:13][NH:12][CH2:17]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(CC(=O)O)CC2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)CC1CCC2(CCNCC2)CC1
Reaction time: 0.25 h

Procedure:
Methanol (50 mL) was cooled in an ice bath and SOCl2 (2 mL) was added dropwise with stirring. After 15 min, 2-(3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (0.34 g, purchased from WuXi Pharmatech) was added. The mixture was stirred at rt for 2 d and concentrated to afford methyl 2-(3-azaspiro[5.5]undecan-9-yl)acetate as its hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][C:10]2[N:9]=[CH:8][C:7]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:6]=3[C:5]=2[C:4](=O)[CH2:3]1.O.NN.[OH-].[K+]>C(O)CO>[CH3:1][C:2]1([CH3:20])[CH2:11][C:10]2[N:9]=[CH:8][C:7]3[NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[C:6]=3[C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CC(=O)c2c(ncc3[nH]c4ccccc4c23)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC1(C)CCc2c(ncc3[nH]c4ccccc4c23)C1
Yield: 45.9 %

Procedure:
3,3-Dimethyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolin-1-one of Example 1h (1.36 g, 5.14 mmol) was added to a mixture of ethylene glycol (8 mL) and hydrazine monohydrate (5 mL) at room temperature under stirring. The mixture was refluxed for 1 h, cooled, potassium hydroxide (1 g) was added, and the reaction mixture was refluxed for 2 h. The excess of hydrazine and water was slowly distilled off at 1 psi until the vapor temperature reached 190° C. The residue was cooled, diluted with water (60 mL), and the solid product was filtered off, washed with water and recrystallized from ethanol-water, 1:1. The product was isolated as colorless solid (0.59 g, 46%). Crystallization from toluene yielded the analytically pure sample; m.p. 275-277° C. 1H NMR (DMSO-d6) δ 1.03 (s, 6H), 1.72 (t, 2H), 2.76 (s, 2H), 3.30 (t, 2H), 7.20-7.23 (m, 1H), 7.49-7.60 (m, 2H), 8.17 (d, 1H), 8.66 (s, 1H), 11.45 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([C:24]1[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=1)/[CH:4]=[CH:5]/[C:6]1[CH:23]=[CH:22][C:9]([O:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:34][C:2]([F:1])([F:33])[CH:3]([C:24]1[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[CH:23]=[CH:22][C:9]([O:10][NH2:11])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Oc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NOc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 90 °C
Yield: 50.4 %

Procedure:
To a stirred solution of (E)-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)phenoxy) isoindoline-1,3-dione (0.2 g, 0.4 mmol) in EtOH was added hydrazine hydrate (0.1 g, 1.9 mmol), and the resultant reaction mixture was heated at 90° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2. washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude title compound as a gummy liquid (0.08 g, 53%): 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 2H), 6.98 (s, 1H), 6.82 (s, 2H), 6.48 (m, 1H), 6.20 (m, 1H), 5.02 (s, 1H), 4.08 (m, 1H); ESIMS m/z 394.94 ([M−H]−).