Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br>C(O)C>[Br:12][CH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: BrBr
Solvent: CCO
Product: COC(=O)c1ccc(CBr)cc1
Reaction time: 8 h

Procedure:
A methyl 4-methylbenzoate (MMB) solution (110 g, 0.73 mol) in CB (150 g) in a 250 mL round bottomed flask was heated by a heating mantle connected to a temperature controller to temperatures between 136 to 140° C. Liquid bromine (84.4 g, 0.53 mol or ~72 mol %), (Aldrich, 99.5+%, A.C.S. reagent) was fed via Viton tubings using Cole-Parmer computerized Drive with Easy-Load pump head. The bromine feed rate was adjusted to 0.50 mL/minute throughout the 52 minutes of addition time. Heating and stirring were continued for a few minutes after all bromine had been added, and then the reaction mixture was allowed to cool down. The "smoking" orange mixture was transferred to a separatory funnel and was washed with water (250 mL) to produce a colorless organic phase. The bottom layer (organic) was separated and concentrated under reduced pressure (rotary evaporator) to remove most of the chlorobenzene. The residual oily mixture was allowed to stand overnight. An impure crystalline solid was obtained. The crude solid was dissolved in 20% aqueous ethanol solution (450 mL) and allowed to cool in a refrigerator for 2 hours. The resulting white crystals were washed with 50% aqueous ethanol (200 mL) to produce 50.5 g (42% based on added bromine) of highly pure (~99%) material. No attempt was made to optimize the recovered yield.
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].[NH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:35])([F:36])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:37][CH2:38][C:39]([OH:41])([CH3:42])[CH3:40])=[O:9])=[O:4]
Reactant: O=C(O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(O)CNC(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 6.8 %

Procedure:
(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), 1-amino-2-methylpropan-2-ol (5.85 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.2 min) to provide (R/S)-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-(2-hydroxy-2-methylpropyl)propanamide (2 mg, 2.99 μmol, 6.83% yield): LCMS=574.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.36 Hz), 7.50-7.79 (7 H, m), 5.11 (1 H, s), 3.48-3.58 (2 H, m), 3.14-3.22 (2 H, m), 2.48 (2 H, t, J=6.71 Hz), 1.16 (3 H, s), 1.16 (3 H, s); HPLC peak RT=8.2 min (Method A).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:3]([OH:5])=[O:4].O=S(Cl)Cl.[CH3:15]O>>[CH3:15][O:4][C:3](=[O:5])[C@@H:2]([NH2:1])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: CO
Reactant: N[C@@H](CCCCO)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCCCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
(S)-2-Amino-6-hydroxy-hexanoic acid (Chemstep) (5.54 mmol, 1.37 g) was dissolved in 100 mL of MeOH and cooled at 0° C. SOCl2 (13.8 mmol, 1 mL, 2.5 eq) was added dropwise. The reaction mixture was stirred overnight at room temperature after which time the solvent was removed in vacuo. The crude solid was recrystallised from MeOH (3×100) to give the methyl ester 82 as an oil (5.52 mmol, 0.89 g, 99%).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:20]([OH:39])[C@:21]4([OH:38])[C:29](=[O:30])[C:28]([C:31]([NH2:33])=[O:32])=[C:27]([OH:34])[C@@H:26]([N:35]([CH3:37])[CH3:36])[C@@H:22]4[CH2:23]3)[C:17](=[O:18])[C:14]=2[C:15]=1[OH:16])=[O:8])([CH3:4])[CH3:3].[ClH:43]>C(C(C)=O)C>[CH3:4][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:17]([OH:18])[C:14]=2[C:15]=1[OH:16])[C:20](=[O:39])[C@@:21]1([OH:38])[C@H:22]([C@H:26]([N:35]([CH3:36])[CH3:37])[C:27]([C:28]([C:31]([NH2:33])=[O:32])=[C:29]1[OH:30])=[O:34])[CH2:23]3)=[O:8])([CH3:1])[CH3:3].[ClH:43]
Reactant: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CCC(C)=O
Product: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 82 %

Procedure:
50.0 mg Tigecycline (Tygacil® 50 mg, Wyeth®, powder for infusion) were dissolved in 500 μl ethylmethylketone and the solution was stirred at room temperature. After about one minute an orange precipitate appeared (essentially pure form Ill). Afterwards 8.4 mg (1 eq) concentrated hydrochloric acid were added and the suspension was stirred for approximately 3 hours. The solid was filtered off, washed with ethylmethylketone and dried under vacuum at room temperature to obtain 43.7 mg (82% yield) of crystalline form A of Tigecycline hydrochloride.
Reaction SMILES: [Ca].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][CH:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH3:11])[CH:7]=[CH:8][CH:9]=1.[ClH:25]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:25].[ClH:25].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc([C@@H](C)NC2CCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Agent: [Ca]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)N[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 25 g of tert-butyl(S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylamine dissolved in 500 ml of methylene chloride was added dropwise 100 ml of a solution of 49 g of anhydrous trifluoromethanesulfonic acid in methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., and then, to the mixture was added dropwise 100 ml of a solution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylene chloride at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate. (2) To a solution of 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolved in 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 16 hours. The resulting precipitates were collected by filtration, washed with ethyl acetate, and recrystallized from methanol and tetrahydrofuran twice to obtain 8.54 g of (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.003).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].B(F)(F)F.CC[O:30]CC.O>O1CCCC1>[CH2:1]([O:8][CH:9]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:10][CH2:11][CH2:12][OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(COc1ccc(F)cc1)OCc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCCC(COc1ccc(F)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a mixture of 4-benzyloxy-5-(4-fluorophenoxy)-1-pentene (2.86 g., 10 mmoles), sodium borohydride (0.47 g., 12.5 mmoles), and tetrahydrofuran (25 ml.) is added dropwise a solution of boron fluoride etherate (2.1 ml., 16.7 mmoles) in tetrahydrofuran (5 ml.) at ice-bath temperatures under a nitrogen atmosphere. The resulting mixture is further stirred at room temperature overnight (ca.15 hours). The reaction flask is chilled in an ice bath and water (2 ml.) is very cautiously added to destroy the excess hydride, followed by the additions of sodium hydroxide (5N, 4 ml.) and hydrogen peroxide (30%, 8 ml.). The final mixture is stirred at room temperature for one-half hour, diluted with cold water and then extracted with chloroform three times. The combined extracts are washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo leaving the title compound as a viscous oil (3.00 g., 10 mmoles, 100%). ir (neat) 2.97, 3.30, 3.41, 6.22, 6.68, 6.90, 8.03, 8.30, 9.16, 9.44, 12.10, 13.20, 13.60, 14.40μ; pmr (CCl4)δ1.4-1.9 (4H, m), 3.2-4.2 (6H, m), 4.58 (2H, broad s), 6.6-7.1 (4H, m), 7.20 (5H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Oc1ccccc1
Agent: Cl[Sn]Cl
Product: Nc1cc(Cl)ccc1Oc1ccccc1
Yield: 78.6 %

Procedure:
The product from Example 42a (13 g, 52.1 mmol) was reacted with SnCl2 (49.3 g, 260 mmol) following the procedure from Example 1f giving the title compound as a white solid 9.0 g, 79%).
Reaction SMILES: N#N.CCN(CC)CC.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:22][C:23]([OH:25])=O)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH2:26]([O:28][C:29]([CH2:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:30])[CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:26]([O:28][C:29](=[O:30])[CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:23](=[O:25])[CH2:22][C:14]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:12]([O:11][CH3:10])[CH:13]=2)[CH2:34][CH2:33]1)[CH3:27]
Reactant: CCOC(=O)CN1CCNCC1
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN1CCN(C(=O)Cc2cc(OC)c(OC)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDCHCl (188 mg, 0.98 mmol) and Et3N (137 mL, 0.98 mmol) in anhydrous DCM (1.0 mL) and stir the resulting solution for 5 min at rt. Add 2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8 mg, 0.07 mmol) and stir the resulting solution for 10 min. Add 1-(Ethoxycarbonylmethyl)piperazine (63) (112 mg, 0.65 mmol) and stir the reaction solution overnight at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with DCM (3 times). Wash the combined organic layer with water and brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/MeOH 10+1) to obtain {4-[2-(3,4,5-Trimethoxy-phenyl)-acetyl]-piperazin-1-yl}-acetic acid ethyl ester (64) (99 mg, 40%) as a colorless oil. 1H NMR (400 MHz, CDCl3): 1.25 (t, 3H, J=7.1 Hz); 2.48 (br.m, 2H); 2.58 (br.m, 2H); 3.21 (br.s, 2H); 3.53 (br.m, 2H); 3.65 (s, 2H); 3.71 (br.m, 2H); 3.81 (s, 3H); 3.82 (s, 6 H); 4.16 (q, 2H, J=7.1 Hz); 6.42 (s, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[I-].[K+].C1(C)C=CC=CC=1>[C:12]1([NH:11][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(O)c1cccnc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
5.0 g (31.7 mmol) of 2-chloronicotinic acid, 5.9 g (63.5 mmol) of aniline, and 0.1 g of potassium iodide were heated up 140° C., and toluene (30 mL) was added to this reaction mixture. The resulting mixture was stirred for 2 hours at 100° C. The reaction mixture was cooled, and then the solvent was distilled off. Chloroform was added to the residue, and insoluble materials were filtered off. The filtrate was concentrated, and thus 7.5 g of the title compound was obtained as crude pale yellow crystals (yield: quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[C:3]=1[N+:11]([O-])=O.O.O.[C:16](O)(=[O:20])[C:17](O)=[O:18]>C(O)C>[OH:18][C:17]1[C:16]([OH:20])=[N:1][C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[C:3]=2[N:11]=1
Reactant: Nc1ccc2sccc2c1[N+](=O)[O-]
Reactant: O=C(O)C(=O)O
Solvent: CCO
Solvent: O
Product: Oc1nc2ccc3sccc3c2nc1O
Yield: 100.8 %

Procedure:
A solution of 5-amino-4-nitrobenzo[b]thiophene (0.50 g, 2.6 mmol) in 50 ml of 96% ethanol was hydrogenated at room temperature and atm. pressure in the presence of 5% palladium-on-carbon until the theoretical amount of hydrogen was absorbed. The catalyst was filtered off, and the filtrate was acidified with 1 N hydrochloric acid and evaporated to dryness. The residue was refluxed with oxalic acid dihydrate (0.40 g, S.1 mmol) in 25 ml of 4M hydrochlorio acid for 2 h. The mixture was cooled, and the precipitated solid was isolated by filtration, washed with water, ethanol and ether, and dried. The crude product was dissolved in a minimum amount of 2N sodium hydroxide, treated with decolourising charcoal, and filtered. The filtrate was acidified with 4M hydrochloric acid and the resulting precipitate was collected by filtration, washed with water, ethanol and ether to give 0.22 g (39%) of the thienoquinoxaline; m.p. 186.6° C.; IR (KBr): 1680 cm-1 ; H-NMR (DMSO-d 6): 7.13 (d,J=9 Hz, IH, ArH), 7.62 (D,J=9 Hz, IH, ArH), 7.72 (d,J=5 Hz, IH, ArH),
Reaction SMILES: [F-:1].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8](Cl)[C:9]=1[F:10].S1(CCCC1)(=O)=O>>[Cl:3][C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:7]=[C:8]([F:1])[C:9]=1[F:10]
Reactant: [F-]
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: Fc1cc(C(F)(F)F)cc(Cl)c1F

Procedure:
A mixture of 55 parts of anhydrous potassium fluoride and 45.32 parts of 3,5-dichloro-4-fluorobenzotrifluoride in 291 parts of sulfolane was heated and maintained at about 216° to 256° for a period of about 55 hours, while product vapors were removed through a distillation column at a head temperature of about 130°-150° C. A total of 32.02 parts of distillate was collected and analyzed by gas chromatography/mass spectrometry. The distillate was found to be 25.1 percent 3,5-dichloro-4-fluorobenzotrifluoride; 65.9 percent 3-chloro-4,5-difluorobenzotrifluoride; 8.6 percent 3,4,5-trifluorobenzotrifluoride and trace amounts of 4-chloro-3,5-difluorobenzotrifluoride. The desired 3-chloro-4,5-difluorobenzotrifluoride was isolated by distillation (b.p. 122° C.) to recover it in essentially pure form (greater than 99 percent pure). The 3,5-dichloro-4-fluoro isomer is recycled.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@H:10](OS(C(F)(F)F)(=O)=O)[C:11]2=[O:21])[CH2:3]1.C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3C[C@@H](O)C2=O)C1.FC(F)(F)S(O)(=O)=O.[Cl-:60].[Li+]>CN(C=O)C.O>[CH3:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][C@@H:10]([Cl:60])[C:11]2=[O:21])[CH2:3]1
Reactant: [Cl-]
Reactant: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@@H](OS(=O)(=O)C(F)(F)F)C[C@@H]32)C1
Agent: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](O)C[C@@H]32)C1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](Cl)C[C@@H]32)C1
Reaction time: 21 h
Yield: 96.5 %

Procedure:
800 mg of 3β-methyl-16β-trifluoromethylsulfonyloxy-5-androsten-17-one, prepared from 3β-methyl-16α-hydroxy-5-androsten-17-one and trifluoromethane sulfonic acid was placed in 16 ml DMF and was treated with 100 mg Lithium chloride at room temperature. The reaction mixture was stirred magnetically for 21 hours. Water is then added and the resulting crystalline ppt was collected. The crystals were washed with additional water and were then dissolved in CH2Cl2, filtered through anhydrous sodium sulfate and the solvent was evaporated off. The resulting crystals were recrystallized from CH3OH, yielding 570 mg of final product. m.p. 159°-165° C.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH3:8][NH:9][CH3:10].C1COCC1>CO>[CH3:8][N:9]([CH3:10])[C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[OH:7]
Reactant: CNC
Reactant: C1CCC2OC2C1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)[C@@H]1CCCC[C@H]1O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of cyclohexene oxide (3.64 mL, 36.0 mmol) in 30 mL of dry methanol was added dropwise 2.0 M dimethylamine in THF (15.0 mL, 30.0 mmol). The reaction mixture was stirred at 0° C. for 4 h. The solution was then warmed to room temperature and stirred for 18 h. The reaction mixture was then concentrated under reduced pressure to afford 1.11 g (26% crude yield) of the crude product which was used in the following reaction without purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N:19]1([CH2:18][CH2:17][N:2]2[CH:3]=[C:4]([B:6]3[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]3)[CH:5]=[N:1]2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: Cl
Product: CC1(C)OB(c2cnn(CCN3CCCC3)c2)OC1(C)C
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 1-(2-chloroethyl)pyrrolidine hydrochloride according to Method AC (heating to 90° C. for 6 days before addition of further 1-(2-chloroethyl)pyrrolidine hydrochloride, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (45%). LCMS (ES+) 292 (M+H)+, RT 1.81 minutes (Method 1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>ClCCl.N1C=CC=CC=1>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCCCCCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
A solution of 6-chlorohexan-1-ol (25.0 g, 0.183 mol) in dichloromethane (DCM) (166 ml) and pyridine (33 ml) was cooled to −5° C. Toluene-p-sulphonyl chloride (40.1 g, 0.210 mol) was slowly added to the stirred solution and left to react overnight. The reaction mixture was treated with ice (80 g) and left stirring for 1 h. The organic layer was washed with ice cold 2M-sulphuric acid and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by column chromatography [DCM] to give a white powder 40.20 g, 85%; mp 27-28° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[C:6]([NH2:13])=[N:5]2.[C:14](OC(=O)CC)(=O)[CH2:15][CH3:16]>C(O)(=O)CC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]1[NH:12][C:14]([CH2:15][CH3:16])=[N:13][C:6]1=[N:5]2
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1nc2ccc(Cl)cc2nc1N
Solvent: CCC(=O)O
Product: CCc1nc2nc3cc(Cl)ccc3nc2[nH]1
Yield: 88.1 %

Procedure:
78 G (0.4 mole) of 6-chloro-2,3-diamino-quinoxaline were dissolved in 500 ml of anhydrous propionic acid and 105 g (0.8 mole) of propionic anhydride were added thereto. The reaction mixture was heated to the boil under reflux for 5 hours. After cooling, the solvent was distilled off in vacuo, the residue was taken up in dilute sodium hydroxide solution, the mixture was filtered, the filtrate was acidified with dilute hydrochloric acid and the resulting precipitate was filtered off. It was well washed with water and dried in vacuo at 110°C. 82 g (representing 88% of theory) of 6-chloro-2-ethyl-1H-imidazo[4,5-b]quinoxaline of melting point 190°C (decomposition) were obtained.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:17][CH:16]=3)=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([O:37]S(C)(=O)=O)=[CH:33][CH:32]=3)[S:11][C:10]=2[CH:42]=1)(=O)=O.O1CCCC1.[OH-].[Na+]>CO>[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14](=[O:30])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:19][CH:20]=3)=[C:12]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:11][C:10]=2[CH:42]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 3.6 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene was dissolved in 100 ml. of tetrahydrofuran and 40 ml. of methanol, and 10 ml. of 5 N sodium hydroxide was added. The mixture was stirred for 16 hours at ambient temperature, and was then worked up by the procedure of Example 1 above to obtain 3.5 g of a yellow solid. The impure product was purified by column chromatography on silica gel, eluting with a gradient solvent from 5% methanol in chloroform to 30% methanol in chloroform. The product-containing fractions were evaporated to obtain 1.85 g. of oily product, which was recrystallized from acetone to obtain 1.25 g of purified product, m.p. 141°-144° C.