Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27]>C(O)(=O)C.O>[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27].[Cl:26]([OH:30])(=[O:29])(=[O:28])=[O:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10]3=[CH:13][S:14][CH:15]=[C:9]3[C:8]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[N:7][C:6]=2[CH:18]=1
Reactant: CSC1=Nc2cc(Cl)ccc2N(C)c2cscc21
Reactant: CN1CCNCC1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(C2=Nc3cc(Cl)ccc3N(C)c3cscc32)CC1

Procedure:
A solution of 0.7 g. of 7-chloro-4-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 3.5 ml. of N-methylpiperazine is treated with 1-2 drops of glacial acetic acid and heated under reflux for 4 days. The solution is concentrated to dryness and the residue is warmed with dilute acetic acid. The acidic solution is filtered, cooled and made alkaline with concentrated ammonium hydroxide. The sticky precipitate is collected and dissolved in chloroform. The dried chloroform solution is concentrated under reduced pressure to give an oil. An ethanolic solution of the oil is treated with 70% perchloric acid and is diluted with water. The precipitate is collected and recrystallized from ethanol to give a white solid, m.p. 212°-215° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([Br:12])=[CH:10][N:9]=[C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[N:7]=1.CCN(C(C)C)C(C)C.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCOCC1>[Br:12][C:11]1[C:6]([NH:5][CH2:4][CH2:3][CH2:2][NH:1][C:44]([NH:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])=[N:7][C:8]([NH:13][C:14]2[CH:15]=[C:16]([NH:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[CH:17]=[CH:18][CH:19]=2)=[N:9][CH:10]=1
Reactant: NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br
Reactant: O=C=Nc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCCNc1nc(Nc2cccc(NC(=O)N3CCCC3)c2)ncc1Br)Nc1ccccc1
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a suspension of N-(3-((4-((3-aminopropyl)amino)-5-bromo-2-pyrimidinyl)amino)phenyl)-1-pyrrolidinecarboxamide (100 mg, 0.2 mmol) and DIEA (0.14 mL, 0.8 mmol) in 1,4-dioxane (5 mL) was added phenyl isocyanate (35 mg, 0.3 mmol). The resulting solution was stirred overnight and concentrated. The crude residue was directly purified by prep HPLC using acetonitrile/water to give the title compound (68 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][S:7][C:8]2[N:13]=[N:12][C:11]([O:14]CC3C=CC(OC)=CC=3)=[C:10]([O:24]CC3C=CC(OC)=CC=3)[CH:9]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7][C:8]2[CH:9]=[C:10]([OH:24])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:34][CH:35]=1
Reactant: COc1ccc(COc2cc(SCc3ccc(Cl)cc3)nnc2OCc2ccc(OC)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1[nH]nc(SCc2ccc(Cl)cc2)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 5471.2 %

Procedure:
To a solution of 6-[(4-chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 8; 527 mg, 1.04 mmol) in methanol (5177 μl) was added a solution of hydrogen chloride in dioxane (4.0 M, 5177 μl, 20.71 mmol) and the reaction was allowed to stir at room temperature for 72 hours. The resulting mixture was concentrated in vacuo to afford a yellow solid which was recrystallised from ethanol to afford 6-[(4-chlorobenzyl)sulfanyl]-4-hydroxypyridazin-3(2H)-one as white crystals (153 mg, 56.9 mmol, 55%).
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C@H:3]1[O:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>ClCCl.CN(C1C=CC=CN=1)C>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:13]([O:12][C@@H:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[O:1][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:20])[CH3:19]
Reactant: CCOC(=O)CC(=O)O[C@@H]1C=Cc2ccccc2[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)O[C@@H]1C=Cc2ccccc2[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 89.6 %

Procedure:
To a dried round bottom flask, 7 (270 mg, 0.98 mmol), imidazole (134 mg, 1.96 mmol), dimethylaminopyridine (6 mg, 0.05 mmol) were dissolved in dichloromethane (4 mL). Tert-butyldimethylsilyl chloride (222 mg, 1.47 mmol) was then added portionwise and allowed to react for 24 hours. The reaction was then quenched with water, extracted with dichloromethane, dried over Na2SO4 and concentrated in vacuo. Flash chromatography (10% ethyl acetate in hexanes) gave a colourless oil 8 (343 mg, 90%). Rf 0.48 on silica gel (10% ethyl acetate:hexanes. IR (KBr, cm−1) 2983 (w), 1731 (s), 1453 (w), 1370 (m), 1150 (s), 1031 (m); 1H NMR (400 MHz, CDCl3) δ 7.41-7.39 (1H, m), 7.24-7.22 (2H, m), 7.07-7.05 (1H, m), 6.47 (1H, dd, J=9.9, 1.8 Hz), 5.83 (1H, dd, J=9.7, 2.7 Hz), 5.60 (1H, ddd, J=9.3, 2.9, 2.0 Hz), 5.00 (1H, dd, J=9.3, 0.5 Hz), 4.22-4.15 (2H, m), 3.40 (2H, dd, J=19.6, 16.0 Hz), 1.57 (1H, s), 1.25 (3H, t, J=7.1 Hz), 0.92 (9H, s), 0.13 (3H, s), 0.09 (3H, s); 13C NMR (400 MHz, CDCl3) δ 166.3, 166.2, 136.2, 132.1, 129.4, 128.0, 127.9, 126.5, 125.9, 125.7, 76.4, 71.6, 61.6, 41.7, 25.8, 18.1, 14.0, −4.3, −4.5. HRMS calcd for C17H21O5Si (M+-C4H9): 333.1158. Found: 333.1149.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:17]2[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[N:10][C:11]=3[CH3:24])[CH:16]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (85 mg, 0.26 mmol) and TBTU (91 mg, 0.28 mmol) in DMF (3.0 mL) was added DIPEA (220 μL, 1.28 mmol). Then 4-aminotetrahydropyran (29 mg, 0.28 mmol) was added and the mixture was stirred at room temperature under Ar for 30 min. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (72 mg, 68%) as a white solid. MS: m/e=415.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](OC(F)(F)F)[CH:5]=[CH:4][C:3]=1[NH2:13].C[Al](C)C.C[O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][N:23]=1)=O.Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:13][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][N:23]=1)=[O:19]
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cn1
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1Cl)c1ccc(OCC(F)(F)F)cn1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-4-trifluoromethoxy-phenylamine (2.0 g, 9.29 mmol) in toluene (50 mL) was added to trimethylaluminum (2.0 M 4.65 mL) then 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester 3 (1.1 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give 5-(2,2,2-Trifluoro-ethoxy)-pyridine-2-carboxylic acid (2-chloro-phenyl)-amide 4 as a solid. Yield: 1.0 g, 71%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[C:33]([F:32])([F:42])[F:43])[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccccc2C(F)(F)F)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 438 mg (1.02 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 20 ml of dry acetonitrile is mixed with 382 mg (1.6 mmol) of 2-trifluoromethylbenzyl bromide and 441.3 mg (3.19 mmol) of anhydrous potassium carbonate and heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by preparative HPLC. 181 mg (0.32 mmol, 31.3% of theory) of a colorless foam are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[C:10](OC(OCC)OCC)(=O)C>C1CCCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:10]=[N:9][N:8]=2)[CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CCOC(OCC)OC(C)=O
Solvent: C1CCCCC1
Product: Fc1ccc2nncn2c1

Procedure:
(5-Fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) in diethoxymethyl acetate (5 mL) was stirred at RT for 2 h. The resulting precipitate was diluted with cyclohexane (5 mL) and filtered to give Intermediate Fa (379 mg, 70%). NMR (400 MHz, CDCl3): 7.25 (1H, m), 7.84 (1H, m), 8.09 (1H, t, J=2.5 Hz), 8.84 (1H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:11])C.CC1(C)N([O])C(C)(C)CCC1>C(#N)C.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:11])=[O:8]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: OCC1CCCCO1
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CC#N
Solvent: O
Product: O=C(O)C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(Tetrahydro-2H-pyran-2-yl)methanol (0.51 g, 4.30 mmol) was dissolved in 10 mL of 1:1 ACN/water mixture, and bis-acetoxyiodobenzene [BAIB] (3.04 g, 9.46 mmol) was added to the mixture. It was then cooled to 0 C in an ice bath, and TEMPO (0.134 g, 0.86 mmol) was added under argon flow. The mixture was stirred at room temperature for 3 hours, and the reaction was quenched by addition of 2×20 mL of 1 M NaOH. Basic solution was washed 3×30 mL of EtOAc, and re-acidified with 1 M HCl to ca. pH 2. Aqueous layer was then extracted 6×30 mL of EtOAc, organic layers were combined, dried over sodium sulfate and evaporated. The title compound was isolated as an oil (0.34 g, 61%) was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ4.11 (d, 1H, J=10.5 Hz), 3.98 (d, 1H, J=9.9 Hz), 3.53 (m, 1H), 2.10-1.92 (m, 3H), 1.60-1.54 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[C:7](=[CH:12][N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1.[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]>>[C:16]([O:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[C:7](=[CH:12][N:13]([CH3:15])[N:14]=2)[N:8]=[C:9]([CH3:11])[CH:10]=1)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Cl
Reactant: Cc1cc(NCCO)c2nn(C)cc2n1
Product: CCCCC(=O)OCCNc1cc(C)nc2cn(C)nc12
Yield: 74 %

Procedure:
The title compound was prepared from 7-(2-hydroxyethylamino)-2,5-dimethylpyrazolo[4,3-b]pyridine (D2) (400 mg) and valeryl chloride by the general method of Example 4. The solid obtained was recrystallized from ether/methanol to give the title compound (300 mg, 74%), m.p. 78°-80° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)C[CH2:15]3)=[O:11])=[CH:2]1.N12CC([CH2:29][OH:30])(CC1)CC2>>[CH3:29][O:30][C:7]1[CH:8]=[C:9]2[C:4]([C:3]([C:10]([O:12][CH2:13][C:14]34[CH2:15][N:17]([CH2:18][CH2:19]3)[CH2:20][CH2:21]4)=[O:11])=[CH:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: OCC12CCN(CC1)C2
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Product: COc1ccc2c(C(=O)OCC34CCN(CC3)C4)c[nH]c2c1

Procedure:
1-Azabicyclo[2.2.1]heptan-4-ylmethyl 6-methoxy-1H-indole-3-carboxylate was synthesized using the procedure described for (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate using 1-Azabicyclo[2.2.1]heptan-4-ylmethanol. MS: (m/e) 300.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49])[CH:38]=1>>[F:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][O:1][CH:2]2[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[CH:10][CH:9]=3)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]2)=[CH:38][C:39]=1[O:44][CH2:45][CH2:46][CH2:47][O:48][CH3:49]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1cc(CCl)ccc1F
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1F

Procedure:
Analogously to Method D, 0.213 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.114 g of 4-chloromethyl-1-fluoro-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a colourless oil. Rt=6.28.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>>[N:44]1([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Temperature: 105 °C

Procedure:
A suspension of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17β-ol (1.80 Kg, 5.006 mol) in a mixture of morpholine (11.44 L) and purified water (1.144 L) was prepared at 20-24° C. and under N2 atmosphere. To the suspension was added p-toluenesulphonic acid (1.24 Kg, 6.508 mol) at 20-24° C. and under N2 atmosphere. The suspension was stirred in the darkness and heated to reflux (100-110° C.) for 40 h. After 40 h the reaction mixture was cooled to 20-24° C., and poured into a second vessel maintained at about 4° C. containing a 2% s solution of sodium carbonate (128 L), while stirred vigorously. The resulting suspension was stirred for 1 hour at about 4° C. The obtained solid was filtered off under vacuum, washed with cold purified water (100 L), and dried in a vacuum oven at about 40° C. for at least 48 hours, to give 2.07 Kg (4.49 mol) of a white solid. (89.7% molar yield and purity of 94.12% area by HPLC) m.p. 225° C.; [α]D20+82.00 (c=1.02 in CHCl3). The product could be used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O.[C:11](Cl)(Cl)=[S:12]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[N:4]=[C:11]=[S:12]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(I)cc1Cl
Solvent: ClCCl
Solvent: O
Product: S=C=Nc1ccc(I)cc1Cl
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a stirred solution of 2-chloro-4-iodoaniline (1.0 g, 3.9 mmol) in DCM (50 mL) was added water (20 mL) followed by thiophosgene (476 mg, 4.1 mmol). The reaction mixture was stirred overnight before the layers were separated and the organic layer dried (Na2SO4) and evaporated in vacuo to give the desired product as a brown solid (1.0 g, 86%). δH (CDCl3) 7.79 (1H, d, J=1.9 Hz), 7.58 (1H, dd, J 1.9, 8.4 Hz), 6.97 (1H, d, J=8.4 Hz).
Reaction SMILES: [Si](O[C@@H]1CCC[C@H](NC2C(F)=CN=C(C)C=2C2C3C(=NC=C(Cl)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)[C@H]1O)(C(C)(C)C)(C)C.[Si]([O:52][C@:53]1([CH3:88])[CH2:58][CH2:57][CH2:56][C@H:55]([NH:59][C:60]2[C:65]([F:66])=[CH:64][N:63]=[C:62]([C:67]3[C:75]4[C:70](=[N:71][CH:72]=[C:73]([Cl:76])[CH:74]=4)[N:69](S(C4C=CC(C)=CC=4)(=O)=O)[CH:68]=3)[N:61]=2)[C@H:54]1[OH:87])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:76][C:73]1[CH:74]=[C:75]2[C:67]([C:62]3[N:61]=[C:60]([NH:59][C@H:55]4[CH2:56][CH2:57][CH2:58][C@@:53]([CH3:88])([OH:52])[C@@H:54]4[OH:87])[C:65]([F:66])=[CH:64][N:63]=3)=[CH:68][NH:69][C:70]2=[N:71][CH:72]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@](C)(O[Si](C)(C)C(C)(C)C)[C@@H]4O)n3)c3cc(Cl)cnc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)ncc(F)c3N[C@H]3CCC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]3O)c3cc(Cl)cnc32)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)[C@H]1O
Reaction time: 1.5 h

Procedure:
To a stirred solution of (1R,2R,6S)-2-[tert-butyl(dimethyl)silyl]oxy-6-[[2-methyl[5-chloro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyridin-4-yl]amino]cyclohexanol, 50f, (0.11 g; 0.16 mmol) in THF (2 mL) at room temperature, was added tetrabutylammonium fluoride (1.5 equiv) and the reaction mixture stirred for 1.5 h, at which point HPLC-analysis revealed no starting material but the de-tosylated product was observed with minor desilylation. An additional equivalent of TBAF was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was suspended in ethyl acetate (10 mL), washed with H2O (2×4 mL), aqueous saturated NH4Cl solution (2 mL) and brine (2 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to provide 139 mg of crude. The crude residue was purified by reverse phase HPLC (5-95% MeOH/water w/HCl buffer over 15 minutes). to afford 15 mg of desired product, 860. LCMS M+1=392.34
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[C:7]([C:17](=O)[CH3:18])[C:6]=2[CH:20]=1.[NH2:21][OH:22].Cl>CCO.N1C(=O)CC[C@H]1C(O)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[C:7]([C:17](=[N:21][OH:22])[CH3:18])[C:6]=2[CH:20]=1
Reactant: CC(=O)c1c(-c2ccc(O)cc2)oc2ccc(O)cc12
Reactant: NO
Agent: Cl
Agent: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCO
Product: CC(=NO)c1c(-c2ccc(O)cc2)oc2ccc(O)cc12
Yield: 6.5 %

Procedure:
Ketone 110 (1.9 g, 7.1 mmol) was dissolved in a solution of EtOH/Pyr (50 mL/10 mL) and treated with NH2OH—HCl (0.5 g, 7.2 mmol) and heated at reflux until all of the starting material was consumed by TLC analysis. The reaction was worked up by concentrating down and partitioning the residue between EtOAc and 2 N HCl aq, washing the EtOAc layer with saturated NaHCO3 aq, brine and drying over MgSO4. The solution was then filtered, concentrated and chromatographed on silica gel (1:4 EtOAc/hexanes) and the product obtained triturated with CH2Cl2 to yield 0.131 g of the pure oxime. Stereochemistry of the oxime was tentatively defined as cis since no NOE effect between the oxime hydroxyl proton and the adjacent methyl group could be observed: Mp=217° C.; 1H NMR (DMSO-d6) δ 11.27 (s, 1 H), 9.94 (br s, 1 H), 9.23 (br s, 1 H), 7.51 (d, 2 H, J=8.8 Hz), 7.36 (d, 1 H, J=8.3 Hz), 7.03 (d, 1 H, J=2.4 Hz), 6.88 (d, 2 H, J=8.8 Hz), 6.74 (dd, 1 H, J=8.8 Hz, 2.4 Hz), 1.99 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>[OH-].[Na+]>[C:14]([O:13][C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[Cl:1])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C=Cc1ccc(O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1Cl
Temperature: 0 °C

Procedure:
104 g (0.525 mol) of 3-chloro-4-hydroxy-cinnamic acid are dissolved in 530 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 107 g (1.05 mols) of acetic anhydride are introduced dropwise over the course of 15 minutes at 0°-5° C, whilst stirring. The crystals which have precipitated are then filtered off, suction-dried and recrystallised from alcohol-water. 4-Acetoxy-3-chloro-cinnamic acid of melting point 210°-213° C is obtained.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[CH3:24][C:25]([CH3:32])([CH2:29][CH2:30][CH3:31])[C:26](Cl)=[O:27].Cl>C(OCC)C>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:26](=[O:27])[C:25]([CH3:32])([CH3:24])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCNCc1ccc(F)cc1F
Reactant: CCCC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCN(Cc1ccc(F)cc1F)C(=O)C(C)(C)CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
22.7 g (0.10 mol) of N-hexyl-2,4-difluorobenzylamine and 24.3 g (0.24 mol) of triethylamine are dissolved in 150 ml of diethyl ether. A solution of 17.8 g (0.12 mol) of 2,2-dimethylpentanoyl chloride in 50 ml of diethyl ether is added dropwise at room temperature over the course of 30 minutes. The mixture is stirred for a further 18 hours at room temperature until the reaction is complete (GC check). For work-up, the resultant suspension is adjusted to pH 7 using 70 ml of 2N hydrochloric acid. Everything dissolves, and two phases form, which are separated. The organic phase is washed with 50 ml of water, dried using magnesium sulfate, filtered and evaporated on a vacuum rotary evaporator. 37.8 g of a pale yellow liquid, which is subjected to fractional distillation, are obtained. 21.4 g (63% of theory) of a colourless oil which boils at 126°-127° C. and 0.4 mbar are obtained.