Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH3:30][C:31]1[N:32]=[C:33]([CH2:36][N:37]2[C:42]3[CH:43]=[C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[S:45][C:41]=3[C:40](=[O:52])[N:39]([CH:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)[C:38]2=[O:59])[S:34][CH:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:56]4[CH2:57][CH2:58][CH:53]([N:39]5[C:40](=[O:52])[C:41]6[S:45][C:44]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)=[CH:43][C:42]=6[N:37]([CH2:36][C:33]6[S:34][CH:35]=[C:31]([CH3:30])[N:32]=6)[C:38]5=[O:59])[CH2:54][CH2:55]4)=[O:21])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: Cc1csc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(C)cs5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (159 mg; compound C10), 1-[(4-methyl-1,3-thiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B38), HBTU (167 mg) (additional 76 mg of HBTU are added after 90 min), DIPEA (0.28 ml) and DCM (3 ml). The crude product is purified by flash column chromatography (amino phase silica gel, eluent: EtOAc) and subsequent preparative thin layer chromatography [eluent: DCM/MeOH/triethylamine, 95/5/0.5 (v/v/v)] to yield the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.NC1C=CC=C2C(N(O)C(=O)C=12)=[O:14].[OH-].[Na+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:14])=[CH:4][CH:3]=1
Reactant: Nc1cccc2c1C(=O)N(O)C2=O
Reactant: Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C=O)cc1
Yield: 62 %

Procedure:
172 mg (1.60 mmol) of 4-toluidine were reacted analogously to Example 1 in the presence of 32.1 mg (0.180 mmol) of 3-amino-N-hydroxyphthalimide. After a reaction time of 22 hours, the reaction solution was brought to pH 8 with 2M NaOH, extracted with chloroform and examined by NMR spectroscopy. Yield 62% of 4-aminobenzaldehyde.
Reaction SMILES: [CH2:1]1[CH:12]2[CH:4]([N:5]([CH2:13][C:14]([NH2:16])=O)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1>B.C1COCC1>[CH2:1]1[CH:12]2[CH:4]([N:5]([CH2:13][CH2:14][NH2:16])[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[CH2:3][CH2:2]1
Reactant: NC(=O)CN1c2ccccc2C2CCCC21
Agent: B
Solvent: C1CCOC1
Product: NCCN1c2ccccc2C2CCCC21
Temperature: 25 °C

Procedure:
2-(2,3,3a,8b-Tetrahydrocyclopenta[b]indol-4(1H)-yl)acetamide (90 mmol, 20 g) was dissolved in 1 M BH3.THF (200 mL) and heated to reflux for 18 h. The reaction mixture was allowed to cool to room temperature and then quenched slowly with methanol. The solution was concentrated, dissolved in methanol, and again concentrated. The resulting oil was diluted with ether and extracted twice with 1 N HCl. The aqueous phase was treated with 2.5 N NaOH to pH>10 and extracted with chloroform. The combined chloroform extracts were dried over MgSO4, filtered and concentrated to provide a yellow oil which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37]>C(Cl)Cl>[Br:37][CH2:15][CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([NH:7][C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:9][CH2:10]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCC[C@H]1CC[C@H](Nc2ncccn2)CC1
Reaction time: 1 h

Procedure:
A mixture of trans-2-[4-(pyrimidin-2-ylamino)-cyclohexyl]-ethanol (1.51 g, 6.9 mmol) is dissolved in a solution of methylene chloride (25 mL) containing polymer supported triphenylphosphine (2.87 g, approx 8.6 mmol). The mixture is cooled in an ice water bath, and carbon tetrabromide (2.3 g, 7.0 mmol) is added. The reaction is stirred for 1 hour, and the polymeric material was removed by filtration. The filtrate is concentrated and chromatographed on silica gel using a 2:1 mixture of chloroform and ethyl acetate (EtOAc) as the solvent to give trans-[4-(2-Bromoethyl)-cyclohexyl]-pyrimidin-2-yl-amine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:22]1([CH2:28][C:29]2[N:34]=[C:33]3[CH2:35][O:36][C:37](=O)[C:32]3=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:37]1[C:32]2[C:33](=[N:34][C:29]([CH2:28][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:30][CH:31]=2)[CH2:35][O:36]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: O=C1OCc2nc(CN3CCOCC3)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2ccc(F)cc2C1=C1OCc2nc(CN3CCOCC3)ccc21
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (113 mg, 0.75 mmol.) in THF (1 mL) is placed under an argon atmosphere cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (2 mL of a 1M solution in THF, 2 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. The ice-bath is removed and a solution of 2-morpholin-4-ylmethyl-7H-furo[3,4-b]pyridin-5-one (120 mg, 0.5 mmol) in THF (2 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4 h and then poured into a 10% aqueous HCl solution. The resulting solution is stirred for 48 h at room temperature. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH, EtOAc, Et2O (3×5 mL). The residual solid is purified by chromatography (silica gel, 5% MeOH in EtOAc). The product containing fractions are concentrated to give the title compound as a yellow solid (65 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=O)[CH:4]=1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=[CH:17][N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: COc1cc(C=O)cc2c1OCO2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1cc(C=C[N+](=O)[O-])cc2c1OCO2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
3-Methoxypiperonal (50.0 g) is combined with 71.9 mL of nitromethane in 250 mL of acetic acid; 36 g of ammonium acetate is added, and the mixture is heated to 50° C. for 4 hrs. Solvents are removed in vacuo; the residue is taken up in water and stirred for 20 min. The solution is filtered; the filtrate is washed with water, then ether, to give 51.8 g of a yellow solid.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:10])[NH:2]2.[C:20]([O:27][CH3:28])(=[O:26])/[CH:21]=[CH:22]\[C:23]([O-])=[O:24]>>[CH3:28][O:27][C:20](/[CH:21]=[CH:22]\[C:23]([N:2]1[C@H:3]([C:9]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:10])[CH2:4][C@H:5]2[C@@H:1]1[CH2:8][CH2:7][CH2:6]2)=[O:24])=[O:26]
Reactant: CCCCCCCCOC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Reactant: COC(=O)/C=C\C(=O)[O-]
Product: CCCCCCCCOC(=O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)/C=C\C(=O)OC

Procedure:
This compound was obtained analogously to the method described in Example 1 from n-octyl (1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxylate and monomethyl maleate. MS (DCI) =380 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15](O)=[O:16])=[CH:9][CH:8]=1.[CH3:21][NH2:22]>>[CH3:21][NH:22][C:15](=[O:16])[C:14]#[C:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1
Reactant: CN
Reactant: O=C(O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Product: CNC(=O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 45 %

Procedure:
The title compound is prepared in analogy to example 5 d), starting from [4-(3-fluoro-benzyloxy)-phenyl]-propynoic acid and aqueous methylamine. Colorless solid. Yield=45%. MS: m/e=284.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[BH4-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:12]3[CH2:13][CH2:14][CH2:15]3)[CH2:7][NH:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: O=S1(=O)N=CN(C2CCC2)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=S1(=O)NCN(C2CCC2)c2ccc(Cl)cc21
Reaction time: 0.17 h

Procedure:
To a solution of the 7-chloro-4-cyclobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxide originating from the Step above (3 g) in isopropanol (100 mL) there is added finely ground NaBH4 (2.5 g) and then heating is carried out for 10 minutes at 55° C. The solvent is removed by evaporation under reduced pressure. The residue is taken up in water (100 mL) and brought to acid pH by adding 6N HCl. The title product is extracted with chloroform (3×50 mL). The organic phase is dried over MgSO4 and filtered. The filtrate is evaporated to dryness and the residue is purified by chromatography on a silica column (mobile phase: chloroform). The product obtained is recrystallised from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](Cl)=[O:7].[NH2:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[O:25][CH3:26].CCOCC>C(O)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[CH:18]=[C:17]2[O:25][CH3:26])=[O:7]
Reactant: COc1cc(C)nc2ccc(N)cc12
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1cc(C)nc2ccc(NC(=O)C=Cc3ccccc3Cl)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chlorocinnamoyl chloride (prepared by treatment of 2-chlorocinnamic acid with oxalyl cloride and catalytic DMF in dichloromethane) (0.27 gm) in 1 mL acetic acid was added to a solution of 6-amino-4-methoxy-2-methyl-quinoline (0.25 g, 1.33 mmol) in glacial acetic acid (3 mL). A heavy precipitate formed, and the mixture was stirred for 1 h at room temperature. Ether (25 mL) was added and the solid was filtered, washed with ether, and dried by suction. The hydrochloride salt was suspended in warm water (25 mL) and ethanol (25 mL) and heated until dissolved. After cooling to room temperature, 5N sodium hydroxide was added to give a white precipitate that was filtered, and washed with water. Recrystallization from ethanol afforded the title compound; yield 0.27 g (58%); m.p. 228-229°; MS (FAB): m/z 353 (M+1).
Reaction SMILES: [CH3:1][CH:2](/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:11])[CH3:3].ClC([O:26][CH:27]1[CH:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][CH:29]([CH3:36])[CH2:28]1)=O.C(N(CC)CC)C>ClCCl>[CH3:3][CH:2](/[CH:4]=[CH:5]/[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([O:20][CH3:21])[CH:19]=1)=[O:11])[CH3:1].[CH3:36][C@H:29]1[CH2:28][C@@H:27]([OH:26])[C@H:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30]1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Agent: COc1cc(CNC(=O)CCCC/C=C/C(C)C)ccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of capsaicin (0.7 g, 2.3 mmol) and (−)-menthyl chloroformate (0.5 g, 2.3 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (0.45 g, 4.5 mmol) dropwise at ambient temperature. After the addition, the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with 5% aqueous K2CO3 solution, brine, dried over MgSO4, concentrated to dryness. The obtained crude product was purified through silica gel column chromatography (30% -50% ethyl acetate in hexane as the eluent) to give 0.98 g of capsaicin l-menthol mutual prodrug (87% yield) as clear viscous oil. 1H-NMR and 13C-NMR of the obtained capsaicin l-menthol mutual prodrug were consistent with the desired structure (see FIGS. 34, 35). Mass spectral analysis of the product was consistent with the desired structure (FIG. 36).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1(C)[O:35][C@H:34]([CH2:36]O)[CH2:33][O:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][C:18]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:36][C@@H:34]([OH:35])[CH2:33][OH:32])=[CH:26][CH:27]=5)[CH2:22][CH2:21][C:19]=4[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OC[C@H](O)COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
Nitrogen was bubbled to a solution of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazol-7-ol (Preparation 43C, 0.021 ml, 0.169 mmol) and (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (0.021 ml, 0.169 mmol) in THF (2.5 ml) at room temperature for two min. To this mixture was added triphenylphosphine (0.044 g, 0.169 mmol) in one portion. Nitrogen was bubbled for two more minutes followed by the addition of diethyl azodicarboxylate (0.027 ml, 0.169 mmol) dropwise. The reaction vessel was immersed in a preheated oil bath held at 65° C., heated for 3 h., cooled, and concentrated under reduced pressure. The residue was extracted with ether and washed with water. The aqueous layer was re-extracted with ether and the combined organic layers were washed with brine, dried over magnesium sulfate, concentrated, and dried in vacuo. The residue was taken in 2 ml of acetic acid, cooled to 0° C. and treated with 1 ml 1N HCl. The reaction mixture was stirred at 0° C. for 30 min., concentrated under reduced pressure, and purified by silica gel column chromatography using hexane/ethyl acetate (0 to 30%) to yield (S)-3-(2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]oxazol-7-yloxy)propane-1,2-diol (4.3 mg, 8.92 μmol, 11.84% yield) as a clear oil. The compound had an HPLC retention time of 9.39 min (Condition: Column: Sunfire C18 3.5 um, 3.0×150 mm; (15 min); solvent A: 95/5 water/MeCN with 0.05% TFA; solvent B: 5/95 water/MeCN with 0.05% TFA; Start % B=10 to Final % B=100; Wavelength=220 nm). LC/MS M+1=473.27. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.58-7.68 (5H, m), 7.45 (1H, d, J=8.36 Hz), 7.02 (1H, d, J=2.42 Hz), 6.94 (1H, dd, J=8.36, 2.42 Hz), 4.99 (1H, d, J=5.06 Hz), 4.70 (1H, t, J=5.61 Hz), 4.02-4.09 (1H, m), 3.88-3.95 (1H, m), 3.74-3.84 (1H, m), 3.42-3.50 (2H, m), 3.14 (2H, t, J=7.92 Hz), 2.90-3.00 (2H, m).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[Cl:32][C:33]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:35]([C:34]3[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:33]=3[Cl:32])[OH:36])=[N:3][CH:4]=[C:5]([CH3:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1C(O)c1cc([N+](=O)[O-])ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (472 mg, 1.0 mmol) in THF (3 mL) under nitrogen atmosphere at 0° C. was added dropwise isopropylmagnesium chloride (2 M solution in THF, 1.2 mL, 2.4 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2-chloro-5-nitro-benzaldehyde (352.6 mg, 1.9 mmol) at 0° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2-chloro-5-nitro-phenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (441 mg) in 76% yield. ESMS m/z (relative intensity): 580 (M+H)+ (100), 602 (M+Na)+ (20).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>CN(C=O)C.[Cl-].[Li+]>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([N:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[CH:25][CH:24]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc(N2CCOCC2)cc1
Temperature: 115 °C

Procedure:
Isatoic anhydride (1.63 g, 10 mmol) was dissolved in DMF (40 mL) and added to 4-morpholinoaniline (1.78 g, 10 mmol). The reaction mixture was heated to 115° C. for 2.5 h. It was then cooled to room temperature, diluted with 5% lithium chloride solution (120 mL), and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with water (100 mL), 10% aqueous sodium hydroxide (100 mL), and water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give 2-amino-N-(4-morpholinophenyl)benzamide as a gray solid. Yield 1.71 g (57%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][C@@H:9](OC(OC)=O)[C@@H:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH3:21])[CH:16]([O:19][CH3:20])[O:17][CH3:18])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](OC(OC)=O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:28]2[O:29][C@@H:27]2[C@@:26]2([CH3:30])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH3:21])[CH:16]([O:17][CH3:18])[O:19][CH3:20])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C(OC)OC)CC[C@H]3[C@H]12
Agent: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Product: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 45.4 %

Procedure:
The procedure of Example 17 was repeated except that 40.4 mg (0.0798 mmole) of 1α,2α-epoxy-21,21-dimethoxy-7α-methoxycarbonyloxy-20-methylpregn-5-en-3β-yl acetate was used in lieu of 43.6 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate to give 15.6 mg of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3β-yl acetate. In addition, 14.1 mg of the starting compound 1α,2α-epoxy-21,21 -dimethoxy- 7α-methoxycarbonyloxy- 20-methylpregn-5 -en-3β-yl acetate was recovered. The yield of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3β-yl acetate was 70% based on consumed 1α,2α-epoxy-21,21-dimethoxy-7α-methoxycarbonyloxy-20-methylpregn-5-en-3β-yl acetate.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=C[CH:9]=[C:10](OC(F)(F)F)[CH:11]=2)[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2].[NH:22]1C2=NC=CC=C2C(C(=O)C)=C1>>[C:1]([C:4]1[C:12]2[C:7](=[N:22][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:18][C:19]([OH:21])=[O:20])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Reactant: CC(=O)c1c[nH]c2ncccc12
Product: CC(=O)c1cn(CC(=O)O)c2ncccc12

Procedure:
was prepared in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid from 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone [83393-46-8]. MS (UPLC/MS): 219.2 [M+H]+, 217.2 [M−H]−, 263.3 [M+HCOO]−, 435.3 [2M−H]−; tR (HPLC conditions f): 1.16 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 8.55 (bs, 1H), 8.49 (dd, 1H), 8.36 (dd, 1H), 7.31 (dd, 1H), 5.12 (s, 2H), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:32])[C:17]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl>CO>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:32])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(C(C)c4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Agent: Cl
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(C(C)c4ccccc4)n2)CNCC3)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(1-phenylethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (612 mg, 1.20 mmol) was dissolved in methanol (10 mL). Hydrochloric acid (0.098 mL, 1.20 mmol) was added and the reaction mixture was stirred at 75° C. for 1 h. The solvent was evaporated under reduced pressure and the crude N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-(1-phenylethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (490 mg, 100%) was used as such in the subsequent step. MS (ES+) m/z 411 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][CH:26]3[CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:27]1[CH2:28][CH2:29][CH:26]1[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]=2[F:24])=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2CC1CCN1
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To the crude tert-butyl 2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]azetidine-1-carboxylate (800 mg, 1.63 mmol) dissolved in DCM (4 mL) in ice bath, was dropwise added TFA (2 mL) slowly, stirring for 10 min at which point nostarting material remained by TLC analysis. The solvent was removed and EtOAc added, which was washed with 2M HCl. The combined aq. solution was adjusted with NaOH to pH around 10, and the aq. layer extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent removed to get 450 mg of 1-(azetidin-2-ylmethyl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine, which was used in the next step directly without further purification.