Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2CC2C=CC(OC)=CC=2)[CH2:8][C@H:7]([O:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[NH:25]2)[CH2:8][C@H:7]([O:9][C:10](=[O:18])/[CH:11]=[C:12](/[CH3:17])\[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:6][C@@H:5]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:4]1
Reactant: CCCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCCC)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CCCCC[C@@H]1C[C@@H](OC(=O)/C=C(/C)CCCC)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (Z)-((2R,4R,6R)-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-6-pentyl-tetrahydro-2H-pyran-4-yl)-3-methylhept-2-enoate is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH:12]([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH:12]([CH3:18])[C:13]([OH:15])=[O:14])=[CH:19][CH:20]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)C(C)Oc1ccc(C2CCOCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ccc(C2CCOCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
7.6 g of ethyl 2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoate were added to a solution of 17 ml of 2N sodium hydroxide and 100 ml of ethanol and the mixture was stirred for 2 hours at room temperature and then was refluxed for 30 minutes. The mixture was evaporated to dryness and the residue was dissolved in 20 ml of N sodium hydroxide. The solution was washed with ether and acidified with 4N hydrochloric acid. The mixture was filtered and the recovered crystals were washed with water and dried. The product was crystallized from a 50-50 cyclohexane-ethyl acetate mixture to obtain 6.1 g of 2-[p-(4-tetrahydropyranyl)-phenoxy]-propanoic acid melting at 156° C.
Reaction SMILES: Cl.[CH3:2][NH2:3].[Na].F[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]>C1COCC1>[CH3:2][NH:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: CNc1ccccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 95.2 %

Procedure:
Methylamine hydrochloride (2.7 g) and a 10% aqueous solution of sodium hydroxyde (30 ml) were added to a solution of 1-fluoro-2-nitrobenzene (2.82 g) in THF (20 ml). The mixture was kept at 23° for 24 h. The reaction mixture was then concentrated in vacuo, taken up with 10% aqueous sodium hydroxide (30 ml) and extracted with EA (3×30 ml). The combined organic layers were washed with a saturated ammonium chloride solution (50 ml), brine (50 ml) and dried. Evaporation of the solvent gave the title compound as an orange oil (2.894 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([F:17])=[C:7]([OH:16])[C:8]([F:15])=[C:9]([F:14])[C:10]=1[N+:11]([O-:13])=[O:12])[CH:2]=[CH2:3].[F:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[C:23]([F:28])[C:22]([F:29])=[C:21](F)[C:20]=1[F:31].C(=O)([O-])[O-].[K+].[K+]>C1(=O)OCCC1>[N+:25]([C:24]1[C:23]([F:28])=[C:22]([F:29])[C:21]([O:16][C:7]2[C:8]([F:15])=[C:9]([F:14])[C:10]([N+:11]([O-:13])=[O:12])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:6]=2[F:17])=[C:20]([F:31])[C:19]=1[F:18])([O-:27])=[O:26]
Reactant: C=CCOc1c(F)c(O)c(F)c(F)c1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C1CCCO1
Product: C=CCOc1c(F)c(Oc2c(F)c(F)c([N+](=O)[O-])c(F)c2F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
24.9 g of 3-(prop-2-enyloxy)-4-nitro-2,5,6-trifluorophenol prepared as described in Example 6 (0.1 mol) and 21.3 g of pentafluoronitrobenzene (0.1 mol) are dissolved in 300 ml of γ-butyrolactone in a three-neck flask fitted with stirrer. 30 g of potassium carbonate (0.22 mol) are then added in portions, and the mixture is stirred at room temperature for 24 hours. The reaction solution is then filtered via a fluted filter, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 300 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated crude product is then recrystallized from a mixture of methylene chloride and petrol ether (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].[N:18]1([C:24]2[C:25](=[O:30])[NH:26][CH2:27][CH2:28][CH:29]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C.O>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:29]2[C:24]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)([C:25](=[O:30])[NH:26][CH2:27][CH2:28]2)[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1)=[O:17])[CH3:2]
Reactant: O=C1NCCC=C1N1CCOCC1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NN(c2ccc(OC)cc2)C2(N3CCOCC3)C(=O)NCCC12
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 582 mg, 2.0 mmol) in ethyl acetate (EtOAc, 10 mL) was treated with 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (45, 364 mg, 2.0 mmol, 1.0 equiv) at 0–5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 505 mg, 0.70 mL, 5.0 mmol, 2.5 equiv) at 0–5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was treated with water (10 mL) and EtOAc (10 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated NaCl aqueous solution (5 mL), dried over MgSO4, and concentrated in vacuo. The residue was directly purified by flash column chromatography (SiO2, 15–40% EtOAc/hexane gradient elution) to afford the desired 1-(4-methoxy-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridin-3-carboxylic acid ethyl ester (51, 523 mg, 805 mg theoretical, 65%) as pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 51, CIMS m/z 401 (M+−H, C20H26N4O5).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.[C:16]([N:19]1[CH2:24][CH2:23][CH:22]([C:25]([N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=O)[CH3:37])[CH:31]=2)[CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1)(=[O:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].C(O[Ti+](OC(C)C)OC(C)C)(C)C.O.CO>[C:16]([N:19]1[CH2:20][CH2:21][CH:22]([C:25]([N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]([NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:37])[CH:31]=2)[CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24]1)(=[O:18])[CH3:17]
Reactant: CCN(C(=O)C1CCN(C(C)=O)CC1)c1cccc(C(C)=O)c1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(C)O[Ti+](OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)C1CCN(C(C)=O)CC1)c1cccc(C(C)Nc2ccccc2Oc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Chlorophenoxy)aniline (95 mg, 0.431 mmol, 1 eq) and 1-acetyl-N-(3-acetylphenyl)-N-ethylpiperidine-4-carboxamide (150 mg, 0.474 mmol, 1.1 eq) were stirred in dry dichloromethane (DCM) (2 mL) at room temperature for 10 min. Tri-isopropoxytitanium chloride (206 μL, 1.654 mmol, 2 eq) was added to the reaction mixture which was stirred at room temperature for 16 hours. Sodium triacetoxyborohydride (365 mg, 1.724 mmol, 4 eq) was then added to the reaction mixture and was stirred at room temperature for a further 24 h. The reaction mixture was then poured onto a solution of saturated aqueous sodium bicarbonate (100 mL) and extracted with DCM (120 mL). The organic layer was washed with brine (120 mL), dried over MgSO4, filtered and concentrated to give the crude as a yellow oil. Purification of the crude by flash chromatography (ISCO) eluting with a gradient [0-10% MeOH/DCM] gave as a pale yellow oil. 1H NMR (270 MHz, CDCl3) δ 0.98 (3H, dt, J=3.1, 7.0 Hz, CH3), 1.25 (1H, m, CH2), 1.50 (3H, d, J=6.2 Hz CH3), 1.50-1.71 (3H, m, CH2), 1.95 (3H, d, J=7.2 Hz) 2.05-2.20 (2H, m, CH2), 2.40 and 2.65 (1H, m, CH), 3.50-3.72 (3H, m, CH2), 4.30-4.61 (3H, m, CH and NH), 6.32 (1H, d, J=7.8 Hz, ArH), 6.55 (1H, q, J=7.3 Hz, Ar), 6.70-6.90 (4H, m, Ar), 6.95-7.05 (2H, m, Ar), 7.20-7.42 (4H, m, Ar); LCMS (90% MeOH and 10% H2O; Symmetry C18 reverse phase column) tr=2.38 min; (ES+), m/z 520.3; HRMS (ESI) calcd. for C30H35ClN3O3 (M+H)+ 520.2289, found 520.2343. HPLC 99.49% purity.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5](OC)=[O:6])=[CH2:3].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([N:19]1[CH2:3][CH:2]([C:1]([O:10][CH3:11])=[O:9])[CH2:4][C:5]1=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: NCc1ccccc1
Solvent: CO
Product: COC(=O)C1CC(=O)N(Cc2ccccc2)C1

Procedure:
A solution of dimethyl itaconate (50 g, 0.32 mole) in methanol (40 ml) was treated with benzylamine (34.6 ml, 0.32 mole) and the mixture heated under reflux for 2.5 h. The solution was then concentrated in vacuo and the residue purified by distillation (b.p. 162° C.-170° C./0.2 mmHg) to give a pale yellow oil. This solidified on standing to give the title compound (D16) as a beige solid (66.2 g, 89%), m.p. 62° C.-63° C.
Reaction SMILES: C(C(CCC)=O)=C.N12CCCN=C1CCCCC2.C[O-].[Na+].CO.[CH2:24]([C:28]1([CH2:42][CH2:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])[CH2:36][C:35]2[C:30](=[CH:31][C:32]([F:40])=[C:33]([O:38][CH3:39])[C:34]=2[Cl:37])[C:29]1=O)[CH2:25][CH2:26][CH3:27].Cl>O1CCCC1.C(O)(=O)C>[CH2:24]([C:28]12[CH2:42][CH2:43][C:44](=[O:48])[C:45]([CH2:46][CH3:47])=[C:29]1[C:30]1[C:35](=[C:34]([Cl:37])[C:33]([O:38][CH3:39])=[C:32]([F:40])[CH:31]=1)[CH2:36]2)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCC1(CCC(=O)CCC)Cc2c(cc(F)c(OC)c2Cl)C1=O
Agent: C=CC(=O)CCC
Agent: C[O-]
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC12CCC(=O)C(CC)=C1c1cc(F)c(OC)c(Cl)c1C2
Temperature: 60 °C

Procedure:
A sample of the crude product from step 2 in the preceding example (386 mg, 1.36 mmol) in anhydrous tetrahydrofuran (2.7 mL) was treated with propyl vinyl ketone (0.188 mL, 1.63 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.041 mL, 0.272 mmol). The mixture was stirred and heated in an oil bath at 60° C. for two hours. TLC showed very little reaction. The mixture was treated with 0.5M sodium methoxide in methanol (0.54 mL, 0.272 mmol) and then stirred with heating at 60° C. for an additional 16.3 hours. After cooling to room temperature, the solvent was evaporated under vacuum to give a residue consisting mainly of 2-butyl-4-chloro-6-fluoro-5-methoxy-2-(3-oxohexyl)-1-indanone. This material was dissolved in acetic acid (6 mL), treated with aqueous 6N HCl (3 mL), and stirred while heating in an oil bath at 80° C. for 22.3 hours. After cooling, the mixture was partitioned between EtOAc (150 mL) and water (150 mL). The organic phase was washed with aqueous K2CO3 (100 mL) and brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (420 mg). The crude product was purified by preparative layer chromatography on four 0.1×20×20 cm silica gel GF plates, developing three times with 10% EtOAc in hexanes. The product bands were combined, eluted with EtOAc, and the eluent evaporated under vacuum to give 9a-butyl-8-chloro-4-ethyl-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an oil (153 mg). The product contained trace amounts of 9a-butyl-6-chloro-4-ethyl-8-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as evidenced by 1H NMR spectroscopy.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][CH3:7])C.Cl.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH3:7][S:6][CH2:5][CH2:4][NH:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:27])[F:28])=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(CSC)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CSCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A solution of 2-(methylthio)-acetaldehyde diethyl acetal (0.465 g, 2.83 mmol) in 0.5 M HCl (5.66 mL, 2.83 mmol) was heated to 50° C. and stirred under nitrogen for 1 h. The reaction mixture was allowed to cool and extracted with CH2Cl2 (20 mL). The organic solution was dried (hydrophobic frit), and stood over molecular sieves for 2 h then decanted off into a clean flask. To this solution was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.67 g, 2.83 mmol) followed by sodium triacetoxyborohydride (1.68 g, 7.93 mmol) and acetic acid (0.162 mL, 2.83 mmol). The resultant mixture was stirred at room temperature under nitrogen for 16 h. The reaction was quenched with sat. NaHCO3 aq. (30 mL) and extracted with CH2Cl2 (2×40 mL), the organic solution was passed through a hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (90 g Silica column) eluted with 1:19 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (397 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH3:14])=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:7]2[NH:6][C:5]([CH:9]=[O:10])=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=2[CH2:1][CH3:2])=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCc1c(-c2ccc(F)cc2)[nH]c(C=O)c1C(=O)OC
Temperature: 85 °C

Procedure:
Methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate was obtained following the procedures described in Example 3. To a solution of methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate (0.123 g, 0.40 mmol) in dimethoxyethane (4.0 mL) was added K3PO4 (0.426 g, 2.00 mmol), Pd(PPh3)4 (0.0463 g, 0.04 mmol), and 4-fluorophenylboronic acid (0.0842 g, 0.60 mmol). The reaction was deoxygenated by bubbling argon through the solution prior to being heated to 85° C. and refluxed for 16 h under argon. After cooling to ambient temperature, the reaction was filtrated through a pad of silica gel and concentration. The resultant residue was dissolved in acetonitrile and purified by reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 10.15 (s, 1H); 7.43 (dd, J=3.4, 5.2 Hz, 2H); 7.18 (app t, 8.6 Hz, 2H); 3.94 (s, 3H); 2.80 (q, J=7.4 Hz, 2H); 1.22 (t, J=7.4 Hz, 3H). HRMS (ES) exact mass calculated C15H15FNO3 (M+H): 276.1312. Found 276.1264
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:6]2[C:5]3[CH2:9][CH2:10][CH2:11][C:4]=3[N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3c2CCC3)CC1
Temperature: 60 °C
Yield: 46.2 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (2.71 g, 14.34 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.45 g, 17.20 mmol, 1.2 equiv) in anhydrous DMF (40 mL) was heated to 60° C. for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO4 and the product purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (14:3→1:1) providing 2.34 g (47%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.32-1.43 (m, 2H), 1.39 (s, 9H), 1.79-1.82 (m, 2H), 2.0 (quint, J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.80-2.88 (m, 2H), 3.93-3.98 (m, 2H), 4.04-4.13 (m, 1H), 7.07 (d, J=8.0 Hz, 1H). 13C NMR (75 MHz, DMSO): δ 21.12, 26.42, 28.04, 31.17, 33.19, 42.55, 47.12, 78.53, 114.87, 153.84, 157.95, 159.02, 172.18. MS (ISP): 353.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]([CH3:22])([CH3:21])[CH:14]=3)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1>C(O)(=O)C.[Pt](=O)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C:13]3[C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]([CH3:22])([CH3:21])[CH:14]=3)=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: CC1(C)C=C(C(=O)c2ccc3cnccc3c2)C(C)(C)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC1(C)C=C(C(=O)c2ccc3c(c2)CCNC3)C(C)(C)CC1
Reaction time: 3 h
Yield: 42.2 %

Procedure:
To the product of Example 10i (130 mg, 0.47 mmol) in acetic acid (2 mL) was added platinum dioxide (20 mg) and the reaction mixture was stirred under an atmosphere of hydrogen for 3 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate and the aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the title compound (59 mg, Yield: 42%). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 5.77 (s, 1H), 4.11 (s, 2H), 3.21 (t, J=5.6 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H), 2.32 (s, 1H), 1.58 (s, 4H), 1.24 (s, 6H), 1.05 (s, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[S:7])=[CH:4][CH:3]=1.C(Cl)CCl.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1[OH:29])([CH3:18])([CH3:17])[CH3:16].Cl>[Ti](Cl)(Cl)(Cl)Cl.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[CH:22]=[C:21]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:20]([OH:29])=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:24]=2)=[S:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Cc1ccc(C(=S)Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCCl
Solvent: CCCCCC
Product: Cc1ccc(C(=S)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
A solution of 54.4 g. (0.29 mole) of 4-methylthiobenzoyl chloride in 200 ml. of dichloroethylene is added gradually to 55 g. (0.29 mole) of titanium tetrachloride. After cooling this mixture, a solution of 60 g. of 2,6-di(t-butyl)phenol in 200 ml. of dichloroethylene is added. The resulting mixture is stirred for several hours, then hydrolyzed with 10 percent hydrochloric acid. The organic layer is separated, washed with water, dried and evaporated to provide a yellow oil. This product is mixed with hexane to provide a white solid which is recrystallized from hexane to provide 4-(4-methylthiobenzoyl)-2,6-di(t-butyl)phenol, m.p. 135°-136 C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ccnc23)CC1

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f1) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:51][CH2:50][C:45]2([O:49][CH2:48][CH2:47][O:46]2)[CH2:44][CH2:43]1)=O>>[O:49]1[C:45]2([CH2:50][CH2:51][N:42]([CH2:40][CH2:39][O:37][C:36]3[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]4[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=4[CH:17]4[CH2:26][CH2:25][C:24]5[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=5[CH2:18]4)=[CH:3][C:2]=3[F:1])[CH2:43][CH2:44]2)[O:46][CH2:47][CH2:48]1
Reactant: O=C(CCl)N1CCC2(CC1)OCCO2
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC4(CC3)OCCO4)c(F)c2)c1
Yield: 36.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)ethanone (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.4 mg) was obtained.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH:16]=3)([CH3:14])[C@@H:12]([O:21]C(C)(C)C)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.NC1C=CC=CC=1.N.Cl([O-])(=O)(=O)=O.[Li+].Cl>C(O)C.[Hg].O>[CH3:14][C@@:13]12[C@@H:12]([OH:21])[CH2:11][CH2:10][C@H:9]1[C@@H:8]1[CH2:7][CH2:6][C:5]3[C@@H:18]([C@H:17]1[CH2:16][CH2:15]2)[CH2:19][CH2:20][C:3](=[O:2])[CH:4]=3
Reactant: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@]2(C)[C@@H](OC(C)(C)C)CC[C@@H]12
Agent: Cl
Agent: N
Agent: [Hg]
Solvent: O
Solvent: CCO
Solvent: Nc1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O

Procedure:
1.0 g. of 3-methoxy-17β-tert.-butoxy-1,3,5(10),9(11)-estratetraene is dissolved in 4 ml. of aniline and 3 ml of ethanol, added to 150 ml. of liquid ammonia, 5 g. of lithium perchlorate and electrolyzed for 2 hours at 1 ampere on a mercury electrode in a cell divided by a porous glass plate. After the mixture has been worked up, the crude product (1.1 g.) is dissolved in ethanol and heated with 3 ml. of concentrated hydrochloric acid. By gently adding water, 0.6 g. of nortestosterone is obtained after cooling which, after recrystallization from isopropyl ether, has a melting point of 108°-110° C.