Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24](O)=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:7]=1[C:8]#[CH:9].Cl.[CH3:28][NH:29][O:30][CH3:31].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.Cl.Cl.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([N:29]([O:30][CH3:31])[CH3:28])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6](/[N:10]=[N:11]/[N:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[C:7]=1[C:8]#[CH:9]
Reactant: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#Cc1c(Cl)cc(C(=O)N(C)OC)c(-c2cccc(F)c2)c1/N=N/N1CCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 101.9 %

Procedure:
A solution of 4-chloro-5-ethynyl-3′-fluoro-6-[(E)-pyrrolidin-1-yldiazenyl]biphenyl-2-carboxylic acid (830 g, 2.2 mol), N,O-dimethylhydroxylamine hydrochloride (280 g, 2.9 mol), 1-hydroxybenzotriazole hydrate (360 g, 2.4 mol), and N,N-diisopropylethylamine (1.4 L, 7.8 mol) in tetrahydrofuran (5 L) was treated with EDCI HCl (520 g, 2.7 mol) and stirred at room temperature for 36 hours. The reaction mixture was cooled to approximately 5° C. and treated with 2.0 M hydrogen chloride in water (3.4 L, 6.7 mol) in portions while maintaining the internal temperature lower than 10° C. The organic layer was separated and the aqueous layer was extracted with tetrahydrofuran (2 L). The combined organic layers (˜6 L, pH ˜5) were washed with 2.0 M hydrogen chloride in water (2 L), 0.5 M sodium carbonate in water (2 L), and brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil. This material was azeotroped with toluene to give the desired product (theoretical yield 930 g) as a brown oil. This material was used in the next step without further purification. A small sample was purified for spectroscopic analysis. LCMS for C21H21ClFN4O2 (M+H)+: m/z=415.1; Found: 415.0; 1H NMR (400 MHz, DMSO-d6): δ 7.44 (s, 1H), 7.35-7.29 (m, 1H), 7.12-7.06 (m, 1H), 6.93-6.84 (m, 2H), 4.48 (s, 1H), 3.62-3.58 (m, 2H), 3.29 (s, 3H), 3.25-3.17 (m, 2H), 2.93 (s, 15 H), 2.85 (s, 1.5H), 1.89-1.77 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH:9]([CH3:11])[C:8]([OH:12])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=O)[CH2:6]1)=[O:4].[CH2:18]([OH:21])[CH2:19][OH:20].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:18]1[O:21][C:13]([CH:7]2[C:8](=[O:12])[CH:9]([CH3:11])[CH2:10][N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)([O:15][CH2:16][CH3:17])[O:20][CH2:19]1
Reactant: OCCO
Reactant: CCOC(=O)C1=C(O)C(C)CN(C(=O)OC)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC1(C2CN(C(=O)OC)CC(C)C2=O)OCCO1

Procedure:
A mixture of 1.9 g (7.8 mmol) of (RS)-ethyl 1-methoxycarbonyl-4-hydroxy-5-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate (prepared as described in Acta Chem. Scand. B32, 327 (1978)), ethylene glycol (2.2 ml), 4-toluenesulfonic acid (0.15 g), and toluene was refluxed for 20 hours using a Dean-Stark water separator. The mixture was washed with aqueous sodium bicarbonate, dried and evaporated in vacuo. The crude product was distilled at 0.5 mm Hg, B.P. 148°-152° C. Yield 1.6 g.
Reaction SMILES: Cl.[F:2][C:3]1[C:8](F)=[C:7]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:6]=[CH:5][C:4]=1[C:15]1[S:19][C:18]([N:20]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)[CH2:21]2)=[N:17][N:16]=1.[OH2:36]>O1CCOCC1.CO.CS(C)=O>[CH2:21]1[C:22]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:23][N:20]1[C:18]1[S:19][C:15]([C:4]2[C:3]([F:2])=[CH:8][C:7]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)=[CH:6][C:5]=2[OH:36])=[N:16][N:17]=1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(-c4cn[nH]c4)c(F)c3F)s1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Solvent: CO
Product: Oc1cc(-c2cn[nH]c2)cc(F)c1-c1nnc(N2CC3(CCNCC3)C2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
HCl (4M solution in dioxane, 545 μL, 2.179 mmol) was added to a stirred suspension of tert-butyl 2-(5-(2,3-difluoro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (53 mg, 0.109 mmol) in dioxane (4 mL). The reaction mixture was stirred at room temperature for 2 hours then diluted with dioxane (2 mL), MeOH (5 mL), DMSO (5 mL) and a small amount of water, then loaded onto a 2 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (15 mL) then flushed with 10% DCM in [7M NH3 in MeOH] (20 mL). The DCM/MeOH/NH3 was removed in vacuo to afford the crude product as a brown solid. The crude material was heated in MeOH (5 mL) and the resulting suspension was cooled to room temperature then filtered under vacuum and rinsed with MeOH to afford the title compound as a pale brown solid (23 mg, 55% yield). LC-MS: Rt 0.68 min; MS m/z 387.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.17 (s, 2H), 7.15-7.05 (m, 2H), 3.87 (s, 4H), 2.70 (t, J=5.1 Hz, 4H), 1.73 (t, J=5.3 Hz, 4H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][NH:7][C:8]([NH2:10])=[O:9].[Li]CCCC.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]>C1COCC1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30]([N:7]([CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=2)[C:8]([NH2:10])=[O:9])=[S:31])[CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NC(=O)NCc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC(=O)N(Cc1cccc(C(F)(F)F)c1)C(=S)Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-trifluoromethyl benzyl urea (218 mg, 1 mmol) in dry THF (2 mL) under nitrogen was added dropwise n-BuLi (2.5 M in hexane, 0.4 mL). The mixture was stirred at RT for 30 min and then 3,4-dichlorophenyl isothiocyanate (204 mg, 1 mmol) in dry THF (2 mL) was added dropwise. HPLC analysis after 5 min revealed complete reaction to the expected product. Saturated NaHCO3 (5 mL) and Et2O (15 mL) were added and the phases were separated. The aqueous phase was extracted with Et2O (2×15 mL). The combined organic phases were washed with brine (5 mL) and were dried over MgSO4. Concentration in vacuo gave 412 mg of a yellow oil. Purification by flash chromatography (silica, 20-30% EtOAc in n-hexane) gave 193 mg (46%) of pure product according to 1H NMR.
Reaction SMILES: [OH:1][C@@:2]1([C:35]([F:38])([F:37])[F:36])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[OH-].[Na+].Cl>C(O)C>[OH:1][C@@:2]1([C:35]([F:37])([F:38])[F:36])[C:14]2[CH:13]=[C:12]([O:15][CH2:16][CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[CH:11]=[C:10]([C:22]3[CH:23]=[N:24][N:25]([C:27]([CH3:33])([CH3:34])[C:28]([OH:30])=[O:29])[CH:26]=3)[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CCOC(=O)C(C)(C)n1cc(-c2cc(OCCC(C)(C)O)cc3c2-c2ccccc2[C@]3(O)C(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)CCOc1cc(-c2cnn(C(C)(C)C(=O)O)c2)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 108 %

Procedure:
Ethyl 2-{4-[(9R)-9-hydroxy-2-(3-hydroxy-3-methylbutyloxy)-9-(trifluoromethyl)-9H-fluoren-4-yl]-1H-pyrazol-1-yl}-2-methylpropionate (68.4 g) was dissolved in ethanol (256 ml), 4N aqueous sodium hydroxide (128 ml) was added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (333 ml) was added dropwise, and the mixture was extracted with ethyl acetate (500 ml). The obtained organic layer was washed successively with water (400 ml, twice) and saturated brine (400 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated to give the title compound (70.0 g).
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:12]=2)[CH2:7][C@H:6]1[C:29](=[O:42])[NH:30][C@H:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][CH2:33][CH3:34])=[O:4].[Li+].[OH-].Cl.C(OC(=O)[NH:52][C@H:53]([C:58](=[O:71])[NH:59][C@@H:60]([CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1)[C:61](=[O:64])[NH:62][CH3:63])[C:54]([CH3:57])([CH3:56])[CH3:55])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([C@@H]1C[C@@H](O)C[C@H]1C(=O)N[C@]1(C(OCC)=O)C[C@H]1C=C)=O)(C)(C)C>O1CCOCC1.O.CN(C=O)C>[C:38]([O:37][C:35](=[O:36])[C@@H:31]([NH:30][C:29]([C@@H:6]1[CH2:7][C@@H:8]([O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:12]=2)[CH2:9][C@H:5]1[C:3](=[O:4])[NH:52][C@H:53]([C:58](=[O:71])[NH:59][C@@H:60]([CH:65]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1)[C:61](=[O:64])[NH:62][CH3:63])[C:54]([CH3:56])([CH3:57])[CH3:55])=[O:42])[CH2:32][CH2:33][CH3:34])([CH3:40])([CH3:41])[CH3:39]
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Compound 43 (38 mg, 0.066 mmol) was dissolved in dioxane/water 1:1 (4 mL) and the solution was cooled to 0° C. and 1 M LiOH (132 ul, 0.132 mmol) was added. The temperature was raised to room temperature and the solution was stirred for 2 hours after which it was neutralized by addition of 1M HCl and evaporated and coevaporated with toluene. The residue and deprotected amine 38 (1.1 eq) was dissolved in DMF and coupled using the standard HATU coupling conditions as in the synthesis of compound 34. The crude product was extracted with EtOAc, washed with brine, dried, filtered and concentrated. Purification with HPLC (MeOH/water 9:1+0.2% TEA) provided compound 44 (44 mg, 81%) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].[CH2:9]([OH:12])[CH:10]=[CH2:11].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:9]([O:12][CH2:2][C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4])[CH:10]=[CH2:11]
Reactant: CON(C)C(=O)CBr
Reactant: C=CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCOCC(=O)N(C)OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Scheme 1, steps A and B: Bromoacetyl bromide (1.06 equiv.) is added to a solution of N,O-dimethylhydroxylamine hydrochloride (1.0 equiv.) (Volumes are in mL/g of this compound) in a stirring mixture of water (4 mL/g), toluene (4 mL/g), and K2CO3 (1.15 equiv.) at 0° C. After warming to room temperature over 1 hour, the layers are separated and the aqueous layer is extracted with toluene (2 mL/g). The combined organic layers are concentrated to give the intermediate 2-bromo-N-methoxy-N-methyl-acetamide containing about 20% toluene. 2-Bromo-N-methoxy-N-methyl-acetamide is added to a mixture of allyl alcohol (6.3 equiv) and K2CO3 (2 equiv.) over 3 hours at 30° C. After 2 hours at 30° C., toluene (4 mL/g) is added, the mixture is cooled to 0° C., and filtered. The filter cake is rinsed with cold (0° C.) toluene (2.7 mL/g) and the combined filtrate is washed with a 3 weight % solution of KHSO4 in water (0.6 mL/g). The toluene solution is concentrated while additional toluene (11 mL/g) is added to remove water and allyl alcohol. The concentrated toluene solution is washed with water (0.5 g/g), further concentrated to remove most of the toluene, and then distilled to give the title compound. LC-MS (m/z): 160 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2OCC[O:11]2)=[C:6]([SiH:15]([CH3:17])[CH3:16])[CH:5]=1)[CH:2]=[CH2:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[C:6]([SiH:15]([CH3:17])[CH3:16])[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1ccc(C2OCCO2)c([SiH](C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: C=CCc1ccc(C=O)c([SiH](C)C)c1
Yield: 85.8 %

Procedure:
A solution of 2-(4-allyldimethylsilylphenyl)-1,3-dioxolane (3 Scheme 18, 12 g, 52.5 mmol) and p-toluenesulfonic acid (100 mg) in acetone (300 mL) was heated under reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and acetone (300 mL) was added to the residue. After refluxing for 3 h, the solution was concentrated, and the crude oil was purified by silica gel chromatography (1:20 ethyl acetate/hexanes) to afford a colorless oil (9.2 g, 86%); 1H NMR (300 MHz, CDCl3) δ 0.32 (s, 6 H), 1.78 (d, J=8.10 Hz, 2 H), 4.84 (s, 1 H) 4.89 (m, 1 H), 5.76 (m, 1 H), 7.67 (d, J=8.10 Hz, 2 H), 7.85 (d, J=8.10 Hz, 2 H), 10.05 (s, 1 H); 13C NMR (75 MHz, CDCl3) −3.4 (2C), 23.5, 114.2, 128.8 (2C) 133.7, 134.4, (2C), 136.9, 147.6, 192.8; HRMS calcd for C12H16OSi 204.0971, found 204.0972.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.[CH3:17][NH:18][C:19](SC)=[CH:20][N+:21]([O-:23])=[O:22]>O1CCCC1.O>[N:15]1[C:9]2[NH:8][C:7]3[CH:16]=[C:3]([CH2:2][NH:1][C:19]([NH:18][CH3:17])=[CH:20][N+:21]([O-:23])=[O:22])[CH:4]=[CH:5][C:6]=3[S:11][C:10]=2[N:12]=[CH:13][CH:14]=1
Reactant: CNC(=C[N+](=O)[O-])SC
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Solvent: C1CCOC1
Solvent: O
Product: CNC(=C[N+](=O)[O-])NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 60 °C
Reaction time: 8 h
Yield: 13.9 %

Procedure:
0.7 g of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine and 1.35 g of N-methyl-1-methylthio-2-nitro-1-ethenamine were dissolved in a solvent mixture of tetrahydrofuran (50 ml) with water (3 ml) and stirred at 60° C. for 8 hours. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with methanol/dichloromethane) to thereby give 0.14 g of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:9][CH2:8][CH2:7][CH:6]2[N:3]1[C:4](=[O:10])[CH2:5]2.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[Si:32]([C:39]([CH3:41])=[O:40])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Si:32]([C:39]([CH:5]1[C:4](=[O:10])[N:3]2[CH:6]1[CH2:7][CH2:8][CH2:9][C:2]2([CH3:11])[CH3:1])([OH:40])[CH3:41])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC1(C)CCCC2CC(=O)N21
Reactant: CC(=O)[Si](C)(C)C(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC1(C)CCCC2C(C(C)(O)[Si](C)(C)C(C)(C)C)C(=O)N21
Reaction time: 0.32 h

Procedure:
A solution of (6RS)-2,2-dimethyl-1-azabicyclo[4.2.0]octan-8-one (104 mg, 0.671 mmol) in 1 ml of tetrahydrofuran is added to a solution of lithium diisopropylamide (0.705 mmol made from 99 μl of diisopropylamine and 320 ml of a 2.2M solution of n-butyllithium in n-hexane) in 4 ml of tetrahydrofuran at -78° C. The enolate solution is aged for a period of 12 minutes and then methyl tert-butyldimethylsilyl ketone is added and stirring is continued for a period of 19 minutes. The reaction mixture is poured into a separatory funnel containing 5 ml of a saturated aqueous solution of ammonium chloride and shaken. The mixture is extracted with 10 ml of diethyl ether and the ether solution is dried over magnesium sulfate. Removal of the solvents in vacuo gives 206 mg of a colorless oil. Plate-layer chromatography of this material on silica gel (1:1 ethyl acetate/cyclohexane) provides 171 mg (81%) of (6RS,7SR)-7-[(SR)-1-(tert-butyldimethylsilyl)-1-hydroxyethyl]-2,2-dimethyl-1-azabicycylo[4.2.0]octan-8-one (Rf 0.41-0.65): m.p. 60°-3° C. (recrystallized from pentane); ir (CH2Cl2) cm-1 3608 (br), 1739; nmr (CDCl3) δ0.03 (s, 3), 0.06 (s, 3), 1.00 (s, 9), 1.34 (s, 3), 1.42 (s, 3), 1.76 (s, 3), 1.85 (m, 2), 3.24 (d, 1, J=1.9 Hz), 3.40 (ddd, 1, J=1.9, 4.9 and 10.6 Hz), 3.88 (m, 2); ms m/e 314 (M+1)+, 298, 198; anal. (C16H31NO3Si)C, H, N.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17]3(OCC[O:18]3)[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][C:27]=1[F:40])[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][N:13]=[C:9]2[N:8]([CH:14]2[CH2:23][CH2:22][C:17](=[O:18])[CH2:16][CH2:15]2)[C:7](=[O:24])[C:6]=1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][C:27]=1[F:40])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2ncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Yield: 98.6 %

Procedure:
A mixture of 4′-{[7-butyl-4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile (2.88 g), 3N hydrochloric acid (20 mL) and tetrahydrofuran (20 mL) was stirred under refluxing for 16 hr. The reaction mixture was neutralized with 1 M aqueous sodium hydroxide solution (60 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (2.61 g, 99%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH2:11]([NH2:16])[C:12]([CH3:15])([CH3:14])[CH3:13]>>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][NH:16][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: O=C(O)c1cccc(Br)n1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CNC(=O)c1cccc(Br)n1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 6-bromo-pyridine-2-carboxylic acid and neopentylamine.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C@H:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][C@H:9]4[OH:35])[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 82.8 %

Procedure:
The procedure of Example 23 was repeated except that 4.9 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregn-5-en-3β-yl acetate was used in lieu of 5 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate to give 3.7 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol (yield: 83%).
Reaction SMILES: [CH:1]1[C:9]2[N:8]3[C:10]([CH:13]4[CH:18]([CH3:19])[CH2:17][CH2:16][N:15](C(OCC5C=CC=CC=5)=O)[CH2:14]4)=[CH:11][N:12]=[C:7]3[CH:6]=[N:5][C:4]=2[NH:3][CH:2]=1.[H][H]>[Pd].CCO>[CH3:19][CH:18]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:10]1[N:8]2[C:9]3[CH:1]=[CH:2][NH:3][C:4]=3[N:5]=[CH:6][C:7]2=[N:12][CH:11]=1
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1c1cnc2cnc3[nH]ccc3n12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC1CCNCC1c1cnc2cnc3[nH]ccc3n12
Yield: 83.9 %

Procedure:
A mixture of benzyl 3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylpiperidine-1-carboxylate (0.55 g, 1.4 mmol) and palladium on carbon (10%, 0.38 g, 0.36 mmol) in EtOH (25 mL) was hydrogenated at room temperature under an atmospheric pressure of hydrogen for about 20 h. The catalyst was removed by filtration through a Celite® pad and the filtrate was concentrated in vacuo to give 8-(4-methylpiperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine (0.30 g, 83%) as a yellow amorphous solid: LC/MS (Table 2, Method a) Rt=0.93 min; MS m/z: 256 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH:14]=[CH:13][S:12][C:11]=3[CH:10]=[C:9]([C:16]([OH:18])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:23]([N:25](CC)[CH2:26][CH3:27])[CH3:24].C(NCC)C>C1(C)C=CC=CC=1.C1CCCCC1.C(OCC)(=O)C>[CH2:23]([N:25]([CH2:26][CH3:27])[C:16]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[CH:14]=[CH:13][S:12][C:11]=2[CH:10]=1)=[O:18])[CH3:24]
Reactant: O=C(O)c1cc(-c2ccccc2)c2ccsc2c1
Reactant: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1cc(-c2ccccc2)c2ccsc2c1

Procedure:
The reaction is carried out as in Example 1, starting with 4-phenylbenzo[b]thiophene-6-carboxylic acid (4 g) and thionyl chloride (3.5 cc) in toluene (40 cc) and then adding triethylamine (13.25 cc) and diethylamine (1.6 cc) in toluene (40 cc). After chromatography of the residue on silica gel using a cyclohexane:ethyl acetate (50:50 by volume) mixture as the eluent and then stirring the product collected in 40°-60° petroleum spirit (30 cc) and filtering, N,N-diethyl-4-phenylbenzo[b]thiophene-6-carboxamide (2.55 g), m.p 60° C. is isolated.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[C:16]1([CH2:22][CH2:23][C:24]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:25])[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:16]1([CH2:22][CH2:23][C:24]2([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[O:25][C:1](=[O:6])[CH2:2][C:3](=[O:4])[CH2:5]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: O=C(CCC1=CCCCC1)C1CCCC1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CC(=O)OC(CCC2=CCCCC2)(C2CCCC2)C1
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Methyl acetoacetate (0.66 g, 5.7 mmol) was added to a cooled 0° C. suspension of NaH (0.23 g, 5.7 mmol, 60% dispersion in mineral oil) in THF (10 ml). After 30 min n-BuLi (2.3 mL, 5.7 mmol, 2.5M in hexanes) was added. The resulting dianion was stirred for an additional 30 min and then treated with a solution 3-Cyclohex-1-enyl-1-cyclopentyl-propan-1-one (0.39 g, 1.9 mmol, Step 4 below (in THF (3 ml). After stirring for 4 h at 0° C., the reaction mixture was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to an orange oil that was used without further purification. The oil was dissolved in methanol (8 mL), treated with potassium carbonate (0.79 g, 5.7 mmol), and refluxed under N2 for 90 min. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to an orange oil that was purified by silica gel chromatography (0% to 20% EtOAc in hexanes). to give the title compound as a white solid. (0.22 g, 40% yield). 1H NMR (CDCl3): δ 1.42-1.98 (br m, 20H), 2.22 (m, 1H), 2.71 (s, 2H), 3.40 (s, 2H), 5.40 (s, 1H). Anal. Calcd. For C18H26O3.0.2H2O: C, 75.53; H, 9.05. Found: C, 73.74; H, 9.01.