Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9].[C:10](OC(=O)C)(=O)[CH3:11]>>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:9]=[C:10]1[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccncc1N
Product: Cc1nc2cnccc2n1C
Yield: 64 %

Procedure:
The solution of N4-methylpyridine-3,4-diamine (2.5 g, 20.3 mmol) in acetic anhydride (25 mL) was refluxed overnight. Then acetic anhydride was evaporated under reduced pressure and 1 N hydrochloride acid was added. Then the mixture was extracted with dichloromethane (50 mL×3). The aqueous layer was neutralized with sodium bicarbonate, and extracted with dichloromethane (50 mL×3). The organic layers were concentrated to give the title compound (1.9 g, yield 64%). LC-MS (ESI) m/z: 148 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.64 (s, 3H), 3.74 (s, 3H), 7.23-7.24 (d, J=5.2 Hz, 1H), 8.39-8.41 (d, J=5.2 Hz, 1H), 8.98 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[CH2:9]([O:16][CH2:17][CH2:18][NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[CH2:9]([O:16][CH2:17][CH2:18][NH:19][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCOCc1ccccc1
Reactant: CC(C)(CO)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(CO)C(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a solution of 3-hydroxy-2,2-dimethylpropanoic acid (2.36 g, 20 mmol), 2-(benzyloxy)ethanamine (3.02 g, 20 mmol), and HOBt (2.71 g, 20 mmol) in dry dichloromethane (100 mL) was added EDCI (3.82 g, 20 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The reaction was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaHCO3 solution, dilute HCl, brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 40% EtOAc in hexanes to give the title compound as colorless oil (4.89 g) in 97% yield. MS 252 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:1][CH2:2][CH2:3][C:4]1([OH:7])[CH2:6][CH2:5]1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1(O)CC1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-(2-hydroxyethyl)cyclopropanol (86 mg, 0.843 mmol) and triethylamine (136 mg, 1.35 mmol, Shantou Xilong chemical factory) in 10 mL of dichloromethane was stirred at −10° C. for 30 min. Methanesulfonyl chloride (106 mg, 0.927 mmol, Shanghai Haiqu chemical Ltd.) was then added via a syringe. The reaction was stirred at −10° C. for 1 hr at rt and then quenched with 1 mL ice-water. The resulted mixture was extracted with dichloromethane (20 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to afford 2-(1-hydroxycyclopropyl)ethyl methanesulfonate as yellow oil (used in the next step without further purification).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([OH:16])=[O:15])[N:11]=[N:10][N:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][O:15][C:14](=[O:16])[CH2:13][N:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:9][N:10]=[N:11]1
Reactant: OCCO
Reactant: O=C(O)Cn1nnnc1-c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccc(F)cc1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 80.7 %

Procedure:
To a solution of 300 mg (1.35 mM) of [5-(4-fluorophenyl)tetrazol-1yl] acetic acid in 2 ml of ethylene glycol was added 0.2 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=25/1) for separation and purification, to give 290 mg (yield 80.7%) of [5-(4-fluorophenyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: C(N(S(C1C=CC(C)=CC=1)(=O)=O)[C@H](C(O)=O)CCCCN)C(C)C.[N+](C1C=CC(S(N[C@H](C(O)=O)CC2C3C(=CC=CC=3)NC=2)(=O)=O)=CC=1)([O-])=O.[CH3:52][C:53]1[CH:58]=[CH:57][C:56]([S:59]([N:62]([C@H:67]([C:99]([OH:101])=[O:100])[CH2:68][CH2:69][CH2:70][CH2:71][NH:72][C:73]([C@@H:75]([NH:86][S:87]([C:90]2[CH:95]=[CH:94][C:93]([N+:96]([O-])=O)=[CH:92][CH:91]=2)(=[O:89])=[O:88])[CH2:76][C:77]2[C:85]3[C:80](=[CH:81][CH:82]=[CH:83][CH:84]=3)[NH:79][CH:78]=2)=[O:74])[CH2:63][CH:64]([CH3:66])[CH3:65])(=[O:61])=[O:60])=[CH:55][CH:54]=1>>[CH3:52][C:53]1[CH:54]=[CH:55][C:56]([S:59]([N:62]([C@H:67]([C:99]([OH:101])=[O:100])[CH2:68][CH2:69][CH2:70][CH2:71][NH:72][C:73]([C@@H:75]([NH:86][S:87]([C:90]2[CH:91]=[CH:92][C:93]([NH2:96])=[CH:94][CH:95]=2)(=[O:88])=[O:89])[CH2:76][C:77]2[C:85]3[C:80](=[CH:81][CH:82]=[CH:83][CH:84]=3)[NH:79][CH:78]=2)=[O:74])[CH2:63][CH:64]([CH3:66])[CH3:65])(=[O:60])=[O:61])=[CH:57][CH:58]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Agent: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc(N)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine hydroclloride (200 mg, 0.59 mmol, example 1, step E) as described in general procedure Bc using Nα-(4-nitrobenzenesulfonyl)-L-tryptophan (300 mg, 0.75 mmol) prepared in step A of example 5. The intermediate, Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-nitrobenzenesulfonyl)-L-tryptophanyl]-L-lysine, was reduced following the conditions of general procedure E. The final product was purified by preparative HPLC to yield 266 mg (58%) of the desired material.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:15]([O:19][C:20](Cl)=[O:21])[CH:16]([CH3:18])[CH3:17]>O.O1CCOCC1>[CH2:15]([O:19][C:20]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 132 %

Procedure:
L-Valine (5.86 g, 50 mmol) was dissolved in a mixture of water (200 mL) containing sodium carbonate (10.6 g, 100 mmol). The solution was cooled to 0° C., then a solution of isobutylchloroformate (6.76 g, 49.5 mmol) in dioxane (100 mL) was added dropwise over 50 min. The ice-bath was removed and the reaction stirred overnight. Dioxane was evaporated, the aqueous phase was extracted once with diethylether and the brought to pH 2 by addition of hydrochloric acid. Extraction with DCM (3×, 150 mL each), drying of the organic phase (sodium sulfate) and evaporation gave 21 (14.2 g) as a colorless solid. 1H-NMR (DMSO-d6) δ 12.48 (bs, 1 H), 7.24 (d, J=8.2 Hz, 1 H), 3.95 (dd, J=6.2, 8.3 Hz, 1 H), 3.73 (d, J=6.7 Hz, 1 H), 2.01 (m, 1 H), 1.83 (m, 1 H), 0.87 (bs, 12 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([O:18][Si](C(C)(C)C)(C)C)[CH3:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH:16]([OH:18])[CH3:17])[CH2:14][CH2:15]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1

Procedure:
In 20 ml of dry tetrahydrofuran was dissolved 1.3 g of trans-N-t-butoxycarbonyl-4-(1-t-butyldimethylsilyloxyethyl)cyclohexylmethylamine, and 5.25 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) were added dropwise thereto with stirring under ice-cooling, and the mixture was stirred at room temperature for 55 minutes. Then, 5.0 ml of tetrabutylammonium fluoride (1.0M tetrahydrofuran solution) were added dropwise thereto and the mixture was stirred at room temperature overnight and further at 50° C. for 9 hours. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed successively with an aqueous citric acid solution, an aqueous sodium chloride solution, an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution. The mixture was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=2/1) to obtain 701 mg of the desired compound as a colorless crystalline solid. Further, 38 mg of the desired compound was obtained from the mother liquid.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1.O1CCCC1>O>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][CH2:10][CH:7]2[CH2:8][CH2:9][CH:4]([CH:3]=[O:2])[CH2:5][CH2:6]2)=[CH:13][CH:14]=1)#[N:17]
Reactant: COC=C1CCC(CCc2ccc(C#N)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCC2CCC(C=O)CC2)cc1
Reaction time: 0.5 h

Procedure:
A mixture of 23.5 of p-[2-(4-methoxymethylenecyclohexyl)ethyl]benzonitrile and 300 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1) was boiled at reflux while gassing with nitrogen for 30 minutes. The cooled reaction mixture was poured into 450 ml of water and extracted three times with 300 ml of diethyl ether each time. The organic phases were washed with 200 ml of water, dried over sodium sulphate and concentrated in vacuo at 50° C. There were obtained 21.9 g of 4-[2-(p-cyanophenyl)ethyl]cyclohexanecarboxaldehyde (trans/cis=4:1) as a colourless oil; Rf-value (methylene chloride) 0.3.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:10]2[C:19]([N+:20]([O-])=O)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[O:2]=[C:3]1[NH:20][C:19]2[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[N:11][C:10]=2[N:6]2[CH:7]=[CH:8][CH:9]=[C:5]12
Reactant: COC(=O)c1cnc(-n2cccc2C(=O)OC)c([N+](=O)[O-])c1
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)[nH]c(=O)c1cccn12
Reaction time: 36 h
Yield: 54 %

Procedure:
Methyl 6-(2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (5.00 g, 16.38 mmol) was dissolved in dichloromethane (Volume: 82 ml) and to this solution was added triphenyl phosphite (0.051 g, 0.164 mmol), ammonium metavanadate (0.115 g, 0.983 mmol) and Pt/C (5% wt.) (0.639 g, 0.164 mmol). The reaction mixture was hydrogenated at 100 psi at 25° C. for 36 h. The reaction mixture was filtered through a short plug of celite and the plug and precipitate were washed well with methanol (100 mL) and then MeOH:DCM (100 mL, 1:1). The solids (celite and Pt/C) were continuously extracted with MeOH/DCM mixture (1:1) in a Soxlet extractor for 2 d. The extracts were combined with the earlier filtrates, concentrated in vacuo, crystallized with MeOH (100 mL) and the resulting solid was filtered off and suspended in ethyl ether (200 mL). The solid were filtered off and dried in vacuum to afford methyl 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (2.15 g, 8.84 mmol, 54.0% yield) as a grey solid. 1H NMR (DMSO-d6) δ 11.49 (s, 1H), 8.69 (s, 1H), 8.15 (br. s., 1H), 8.11 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 6.78 (t, J=3.0 Hz, 1H), 3.91 (s, 3H). [M+H] calc'd for C12H9N3O3, 244. found, 244.
Reaction SMILES: [I:1]I.C([O-])(=O)C.[Tl+].[CH3:8][N:9]([CH3:17])[C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1>C(Cl)Cl>[CH3:8][N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][C:13]([I:1])=[C:12]([OH:16])[CH:11]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: II
Agent: CC(=O)[O-]
Agent: [Tl+]
Solvent: ClCCl
Product: CN(C)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.7 %

Procedure:
Iodine (6.35 g, 25 mmol) in methylene chloride (300 mL) was added dropwise over 3 h to a stirred suspension of thallium(I) acetate (7.90 g, 30 mmol) and 3-dimethylaminophenol (3.43 g, 25 mmol) in methylene chloride (300 mL). The resulting mixture was stirred at room temperature for 24 h and filtered. Evaporation of the solvents and chromatography of the residue over silica gel using 0-5% diethyl ether in hexanes gave 5-dimethylamino-2-iodophenol (2.35 g, 36%).
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7]/[CH:8]=[CH:9]/[CH3:10].[Li]CCCC.B(F)(F)F.CCOCC.[OH:25][C:26]1[C:35]([CH:36]=[O:37])=[C:34]2[C:29]([C:30]([CH2:39][CH2:40][CH3:41])=[CH:31][C:32](=[O:38])[O:33]2)=[C:28]2[O:42][C:43]([CH3:47])([CH3:46])[CH:44]=[CH:45][C:27]=12.[Na]>C1COCC1.C(OCC)C.[Cl-].[Na+].O.O.CCOCC.C1COCC1>[OH:25][C:26]1[C:35]([C@H:36]([OH:37])[C@H:9]([CH3:10])[CH:8]=[CH2:7])=[C:34]2[C:29]([C:30]([CH2:39][CH2:40][CH3:41])=[CH:31][C:32](=[O:38])[O:33]2)=[C:28]2[O:42][C:43]([CH3:46])([CH3:47])[CH:44]=[CH:45][C:27]=12
Reactant: C/C=C/C
Reactant: CCCc1cc(=O)oc2c(C=O)c(O)c3c(c12)OC(C)(C)C=C3
Agent: CC(C)(C)[O-]
Agent: FB(F)F
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@@H](C)[C@@H](O)c1c(O)c2c(c3c(CCC)cc(=O)oc13)OC(C)(C)C=C2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 66.3 %

Procedure:
The organoborane reagent 8 was prepared according to the procedure of Brown and Bhat5. To a stirred mixture of t-BuOK (1.15 g, 10.2 mmol) and trans-2-butene (4.0 mL, 44 mmol) in THF (8 mL) maintained at -78° C., was added BuLi (4.10 mL, 10.2 mmol, 2.5 M in hexanes). The mixture was then kept at -60° C. for 10 min and cooled to -93° C., at which time (+)-(E)-crotyldiisopinocampheylborane (8) (3.89 g, 12.3 mmol) in diethyl ether (14 mL) was added dropwise over a period of 18 min. The reaction mixture was stirred at -93° C. for 30 min, and boron trifluoride etherate (1.63 mL, 13.3 mmol) was then added dropwise over 3 min, followed by compound 7 (2.02 g, 6.43 mmol) in 1:1 Et2O-THF (20 mL) over a period of 12 min. The mixture was stirred at -93° C. for 30 min, then at -78° C. for 5 h. After this time sodium perborate17 (12.3 g, 79.9 mmol) and water (11 mL) were added, and the mixture was stirred for 10 h at room temperature. Brine (30 mL) was added, and the organic layer was separated. The aqueous layer was extracted with EtOAc (2×40 mL), and the combined organic layers were dried (MgSO4), concentrated, and submitted to silica gel chromatography (solvent A) to obtain 9 (1.58 g, 66%) as a syrup: [α]D20 +78° (c 1.0, acetone); 1H NMR (CDCl3): δ 0.93 (t, 3H, J=7.40 Hz, --CH2CH3), 0.96 (d, 3H, J=6.80 Hz, --CHCH3), 1.37, 1.43 (2s, 6H, --C(CH3)2), 1.51 (m, 2H, --CH2CH3), 2.56 (m, 1H, --CHCH3), 2.62-2.88 (m, 2H, --CH2CH2CH3), 4.57 (bs, 1H, --OH), 4.92-5.10 (m, 2H, --CH=CH2), 5.29 (d, 1H, J=7.0 Hz, --CHOH), 5.46 (d, 1H, J=10.0 Hz, H-3), 5.64 (s, 1H, H-9), 5.77-5.96 (m, 1H, --CH=CH2), 6.60 (d, 1H, J=10.0 Hz, H-4), 9.84 (s, 1H, Ar--OH); 13C NMR (CDCl3): δ 13.95, 16.38, 22.96, 27.35, 28.05, 38.48, 44.05, 72.60, 77.54, 102.71, 106.35, 107.09, 109.05, 116.27, 116.52, 126.66, 139.60, 151.00, 151.66, 156.03, 159.41, 161.67. Anal. Calcd for C22H26O5 : C, 71.33; H, 7.07. Found C, 70.46; H, 7.02. MS (negative-ion FAB): m/z 369 (M-1)-, 315.
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6](OCOC)=[C:7]([CH:18]=1)[CH:8]=[N:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17].[CH3:23][O:24][CH2:25][O:26]C1C=CC(C=O)=CC=1>>[CH3:23][O:24][CH2:25][O:26][C:4]1[CH:3]=[CH:18][C:7]([CH:8]=[N:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[OH:17])=[CH:6][CH:5]=1
Reactant: COCOc1ccc(C=O)cc1
Reactant: COCOc1ccc(OC)cc1C=Nc1c(C)cccc1O
Product: COCOc1ccc(C=Nc2c(C)cccc2O)cc1

Procedure:
2-[(4-methoxymethoxybenzylidene)amino]-3-methylphenol (F6) was prepared in a similar manner for the preparation of 2-[(5-Methoxy-2-methoxymethoxybenzylidene)amino]-3-methylphenol (F4) by using 4-methoxymethoxybenzaldehyde (F3) (3.32 g, 20 mmol) instead of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) in 84% (4.56 g): 1H-NMR (500 MHz, CDCl3) δ3.53 (s, 3H), 5.24 (s, 3H), 7.17 (d, 1H, J=9.0 Hz), 7.35 (d, 1H, J=9.0 Hz), 10.52 (s, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C:9](=[O:10])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.CC(O)C.NCCCN.CC(O)C.[OH-].[K+].[H][H]>CC(O)C>[CH3:1][CH:2]1[CH2:11][CH:9]([OH:10])[C:5](=[C:6]([CH3:7])[CH3:8])[CH2:4][CH2:3]1
Reactant: CC(C)=C1CC[C@@H](C)CC1=O
Reactant: [H][H]
Agent: NCCCN
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)=C1CCC(C)CC1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A 100 ml capacity autoclave was charged with 3.04 g (20 mmol) of pulegone, 19.1 mg (0.02 mmol) of RuCl2(PPh3)3, 0.2 M 1,3-diaminopropane 2-propanol solution (0.2 ml), 0.2 M potassium hydroxide 2-propanol solution (1.0 ml) and 2-propanol (14 ml), and the mixture was stirred at 25° C. for 3 hours under a hydrogen pressure of 2 MPa. After completion of the reaction, hydrogen was purged, the reaction solution was concentrated and then distillation was carried out under a reduced pressure to obtain 2.61 g of pulegol. The yield was 85%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[C:43]1[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][N:44]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:43]4[CH:48]=[CH:47][C:46]([S:49]([CH3:52])(=[O:51])=[O:50])=[CH:45][N:44]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNCC2)C[C@H]1c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(S(C)(=O)=O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
A mixture of 20 mg (0.043 mmol) [(3S,4R)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester, 11.2 uL (0.065 mmol) DIPEA and 12.8 mg (0.054 mmol) 2-bromo-5-(methylsulfonyl)pyridine in 1 mL DMF was heated to 60° C. over night. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions the title compound as light yellow viscous oil. MS m/e: 615.3 [M]+.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19](Cl)=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C1COCC1>[OH:20][C:19](=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH2:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: N#CCC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC(O)=C(C#N)C#N)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
To a 60% NaH/mineral oil dispersion (6.0 g, 0.15 moles) in THF (230 ml) in an ice-bath was added dropwise malononitrile (9.9 g, 0.15 mol). The reaction mixture was stirred for 2 hours at 0° C. and 3,4-dimethoxyphenyl acetylchloride (32.2 g, 0.15 mol) in THF (50 ml) was added dropwise over 2 hours. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvent was removed in vacuo, and the residue was partitioned between chloroform and 2N H2SO4. The organic layer was separated and the aqueous layer was extracted with chloroform (2×150 ml). The organic layers were combined and the solvent was removed in vacuo to afford 40.4 g (crude) of (1-hydroxy-(3,4-dimethoxyphenylethylidene))malononitrile as a brown oil, which was used directly in the following reaction without purification.
Reaction SMILES: C(O[C@:5]1([C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[O:28])[C@@H:18]4[CH2:27][C@@H:19]42)[C:14]([Cl:29])=[CH:13]3)[CH2:10][CH2:9]1)[C:6](=[O:8])[CH3:7])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[Cl:29][C:14]1[C:15]2[C@:20]([CH3:21])([C@H:19]3[CH2:27][C@H:18]3[C:17](=[O:28])[CH:16]=2)[C@@H:22]2[C@H:12]([C@H:11]3[C@:25]([CH3:26])([CH2:24][CH2:23]2)[C:5]([C:6](=[O:8])[CH3:7])=[CH:9][CH2:10]3)[CH:13]=1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@@]21C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)C1=CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)[C@@H]5C[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Yield: 44.4 %

Procedure:
One gram of 17α-acetoxy-6-chloro-1α,2α-methylene-4,6-pregnadiene-3,20-dione is heated analogously to Example 1 in "Dowtherm" for 90 minutes to 285° C., worked up, separated, and combined. Recrystallization from ethanol yields 380 mg of 6-chloro-1α,2α-methylene-4,6,16-pregnatriene-3,20-dione (89% of theory), m.p. 243°-246° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[CH:23]=1.[CH2:24]([N:26]([CH2:28][CH3:29])O)[CH3:25].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:26]([CH2:28][CH3:29])[CH2:24][CH3:25])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:6]=2[CH:23]=1
Reactant: CCN(O)CC
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 15, 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a] [1,4]-benzodiazepine is treated with a cold mixture of N,N-diethylhydroxylamine and sodium hydride in dimethylformamide to give 8-bromo-1-[(diethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine, N1 -oxide.