Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:9][CH:8]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH:5]([CH2:6][CH2:7]2)[CH:4]=1)#[N:2].[Mg].C[O-].[Mg+2].C[O-].P([O-])(O)(O)=O.[K+]>O.CO>[C:1]([CH:3]1[CH2:4][CH:5]2[N:10]([CH2:11][C:12]([F:15])([F:14])[F:13])[CH:8]([CH2:7][CH2:6]2)[CH2:9]1)#[N:2]
Reactant: N#CC1=CC2CCC(C1)N2CC(F)(F)F
Agent: C[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC1CC2CCC(C1)N2CC(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 275 %

Procedure:
An oven-dried 50 ml round bottom flask was fitted with a reflux condenser and magnetic stirrer and the apparatus filled with a nitrogen atmosphere. 3-Cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]oct-2-ene (0.26 g, 1 mmol) was charged to the reactor followed by methanol (10 ml). Magnesium turnings (1.0 g, 40 mmol) were added in a single portion and after an induction period of 0.25 hours, a vigorous reaction occurred which was moderated by cooling with an ice bath. The mixture was stirred at 0° C. for 1 hour, during which time the reaction mass thickened (due to magnesium methoxide formation), and was then allowed to warm to ambient. The reaction mixture was added to a solution of potassium dihydrogen phosphate (10 g) in water (40 ml) and stirred for 0.5 hour. Residual solid was removed by filtration and the aqueous filtrate was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (Na2SO4) and concentrated in vacuo to give 3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (0.6 g, 72% yield) as a mixture of epimers (25:75 exo:endo).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:14])[O:13][CH:11]([CH3:12])[CH2:10]1.Cl>[OH-].[Na+]>[OH:13][CH:11]([CH3:12])[CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: CC1CC(=O)O1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(O)CC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
0.3 g of sodium hydroxide was added to 64.8 g of benzylalcohol and the reaction mixture was cooled to 0° C. To this reaction mixture was added 12.9 g of β-butyrolactone and the mixture was stirred for 5 minutes at 0° C. and for 2 hours at room temperature. After reaction, the reaction solution was neutralized by adding 15 ml of 1N-HCl solution and the separated organic layer was washed with saturated sodium bicarbonate aqueous solution and saline, and dried over magnesium sulfate. The resulting organic layer was distilled under reduced pressure to give 23.3 g (79%) of benzyl 3-hydroxybutanoate [Compound (11)]as oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([OH:21])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)C.[NH2:23][NH2:24]>>[OH:21][C:6]1([CH2:5][C:4]([NH:23][NH2:24])=[O:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2
Reactant: NN
Reactant: CCOC(=O)CC1(O)c2ccccc2C=Cc2ccccc21
Product: NNC(=O)CC1(O)c2ccccc2C=Cc2ccccc21
Reaction time: 2 h

Procedure:
A mixture of 4.0 g. of 5-hydroxy-dibenzo[a,d]cyclohepten-5-acetic acid ethyl ester and 8 ml. of anhydrous hydrazine is warmed with stirring at temperature of 80°-85° C. for 2 hours, and then allowed to stand at room temperature for 19 hours. The resulting mixture is evaporated to dryness in high vacuum at 100° C., the residue dissolved in hot ethanol, treated with charcoal and crystallized to obtain 5-hydroxy-dibenzo[a,d]cyclohepten-5-acetic acid hydrazide, m.p. 192°-194° C.
Reaction SMILES: C([NH:3][C@@H:4]1[C:17](=[O:18])[N:6]2[C:7]([C:14]([OH:16])=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12)=O.Cl>CO.O>[NH2:3][C@@H:4]1[C:17](=[O:18])[N:6]2[C:7]([C:14]([OH:16])=[O:15])=[C:8]([CH2:11][S:12][CH3:13])[CH2:9][S:10][C@H:5]12
Reactant: CSCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: Cl
Solvent: O
Solvent: CO
Product: CSCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
(i) 7β-Formamido-3-methylthiomethylceph-3-em-4-carboxylic acid (2.88g) was dissolved in methanol (25 ml.) and the stirred solution was treated with concentrated hydrochloric acid (4.0 ml.). After 1.5 hr. at room temperature the solution was diluted with water (80 ml.) and washed with ethyl acetate (2 × 30 ml.) and ether (2 × 20 ml.), rotary evaporated to remove residual ether, and the pH adjusted to 3.5 with 0.880-ammonia. The precipitate was collected after overnight refrigeration, washed with water (2 × 10 ml), methanol (2 × 10 ml.) and ether (3 × 20 ml.), then dried giving 7β-amino-3-methylthiomethylceph-3-em-4-carboxylic acid as a colourless powder (1.41 g.), m.p. 222°-225° (decomp.), Rf 0.60 (System 2), TLC Rf 0.15, moves 2.0 cm. towards the cathode on electrophoresis at pH 1.9 (3-acetoxymethyl-7β-aminoceph-3-em-4-carboxylic acid moves 1.85 cm. under identical conditions), λmax (pH6 buffer) 266 nm. (ε 9,590), νmax. (Nujol) 1804 (β-lactam), 1536 cm.-1 (carboxylate), τ(D2O with NaHCO3) 4.53 (~0.5-proton doublet, J 4.5 Hz.; C-7 H), 4.88 (1-proton doublet, J 4.5 Hz.; C-6 H), 5.21 (~0.5-proton doublet, J 4.5 Hz.; C-7 H), 6.14, 6.63 [two 1-proton doublets (branches of a quartet), J 18 Hz.; C-2 H2 ], 6.21, 6.68 [two 1-proton doublets (branches of a quartet), J 14 Hz.; C-3 CH2 ], 7.95 (3-proton singlet; SCH3) [Found: C, 41.2; H, 4.6; N, 10.2; S, 23.6. C9H12N2O3S (260) requires C, 41.5; H, 4.6; N, 10.8; S, 24.6%].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[Br-:10].[K+].C(O)(=O)C.B1([O-])OO1.O.O.O.O.[Na+].C(=O)(O)[O-].[Na+]>N.N.N.N.N.N.O.O.O.O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O>[Br:10][C:7]1[CH:8]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:9])[C:5]=1[NH2:6]
Reactant: [Br-]
Reactant: Cc1cc(Cl)ccc1N
Agent: O=[Mo](=O)(O)O
Agent: O=[Mo](=O)=O
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(Br)c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2-methylaniline (1.0 g, 7.06 mmol), potassium bromide (1.01 g, 8.47 mmol), and ammonium heptamolybdate tetrahydrate (87 mg, 0.07 mmol) were suspended in acetic acid (7 mL, 122 mmol) and cooled to 0° C. The reaction was treated with sodium perborate tetrahydrate (1.2 g, 7.77 mmol), stirred at 0° C. for 30 min, and at room temperature for 2 h. The mixture was poured into water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated to afford 1.2 g (78%). 1H-NMR (CDCl3, 500 MHz) δ 7.28 (s, 1H), 6.97 (s, 1H), 4.03 (bs, 2H), 2.17 (s, 3) Mass spec.: 221.90 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[F:22])=[N:12][N:11]3[CH:23]=2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].[C:27]([Si:29]([CH3:32])([CH3:31])[CH3:30])#[CH:28].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:23]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]#[C:27][Si:29]([CH3:32])([CH3:31])[CH3:30])=[C:3]([N+:24]([O-:26])=[O:25])[CH:4]=3)[N:9]=2)[N:12]=1
Reactant: O=[N+]([O-])c1cc(-c2cn3nc(-c4ccccc4F)ccc3n2)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 81.6 %

Procedure:
To a mixture of 2-(4-bromo-3-nitrophenyl)-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.500 g, 1.21 mmol), ethynyltrimethylsilane (2.42 mmol), PdCl2(PPh3)2(0.0242 mmol) in THF (50 mL) containing triethylamine (6.05 mmol) is added CuI (0.0242 mmol). The mixture is degassed with N2 (5 minutes) then heated at 60° C. for 12 hours. The mixture is filtered, followed by washing with EtOAC, filtrate collected, concentrated under reduced pressure and crude product is purified via chromatography using CH2Cl2 to afford the title compound (0.425 g, 81%) as a yellow solid: Rf 0.56 (CH2Cl2); LCMS (m/z)=431.4 [M+H]+, tR=3.86 min.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:24]=[C:25]([CH2:28]O)[S:26][CH:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:25]5[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: Cc1csc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1csc(COc2ccn(-c3ccc4nc(C5CC5)n(C)c4c3)c(=O)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 20.6 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (4-methyl-2-thienyl)methanol (138 mg) and tributylphosphine (322 mg) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg) in dry THF (5 ml). The mixture was stirred under sonication at 60° C. for 2 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM, and the DCM layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (43 mg) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][N:7]=1.CCOC(C)=O.[OH-].[Na+].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:5][C:6]1[N:7]=[CH:8][C:9]([C:10]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)c1ccc(Cl)nc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (2 g) was suspended in 3 ml of fluorobenzene. A solution of 6-chloronicotinoyl chloride (1 g, 5.7 mmol) in 2 ml of fluorobenzene was added to the stirred reaction mixture by syringe and stirred at 80° C. overnight in a closed vial. The reaction mixture was deluted with EtOAc and basified with aqueous sodium hydroxide (pH>8.5). The precipitate formed was removed by filtration. The organic solution was washed with water, dried over magnesium sulfate and concentrated by rotary evaporation. Desired product was purified by column chromatography on silica (EtOAc/hexane) to give 1.22 g (90%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](OCC)(=[O:13])[C:10]([O-])=[O:11]>>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][C:10](=[O:11])[C:9]1=[O:13]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(=O)[O-]
Product: O=c1[nH]c2ccccc2[nH]c1=O

Procedure:
o-Phenylenediamine (10 grams) and ethyl oxalate (100 ml.) were mixed and the mixture was heated, with stirring, to reflux and refluxed for 30 minutes. The reaction mixture was then cooled and the resulting precipitate, the desired 2(1H), 3(4H)-quinoxalinedione, was separated by filtration. The product did not melt below 400°C. It was recrystallized from a mixture of dimethylformamide and water, yielding a purified product which did not melt below 405°C. The identity of the product was confirmed by NMR and IR. Elemental analysis showed
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1.[CH3:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:15][CH2:16][CH:17]([NH:21][C:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][C:7]=2[CH:8]=1)=[O:13])[CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: CCCC(N)CC
Product: CCCC(CC)NC(=O)c1cc2cc(OC)ccc2o1
Yield: 32 %

Procedure:
Prepared in a similar manner to example 4 using 5-methoxybenzofuran-2-carboxylic acid and hexan-3-amine (example 28a). Yield: 32%. 1H NMR (500 MHz, CDCl3): δ 0.96 (m, 6H); 1.40-1.67 (m, 6H); 3.85 (s, 3H); 4.09 (m, 1H); 6.28 (d, 1H); 7.01 (dd, 1H); 7.08 (d, 1H); 7.38 (m, 2H). MS (276, M+H).
Reaction SMILES: O=[C:2]([CH3:9])[CH2:3][C:4]([O:6]CC)=O.Cl.[C:11](=[NH:14])([NH2:13])[CH3:12].C([O-])C.[Na+].O>C(O)C>[CH3:12][C:11]1[N:14]=[C:4]([OH:6])[CH:3]=[C:2]([CH3:9])[N:13]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(O)nc(C)n1
Yield: 35.9 %

Procedure:
Ethyl 3-oxobutanoate (10.0 g, 77 mmol) and acetimidamide hydrochloride (7.23 g, 77 mmol) were added to the solution of sodium ethanolate (10.5 g, 154 mmol) in ethanol (200 mL). And the mixture was refluxed for 20 hours. Water (10 mL) was added to the mixture. The resultant mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=15:1) to give 2,6-dimethylpyrimidin-4-ol as a yellow solid (3.43 g, 36%). LRMS (M+H) m/z: calcd 124.06. found 124.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[CH3:16][Si:17]([CH3:29])([CH3:28])[N:18]=[S@@:19]([CH3:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32].[NH4+].[Cl-]>C1COCC1>[C:20]1([S@@:19]([CH2:27][C:31]([O:33][CH2:34][CH3:35])=[O:32])(=[N:18][Si:17]([CH3:29])([CH3:28])[CH3:16])=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: C[Si](C)(C)N=[S@@](C)(=O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C[S@@](=O)(=N[Si](C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 100 mL round bottom flask equipped with a magnetic stir-bar and a rubber septum was added a solution of 2,2,6,6-tetra-methylpiperidine (8.91 mL, 52.5 mmol) in anhydrous THF (22 mL). The solution was cooled to 0° C. and was treated with n-BuLi (18 mL, 45 mmol) (2.5 M in hexanes) via a syringe. The resulting solution was stirred for 10 min at 0° C., cooled to −78° C., and treated dropwise with a solution of (S)-trimethyl{[methyl(oxo)phenyl-λ6-sulfanylidene]amino}silane (18.7 mmol) in THF (10 mL). The reaction mixture was stirred at −78° C. for 30 min and then was treated with ethyl chloroformate (5.16 mL, 52.5 mmol) dropwise. The reaction mixture was stirred for an hour and warmed to room temperature. The reaction mixture was treated with saturated aqueous NH4Cl (2.5 mL). The white solid which formed was collected by filtration and discarded. The filtrate was treated with additional saturated aqueous NH4Cl solution and the resulting mixture was stored in a −20° C. fridge for 15 hours. The organic layer was collected and concentrated to give the title compound. This material was used directly in the next step of the synthesis
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20]>C1C=CC=CC=1>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][N:20]=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: CN(C)CCCN
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: c1ccccc1
Product: COc1cc(C=NCCCN(C)C)cc(OC)c1OC
Yield: 94 %

Procedure:
Interaction of 21 g of 3,4,5-trimethoxybenzaldehyde with 11 g of 3-dimethylaminopropylamine in 80 ml. of benzene following the procedure described in Example 1 yields 28.2 g of product as an oil, boiling point 162°-167° C. at 0.4-0.5 mm. of Hg.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.N[N:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][CH2:19][C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]1=2.[OH-].[NH4+]>C(O)(C)C>[ClH:1].[N:2]1([CH2:8][CH2:9][C:10]2[C:30]3[C:17]4=[C:18]([CH:27]=[CH:28][CH:29]=3)[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:16]4[C:11]=2[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)CCCN1CCCCC1
Reactant: NN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1c(CCN2CCCCC2)c2cccc3c2n1-c1ccccc1CC3
Yield: 39.7 %

Procedure:
A solution of 5-piperidino-2-pentanone hydrochloride (3.4g.) and 5-amino-10,11-dihydro-5H-dibenz[b,f]azepine hydrochloride (4.2g.) in isopropyl alcohol (50 ml.) was warmed on a steam bath in a nitrogen atmosphere for thirty minutes, cooled and treated with concentrated ammonium hydroxide. The resulting mixture was extracted with ether and the ether extract was washed with water and dried. The resulting solution in ether of the free base 2-(2-piperidinoethyl)-1-methyl-6,7-dihydroindolo[1,7-ab][1]benzazepine was treated with ethanolic hydrogen chloride. The precipitate was collected and a suspension thereof in acetone-isopropyl alcohol was heated, cooled, filtered and recrystallized from methyl alcohol to give 2-(2-piperidinoethyl)-1-methyl-6,7-dihydroindolo[1,7-ab][1]benzazepine hydrochloride (2.5g.), m.p. 291°-293°C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=2)=[C:5]([O:21][CH3:22])[CH:4]=1)=[CH2:2]>C(O)C.C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([F:20])[CH:13]=2)=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: C=Cc1cc(OC)c2ccn(-c3ccc(OC)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1cc(OC)c2ccn(-c3ccc(OC)c(F)c3)c2c1
Yield: 89.7 %

Procedure:
A solution of 6-ethenyl-1-[3-fluoro-4-(methyloxy)phenyl]-4-(methyloxy)-1H-indole (D9) (200 mg, 0.67 mmol) in ethanol (7 mL) and ethyl acetate (7 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and the product purified by silica gel chromatography eluting with 5-70% dichloromethane in hexane to yield the title compound (D10), (180 mg).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=2[N:15]=[N:14]1.Cl.[NH:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1.C(N(CC)CC)C>C1COCC1.C(OCC)(=O)C>[S:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]([N:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)=[O:24])=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: O=C1CCNCC1
Reactant: O=C(O)c1ccc2snnc2c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)c2ccc3snnc3c2)CC1
Reaction time: 8 h
Yield: 29.5 %

Procedure:
CDI (4.5 g) added to a solution of the benzo[1,2,3]thiadiazole-5-carboxylic acid (5 g) stirring in THF (100 ml) at RT. After 1 hour 4-piperidone hydrochloride (3.7 g) and triethylamine (4.3 ml) were added and the mixture stirred overnight. The resulting mixture was diluted with ethyl acetate, washed with 2M HCl (100 ml), saturated NaHCO3 solution (200 ml) and then with saturated brine (200 ml). The organic layer was dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography (silica, eluting with mixtures of ethyl acetate in dichloromethane) to give the product as a yellow oil (2.1 g; MS: APCI+(M+H)262).
Reaction SMILES: Cl.Cl.C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)C=CC=CC=1.CC(C)([O-])C.[K+].C[O:36][C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]2[CH2:50][CH:51]=O)=[CH:41][CH:40]=[CH:39][N:38]=1.O>CN(C=O)C>[O:36]=[C:37]1[C:42]([CH2:43][N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH:45]2[CH2:50][CH2:51][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:41][CH:40]=[CH:39][NH:38]1
Reactant: COc1ncccc1CN1CCCCC1CC=O
Reactant: c1ccc([P+](Cc2ccccn2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cccc1CN1CCCCC1CCCc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
In DMF was dissolved 2.1 g of triphenyl(2-pyridylmethyl)phosphonium dihydrochloride, followed by adding 1.4 g of potassium tert-butoxide thereto at room temperature under stirring. After 15 minutes, a solution of 1.25 g of 2-[1-[(2-methoxy-3-pyridyl)methyl]-2-piperidyl]acetaldehyde dissolved in DMF was added dropwise into the above-mentioned solution at room temperature under stirring, and the mixture was left overnight. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, subsequently ethyl acetate, and subsequently ethyl acetate:methanol=4:1). 760 mg of the resulting brown oil, 0.56 ml of thionyl chloride and 10 ml of ethanol were stirred under reflux for 30 minutes. The reaction solution was cooled to room temperature, a 2N aqueous sodium hydroxide was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, subsequently ethyl acetate, and subsequently ethyl acetate:methanol=4:1). The resulting yellow oil (350 mg) was dissolved in 10 ml of ethanol, 100 mg of 10% palladium-carbon (water-containing product) was added thereto, and the mixture was catalytically hydrogenated at normal pressure under stirring for 1.5 hours. The catalyst was filtered off and the solvent was evaporated. The residue was purified by NH-silica gel chromatography (ethyl acetate, subsequently ethyl acetate:methanol=4:1), to give 310 mg of an oil.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]([OH:13])=O)[CH2:10][CH2:9]1.[CH:14]1([CH2:20][NH:21][CH2:22][C@H:23]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH:39]4[CH3:43])=[CH:30][CH:29]=3)[C:26](=[O:44])[CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:14]1([CH2:20][N:21]([CH2:22][C@@H:23]2[CH2:24][CH2:25][C:26](=[O:44])[N:27]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[CH3:43])=[CH:30][CH:29]=2)[C:11]([CH:8]2[CH2:10][CH2:9]2)=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CC1
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CNCC2CCCCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN(CC2CCCCC2)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.6 %

Procedure:
Triethylamine (0.13 ml, 0.93 mmol, 2 eq) is added to a solution of cyclopropanecarboxylic acid (40 mg, 0.47 mmol, 1 eq) and ((5S)-5-{[(cyclohexylmethyl)amino]methyl}-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 1 (200 mg, 0.47 mmol, 1 eq) in dichloromethane (5 ml). The mixture is cooled with an ice bath. 1-Hydroxybenzotriazole (12 mg, 0.093 mmol, 0.2 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.52 mmol, 1.1 eq) are added. The mixture is stirred at room temperature for 5 hours, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 0.246 g of yellow oil that is purified by chromatography over silicagel (dichloromethane/methanol/ammonia 96/4/0.4) to afford 0.135 g of N-(cyclohexylmethyl)-N-[((2S)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-5-oxopyrrolidin-2-yl)methyl]cyclopropanecarboxamide 77 as a yellow lacquer.