Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1.O>CN(C)C=O.C(OCC)(=O)C>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Yield: 12.2 %

Procedure:
To a solution of trans-2-phenylcyclopropanamine hydrochloride (1.087 g, 6.41 mmol) in N,N-dimethylformamide (DMF) (30 mL) was added potassium carbonate (1.771 g, 12.81 mmol) followed by benzyl 4-(bromomethyl)piperidine-1-carboxylate (1 g, 3.20 mmol). The reaction mixture was refluxed overnight. Water (80 mL) was added followed by 80 mL of ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. The oil was purified via silica gel column (DCM to 100% EtOAc). The fractions were collected and evaporated. The oil was further purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Benzyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (150 mg, 0.391 mmol, 12.21% yield) was isolated as yellow liquid. 1H NMR (400 MHz, METHANOL-d4) δ 7.28-7.41 (m, 5H), 7.18-7.27 (m, 2H), 7.09-7.16 (m, 1H), 7.03-7.09 (m, 2H), 5.12 (s, 2H), 4.00-4.29 (m, 2H), 2.67-2.97 (m, 2H), 2.61 (d, J=6.82 Hz, 2H), 2.26-2.36 (m, 1H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.64-1.84 (m, 3H), 0.91-1.24 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 365.5 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27]([C:30](=O)[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1>>[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27](/[C:30](=[N:8]/[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)/[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: NNc1ccccn1
Product: C/C(=N\Nc1ccccn1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 48 %

Procedure:
The title compound was prepared from pyridin-2-yl-hydrazine and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]ethanone in analogy to the synthesis of example 1 in 48% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 8.86 (dd, 1H), 8.31 (d, 1H), 8.19 (d, 1H), 7.97 (m, 3H), 7.78 (d, 1H), 7.70 (t, 1H), 7.65 (s, 1H), 7.47 (q, 1H), 7.40 (d, 1H), 6.87 (dd, 1H), 4.58 (s, 2H), 2.36 (s, 3H). LCMS (method A): [MH]+=412, tR=4.78 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])#[N:2].ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:34])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1c(C#N)cc(C(=O)N2CS(=O)c3ccccc32)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
3-(3-cyano-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazole (594 mg) was dissolved in chloroform (10 mL), and 70% metachloroperbenzoic acid (433 mg) was added to the solution, and then the mixture was stirred at 0° C. for 5 minutes. The organic solvent was distilled off under reduced pressure, and then 1N sodium hydroxide was added and the precipitated crystal was washed with 1N sodium hydroxide and water to obtain the title compound (619 mg) as a colorless crystal.
Reaction SMILES: C([O-])=O.[NH4+].[F:5][C:6]1[CH:7]=[CH:8][C:9]([N+:26]([O-])=O)=[C:10]([CH:25]=1)[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1>[Pd].CO>[NH2:26][C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:25][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2N)CC1
Reaction time: 0.5 h

Procedure:
Ammonium formate (1.2 g, 19.1 mmol) was added into a suspension of tert-butyl 4-(5-fluoro-2-nitrophenoxy)piperidine-1-carboxylate (2.0 g, 5.8 mmol) and palladium on carbon (5%, 0.4 g) in MeOH (30 mL) at ambient temperature. The solution was stirred for 0.5 hours, filtered through Celite and washed with MeOH. The filtrate was concentrated in vacuo and triturated from diethyl ether to remove the ammonium formate by-products. The sample was purified by flash column chromatography (1:10→1:1 EtOAc/DCM) to yield a colourless oil which crystallised from diethyl ether/petroleum ether (40-60° C.) as a colourless solid (1.6 g, 87%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)O)=[C:9]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:42]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClC(Cl)C>[N:22]1([CH2:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:11][C:10]3[C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH2:1])=[CH:42][C:7]=4[S:8][C:9]=3[C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41]4)=[CH:30][CH:29]=3)=[CH:14][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCc1ccc2c(C(O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: NCc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OCCN4CCCC4)cc3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.32 g (2.3 mmol) of 6-(aminomethyl)-α-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene-3-methanol in 40 mL of anhydrous dichloroethane at 0° C. was added 1.84 g (15.8 mmol) of triethylsilane and 2.62 g (23.0 mmol) of trifluoroacetic acid, respectively, under a nitrogen atmosphere. After one hour at 0° C., the reaction was warmed to room temperature and stirred for 24 h. The reaction was quenched with 10 mL of saturated aqueous sodium bicarbonate and poured into 30 mL of water. The aqueous layer was saturated with sodium chloride, separated from the dichloroethane layer, and extracted with three 50 mL portions of THF. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated at reduced pressure to give 786 mg (60% crude yield) of a brown foam. This material was carried on to the salt in Part D.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.Cl.[C:10]([NH:14][NH2:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)C(C)C)(C)C>C(O)C>[C:10]([NH:14]/[N:15]=[C:2](\[CH3:4])/[C:1]([O:6][CH2:7][CH3:8])=[O:5])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(C)=O
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)/C(C)=N/NC(C)(C)C
Yield: 71.3 %

Procedure:
To a solution of ethyl pyruvate (20.22 g, 174.1 mmol) in ethanol (150 mL) was added t-butyl hydrazine hydrochloride (21.7 g, 174 mmol) and N,N-diisopropylethyl amine (33.4 mL, 192 mmol). After stirring at reflux for 18 hours, the reaction was cooled and the volatiles were removed under reduced pressure. The resultant golden oil was taken up in 300 mL ethyl acetate and washed with 200 mL water and 300 mL saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated to yield (E)-ethyl 2-(2-tert-butylhydrazono)propanoate (23.1 g) as a clear pale yellow oil. +APCI (M+H) 187.3; 1H NMR (400 MHz, CDCl3, δ): 5.51 (br. s., 1H), 4.25 (q, J=7.2 Hz, 2H), 1.89 (s, 3H), 1.32 (t, J=7.1 Hz, 3H), 1.28 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([OH:31])=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([O:31][CH2:5][CH2:6][N:7]7[CH2:12][CH2:36][O:39][CH2:9][CH2:8]7)=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCCN5CCOCC5)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 100 °C
Yield: 21.2 %

Procedure:
A mixture of 4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-hydroxy-9H-pyrido[3,4-b]indole-1-carboxamide (50 mg, 0.104 mmol), 4-(2-chloroethyl)morpholine, HCl (67.4 mg, 0.362 mmol), and cesium carbonate (202 mg, 0.621 mmol) in DMF (6 mL) was heated at 100° C. for 3 hr. The mixture was diluted with ethyl acetate (100 mL) and filtered through CELITE®. The filtrate was washed with water (2×30 mL) and brine (30 mL), and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the purified product (7.1 mg, 0.011 mmol, 10.9% yield) as a pale yellow sold. LCMS (M+H)+=596.29. 1H NMR (500 z, DMSO-d6) δ: 11.72 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.82-7.78 (m, 3H), 7.72 (d, J=6.9 Hz, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.43 (s, 1H), 7.22 (br. S, 1H), 6.79 (br. S, 1H), 5.10 (d, J=17.6 Hz, 1H), 5.00 (d, J=17.6 Hz, 1H), 4.23 (m, 2H), 3.81-3.53 (m, 8H), 2.81 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: [CH2:1]([OH:3])C.C[O-].[Na+].C(OCC)=O.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][C:18]=1[OH:19]>C(O)(=O)C.O>[OH:19][C:18]1[CH:17]=[C:16]([CH3:20])[CH:15]=[CH:14][C:13]=1[NH:12][CH:1]=[O:3]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCO
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(NC=O)c(O)c1
Reaction time: 1 h
Yield: 32 %

Procedure:
To 20 ml of ethanol, there were added under ice-cooling 4.83 g of sodium methoxide and 18.0 g of ethyl formate. Further, 10.0 g (81.3 mmol) of 6-amino-m-cresol was added thereto under ice-cooling. After putting back to room temperature, the solution was stirred under a nitrogen atmosphere for 1 hour. After the completion of the reaction, the reaction mixture was poured into 200 ml of water. The obtained solution was neutralized with glacial acetic acid, extracted with 300 ml of ethyl acetate, washed with 200 ml of 1N hydrochloric acid and 100 ml of a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, 3.98 g (26.4 mmol) of N-(2-hydroxy-4-methylphenyl)formamide was obtained as a pale brown solid. The yield was 32%.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12.[CH3:18][C:19]([OH:23])([C:21]#[CH:22])[CH3:20]>C(NCC)C.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>[OH:23][C:19]([CH3:20])([CH3:18])[C:21]#[C:22][C:2]1[N:3]=[CH:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[N:8]([CH3:17])[CH2:7][C:6]=12
Reactant: C#CC(C)(C)O
Reactant: CN1Cc2c(I)ncn2-c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccccc2C1=O

Procedure:
3.40 g (10 mmol) of 4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 1.5 hours with 0.925 g (11 mmol) of 2-methyl-3-butyn-2-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The solvent was then evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 168°-169°.
Reaction SMILES: C(OC(=O)[NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[N:10]=1)=S)C.Cl.NO.CC[N:26](C(C)C)C(C)C>CO.CCO>[S:17]1[CH:18]=[CH:19][C:15]([C:11]2[N:10]3[N:26]=[C:6]([NH2:5])[N:8]=[C:9]3[CH:14]=[CH:13][CH:12]=2)=[CH:16]1
Reactant: CCOC(=O)NC(=S)Nc1cccc(-c2ccsc2)n1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cccc(-c3ccsc3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
A suspension of ethyl({[6-(3-thienyl)pyridin-2-yl]amino}carbonothioyl)carbamate (4.0 g; 13.01 mmol; 1.0 eq.), hydroxylamine hydrochloride (4.52 g; 65.1 mmol; 5.0 eq.) and DIEA (6.55 mL) in MeOH/EtOH (1:1, 120 mL) was stirred at rt for 2 hours and then at 70° C. for 3 hours. Solvents were removed under reduced pressure, the residue was taken up in dioxane/water (1:1) and filtered to give the title compound as a white powder (2.3 g; 82%). HPLC, Rt: 1.75 min. (purity 94.8%). LC/MS, M+(ESI): 217.3.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.CCN(CC)CC.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:16](=[O:17])[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:3][CH:4]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1csc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(NC(=O)Oc2ccccc2)n1
Yield: 51.2 %

Procedure:
A solution of 2-amino-4-methylthiazole (11.42 g, 0.10 mol) in CH2Cl2 was cooled to 0° C. in an ice bath and treated with Et3N (12.1 g, 0.12 mol). While stirring, the mixture was treated with phenyl chloroformate (15.6 g, 0.10 mol) drop-wise from an addition funnel. After the addition was complete the mixture was stirred for 10 minutes. The reaction mixture was washed with saturated NaHCO3, water, brine and then dried over MgSO4. The solution was filtered and the solvent removed under vacuum in a rotary evaporator and the resulting solid was chromatographed on silica gel (eluting with 40% ethyl acetate/hexane) to give 12 g of the desired carbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ δ 12.38 (bs, 1H), 7.47-7.40 (m, 2H), 7.30-7.19 (m, 3H), 6.52 (d, J=1.1 Hz, 1H), 2.41 (d, J=0.8 Hz, 3H).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:26](=[O:33])[CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:22]([NH:24][N:25]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:26](=[O:33])[CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cc1nnn[nH]1)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)Cc1nnn[nH]1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A solution of 0.190 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1H-tetrazol-5-yl)-acetyl]valerohydrazide in 5 mL of methanol was treated with 0.020 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 2 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.152 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-[2-(1H-tetrazol-5-yl)acetyl]valerohydrazide in the form of a white solid.
Reaction SMILES: BrBr.[CH3:3][O:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([NH2:15])=[S:14])[CH:7]=1.CCOCC>C(O)(=O)C>[CH3:3][O:4][C:5]([C:6]1[C:7]2[S:14][C:13]([NH2:15])=[N:12][C:8]=2[CH:9]=[CH:10][CH:11]=1)=[O:16]
Reactant: COC(=O)c1cccc(NC(N)=S)c1
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)c1cccc2nc(N)sc12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
At 0° C. a solution of bromine (13.4 mmol) in acetic acid (9.4 mL) is added dropwise to a vigorously stirred solution of 3-thioureido-benzoic acid methyl ester (12.5 ml) in acetic acid (37 mL). The mixture is allowed to reach RT, stirred at 70° C. for 4 h and cooled to RT. Ether is added and the precipitate is filtered off. The residue is stirred vigorously in a sat aq. NaHCO3 solution, filtered off and washed with water. The obtained solid is dried in vacuo to give the desired product which is used without further purification. LC-MS: tR=0.62 min; [M+H]+=209.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]#[N:9])=[CH:3][CH:2]=1.[NH2-].[Na+].Br[CH2:13][CH2:14]Br.O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2([C:8]#[N:9])[CH2:14][CH2:13]2)=[CH:3][CH:2]=1
Reactant: N#CCc1ccncc1
Reactant: BrCCBr
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CC1(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.5 g of 4-pyridylacetonitrile are added to a mixture of 2.5 g of sodium amide in 80 ml of DCM, followed by 2.6 ml of 1,2-dibromoethane, and the mixture is stirred overnight at RT. The reaction mixture is poured into water and extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvents are evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with DCM and then with a DCM/MeOH mixture from (99/1; v/v) to (95/5; v/v). 2.5 g of the expected product are obtained.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([CH:2]2[CH2:7][CH2:6][CH:5]([N:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])[CH2:4][CH2:3]2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 48 h

Procedure:
To a solution of 2-(4-oxocyclohexyl)-1H-isoindole-1,3(2H)dione (3.78 g, 15.5 mmol), which was prepared according to the literature (J. Med. Chem., 1993, 1918), 1-benzylpiperazine (2.99 g/17.1 mmol) and AcOH (1.00 ml/17.1 mmol) in dichloroethane (50 ml) was added sodium triacetoxyborohydride (6.57 g/31.0 mmol) and the mixture was stirred for 2 days. The reaction mixture was poured into water (50 ml) and the mixture was extracted with dichloromethane (100 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil (5.00 g/89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][Cl:14])=[C:6]([O:15][CH3:16])[CH:5]=1.C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:5]=[C:6]([O:15][CH3:16])[C:7]([O:10][CH2:11][CH2:12][CH2:13][Cl:14])=[CH:8][C:9]=1[N+:25]([O-:27])=[O:26]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OCCCCl)c(OC)c1
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 94 %

Procedure:
The intermediate from Step 1 (26.4 g, 102 mmol) was taken in acetic acid (185 mL) and acetic anhydride (15 mL) was added. The solution was cooled to 0° C. and 90% nitric acid (15 mL) was added. The reaction mixture was stirred for 10-15 minutes at ambient temperature, then heated to 50° C. for 3 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was cooled and was diluted with ethyl acetate. The ethyl acetate layer was washed with aq. sodium bicarbonate, and concentrated to afford the pure compound 4-(3-chloro-propoxy)-5-methoxy-2-nitro-benzoic acid methyl ester (29.14 g, 94%) yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.68 (s, 1H), 7.33 (s, 1H), 4.24 (t, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.77 (t, 2H), 2.21 (q, 2H).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=O.[N+](=[C:18](P(=O)(OC)OC)C(=O)C)=[N-].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[CH:18]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#C[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C

Procedure:
To crude (R)-tert-butyl 3-formylpiperidine-1-carboxylate in MeOH (20 mL) was added dimethyl 1-diazo-2-oxopropylphosphonate (1.28 g, 5.6 mmol), cooled to 0° C. and then added K2CO3 (2.56 g, 18.6 mmol), followed by MS, TLC. Added water (60 mL), extracted with EtOAc (3×50 mL), organic layer were evaporated and dried to give the desired product (S)-tert-butyl 3-ethynylpiperidine-1-carboxylate (0.86 g).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:17]#[N:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:14]([C:3]1[C:2]([C:17]#[N:18])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:15]
Reactant: CCc1c(Cl)cccc1-c1ccccc1
Reactant: N#C[Cu]C#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1c(C#N)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Under a dry nitrogen atmosphere a mixture of 3-chloro-2-ethyl-[1,1'-biphenyl] (2.3 g, 0.0106 mole), copper cyanide (1.4 g, 0.0016 mole) and pyridine (1.2 g, 0.016 mole) was heated at 195° for approximately 18 hours. The reaction mixture was cooled to room temperature to give a solid. The solid was dissolved in 300 ml of methylene chloride and washed with 25% aqueous ammonium hydroxide and the aqueous phase extracted with 250 ml of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carbonitrile as a solid. A mixture of ethyl-[1,1'-biphenyl]-3-carbonitrile (2.2 g, 0.0106 mole), 40 ml of 10N aqueous sodium hydroxide, and 40 ml of ethanol was heated at reflux for approximately 18 hours. The reaction mixture was cooled and the ethanol evaporated under reduced pressure. The remaining aqueous portion was diluted with 100 ml of water, then extracted with three 150 ml portions of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.4 g).