Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([OH:13])=O.CN.Cl.[CH3:17][N:18](C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:18][CH3:17])=[O:13]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1n[nH]c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 5-bromo-1H-indazole-3-carboxylic acid (1.2 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was added methyl amine (5 mL, 2 M in tetrahydrofuran, 10 mmol), 1, (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.4 g, 7.5 mmol), 1-hydroxybenzotriazole hydrate (1.2 g, 7.5 mmol), and N-methylmorpholine (1.0 g, 10 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purification by flash column chromatography gave the title compound (0.71 g, 56%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6, δ): 13.8 (br. s., 1 H), 8.41 (m, 1 H), 8.31 (s, 1 H), 7.60 (d, J=8.8 Hz, 1 H), 7.51-7.54 (m, 1 H), 2.80 (d, J=4.8 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:20]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNC(=O)c2ccccc2)cc1OC
Temperature: 15 °C
Yield: 85.2 %

Procedure:
To a mixture of 3,4-dimethoxybenzylamine (24.0 g, 0.144 mol), tetrahydrofuran (192 mL) and triethylamine (15.5 g, 0.153 mol) was added dropwise benzoyl chloride (20.7 g, 0.147 mol) at −7-0° C. During addition dropwise, tetrahydrofuran (24 mL) was added thereto to stir the mixture. After adding dropwise, the dropping funnel was washed with tetrahydrofuran (12 mL), and tetrahydrofuran (24 mL) was added again thereto. The reaction mixture was gradually warmed to about 15° C. The reaction was monitored by TLC (eluent: hexane/ethyl acetate (1:1)). To the reaction mixture was added water (48 mL) at 5-8° C., and then added ethyl acetate (144 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (48 mL×2). The combined organic layers were washed successively with 10% hydrochloric acid (48 mL), saturated aqueous sodium hydrogen carbonate solution (48 mL), water (48 mL) and saturated brine (48 mL), and dried over magnesium sulfate (12 g), and the solvent was evaporated under reduced pressure at 40° C. or lower. To the concentrate (40 g) was added ethyl acetate (89 g), and the mixture was homogenized with warming at 50° C., and cooled to 11° C. The solid was collected by filtration, washed with cold ethyl acetate (15 mL), and dried under reduced pressure at 40° C. or lower to give N-benzoyl-3,4-dimethoxybenzylamine (33.3 g, 85.4%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][N:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].NCCC(O)=O.C(O)(=O)C>O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:19]2[N:13]([CH3:12])[C:14](=[O:15])[NH:16][C:17]2=[O:18])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CN1CC(=O)NC1=O
Reactant: COc1cc(C=O)ccc1O
Agent: NCCC(=O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C=C2C(=O)NC(=O)N2C)ccc1O
Yield: 14.8 %

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (4.6 g, 30 mmoles), 1-methyl hydantoin (3.5 g, 30 mmoles), β-alanine (1.4 g, 16 mmoles), and acetic acid (40 ml) is stirred under an inert atmosphere and heated to reflux. After 8 hours the mixture is stirred into water (300 ml) and the precipitate filtered off, rinsed successively with water (3X), ethanol (2X), and ether (2X), and dried. Recrystallization from acetonitrile gave the pure product (1.1 g), mp 197°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4].[C:22]([CH2:26][C:27](O)=O)([CH3:25])([CH3:24])[CH3:23].CC(C)(C)CC=O>CO>[CH3:23][C:22]([CH2:26][CH2:27][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)CC(=O)O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Agent: CC(C)(C)CC=O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.6 %

Procedure:
Aspartame (11.76 g), tertbutylacetic acid (4.64 g) and methanol (100 ml) were charged to a hydrogenation vessel. 3,3-Dimethylbutyraldehyde (4.0 g) was added. The vessel was pressure purged with nitrogen (4×), and 0.48 g of 4% palladium on carbon (containing 50% water) was added. After pressure purging the reactor with nitrogen (4×), followed by hydrogen (4×), the mixture was hydrogenated at 50 psig for 12 hours at room temperature. After completion of the reaction, the vessel was pressure purged with nitrogen (4×). The catalyst was removed from the reaction mixture by filtration through powdered cellulose. Methanol (50 ml) was used to rinse the reaction vessel and the filter cake. The filtrate and wash were combined, and methanol was evaporated under reduced pressure. The solution was reduced to 75 ml total volume, and 75 g of deionized water was added. The remaining methanol was evaporated from the solution under reduced pressure. The resulting solution was stirred at room temperature for 12 hours. Hexane (75 ml) was added, and the solution was stirred for 3 hours at room temperature. The crystallized solid was isolated by filtration and washed with 50 ml deionized water and 50 ml of hexane. The wet product was dried in air to give 8.1 g of neotame (>98% by HPLC).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])[CH:9]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:8]2)([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+]>C1COCC1.CO.CC(O)=O>[CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:10](=[O:17])[CH:9]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:26])[CH2:20][CH2:19]1)[CH2:8]2)([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)C(C1CCNCC1)C2
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)C(C1CCN(C)CC1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-isopropoxy-6-nitro-2-piperidin-4-yl-indan-1-one (Example 1, Step 5) in THF (5 mL) and methanol (5 mL) is added formaldehyde (104.2 uL, 1.39 mmol) and 10 drops of AcOH sequentially. The reaction mixture is stirred at room temperature for 1 h, then sodium cyanoborohydride (175.1 mg, 2.78 mmol) is added in one portion, and the reaction is stirred for an additional 30 min. The reaction is quenched by saturated aqueous NH4Cl and concentrated in vacuo to give an oily residue. This oil is partitioned between EtOAc and brine, the organic extract is dried over Na2SO4, filtered and concentrated under vacuum. Silica gel chromatography (5% MeOH in DCM) affords 5-isopropoxy-2-(1-methyl-piperidin-4-yl)-6-nitro-indan-1-one; MS m/z 333.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[K+].[K+].ICC>O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]1
Reactant: CC#N
Reactant: OC1(c2cccc(Cl)c2Cl)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: O
Product: CCN1CCC(O)(c2cccc(Cl)c2Cl)C1
Temperature: 25 °C

Procedure:
In a sealed tube a mixture of 3-(2,3-dichlorophenyl)pyrrolidin-3-ol (0.35 g, 1.51 mmol), acetonitrile (20 mL), potassium carbonate (0.019 g, 3.77 mmol) and iodoethane (0.24 g, 1.51 mmol) was stirred at ambient temperature over night, additional iodoethane (0.02 mL) was added and the resulting mixture was stirred over night. Water (50 mL) was added, the aqueous phase was extracted with tert-butyl methyl ether (2×50 mL) and the combined organic phase was dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1) gave the title compound (0.13 g). The amine was converted to the oxalic acid salt and recrystallized from methanol/ethanol/diethyl ether: M.p. 206-207° C.; MS m/z (relative intensity, 70 eV) 259 (M+, 5), 173 (7), 145 (6), 72 (23), 71 (bp).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:18](OCC)(=O)[CH2:19][OH:20].Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:18]([CH2:19][OH:20])=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)CO
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(CO)nc(=O)c1-2
Yield: 23.4 %

Procedure:
Sodium (0.68 g) was dissolved in ethanol and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (3.0 g, 13.5 mmol), followed by ethyl glycolate (2.8 g, 27 mmol) were added. The reaction mixture was refluxed overnight, the ethanol was stripped and water, followed by 2N HCl were added to the residue. A precipitate formed which was collected by filtration, washed with saturated NaHCO3, and then water. The product was recrystallized from ethyl acetate, then ether to afford 0.83 g of 1-cyclopentyl-3-ethyl-6-(hydroxymethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 183°-184° C.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]2[NH:7][C:8](=[O:17])[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH:11](O)[C:5]=2[CH:4]=1)#[N:2].S(Cl)(Cl)=O.[CH2:24]([N:26]([CH2:30][CH3:31])[CH2:27][CH2:28]N)[CH3:25].Cl.[OH-].[Na+].[N:35]1C=CC=CC=1>C(Cl)Cl.O>[NH2:35][C:6]1[CH:18]=[CH:19][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH:11]1[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8](=[O:17])[N:7]1[CH2:25][CH2:24][N:26]([CH2:30][CH3:31])[CH2:27][CH3:28]
Reactant: c1ccncc1
Reactant: CCN(CC)CCN
Reactant: N#Cc1ccc2c(c1)C(O)c1ccccc1C(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCN1C(=O)c2ccccc2C1c1cc(C#N)ccc1N
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 2.50 g of 2-cyano-11-hydroxy-5, 11-dihydro-6H-dibenz[b,e]azepin-6-one and 1.78 g of pyridine in 40 ml of methylene chloride was added 1.78 g of thionyl chloride under ice cooling. The mixture was stirred for an hour and ice cooling and then at room temperature for 30 minutes. The reaction solution was added to a solution of 5.81 g of N,N-diethylethylenediamine in 50 ml of methylene chloride at -5° to 0° C. with stirring. After stirring for an hour under ice cooling, 5 ml of water was added thereto. Further 200 ml of methylene chloride and 100 ml of water were added to the reaction mixture, and pH was adjusted to 1 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 200 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 10 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The crude product obtained was subjected to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=16:4:1). A major fraction was concentrated to dryness under reduced pressure to give 1.42 g of 3-(2-amino-5-cyanophenyl)-2-(2-diethylaminoethyl)isoindolin-1-one (Compound 31).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[C:14]([F:17])([F:16])[F:15])[C:8]([OH:10])=O.Cl.[CH3:21][NH:22][O:23][CH3:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][N:22]([CH3:21])[C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:13]([C:14]([F:17])([F:16])[F:15])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:19])[F:18])[CH:6]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C(F)(F)F)c(OCC(F)(F)F)c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a mixture of 3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-benzoic acid from step 6 (9.22 g, 32 mmol), N,O-dimethylhydroxylamine hydrochloride (5.00 g, 51 mmol), N-methylmorpholine (5.62 mL, 51 mmol) and 4-DMAP (391 mg, 3.2 mmol) in DCM (100 mL) and DMF (20 mL) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (7.36 g, 38 mmol). The mixture was stirred at 23° C. for 18 h., poured onto ice cold 1 N HCl, extracted with TBME, washed with sat. NaHCO3-sol. and brine, and dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a brown oil (10.555 g, 100%), which was used without further purification. MS (EI) 331.0 [M].
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:7]=1[CH3:8])=[O:2].C(O)(=O)C.C(Cl)(Cl)Cl.[Br:23]N1C(=O)CCC1=O>O>[Br:23][C:5]1[S:4][C:3]([CH:1]=[O:2])=[C:7]([CH3:8])[C:6]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1c(C2CCCCC2)csc1C=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)sc(Br)c1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a solution of 2-formyl-3-methyl-4-cyclohexylthiophene (4.1 g, 20 mmol, See Example 22) in 30 mL of a mixture prepared from acetic acid and chloroform (1:1), was added solid N-bromosuccinimide (5.3 g, 30 mmol) slowly in portions at 0° C. The reaction mixture was then stirred overnight at room temperature, poured into water, and extracted repeatedly with dichloromethane. The combined organic layers were washed with saturated NaHCO3 and brine solutions, and dried over anhydrous Na2SO4. After the solvent was removed by rotary evaporation, the remaining solid was purified by column chromatography using silica gel and a dichloromethane-petroleum ether (2:3) as eluant. The solvent was removed by rotary evaporation yielding 3.3 g white solid (57%). 1H NMR (CDCl3) δ 9.97 (s, 1, CHO), 2.88 (m, 1,cyclohexyl methane), 2.59 (s, 3,CH3), 1.87 and 1.34 m, 10, cyclohexyl)
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=C(c1csc(N2CC(O)C2)n1)N1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCCCC3)cs2)C1
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 3-hydroxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (310 mg, 1.16 mmol) (obtained as described in Reference Example 27(2)) in methylene chloride (10 ml) were added methanesulfonyl chloride (0.27 ml, 3.48 mmol) and triethylamine (0.49 ml, 3.48 mmol) in an ice bath, and then the mixture was stirred for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-methanesulfonyloxy-1-(4-piperidinocarbonyl-1,3-thiazol-2-yl)azetidine (346 mg, yield 86%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:16]([C:17]2[NH:18][C:19]([C:22]3[CH:27]=[CH:26][C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][CH:23]=3)=[CH:20][N:21]=2)[CH:15]2[CH2:37][CH:12]1[CH2:13][CH2:14]2)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:39][O:40][C:41](=[O:63])[NH:42][CH:43]([C:46]([N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[C:53]1[NH:57][C:56]2[CH:58]=[C:59](Br)[CH:60]=[CH:61][C:55]=2[N:54]=1)=[O:47])[CH2:44][CH3:45].[C:64](OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=CC(Br)=CC=3)=CN=2)C1)=O)(C)(C)C>>[CH3:39][O:40][C:41](=[O:63])[NH:42][CH:43]([C:46]([N:48]1[CH2:52][CH2:51][CH2:50][CH:49]1[C:53]1[NH:57][C:56]2[CH:58]=[C:59]([C:25]3[CH:24]=[CH:23][C:22]([C:19]4[NH:18][C:17]([CH:16]5[CH:15]6[CH2:37][CH:12]([CH2:13][CH2:14]6)[N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:21][CH:20]=4)=[CH:27][CH:26]=3)[CH:60]=[CH:61][C:55]=2[N:54]=1)=[O:47])[CH:44]([CH3:64])[CH3:45]
Reactant: CCC(NC(=O)OC)C(=O)N1CCCC1c1nc2ccc(Br)cc2[nH]1
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl}-biphenyl-4-yl]-11′-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that [2-methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester and {1-[2-(6-bromo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 8.10-7.80 (m, 7H), 5.42-5.30 (m, 1H), 4.65 (s, 1H), 4.40-4.25 (m, 2H), 4.20-3.90 (m, 2H, 3.80-3.60 (m, 6H), 3.00-2.80 (m, 1H), 2.70-2.55 (m, 1H), 2.50-1.60 (m, 12H), 1.10-0.80 (m, 12H); m/z 739.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([N+:30]([O-])=O)=[CH:22][CH:21]=1)([CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]([O:19][C:2]([CH3:18])([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:5]=2)=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(CC(C)(C)Oc2ccc(N)c3ccccc23)ccn1
Yield: 98.6 %

Procedure:
tert-Butyl 4-(2-methyl-2-(4-nitronaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (27) (100 mg, 0.229 mmol) in MeOH (30 mL) and AcOH (8.0 mL) was passed through a Thales H-cube (1.0 mL·min−1, 30° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode). The volatiles were removed under reduced pressure to give tert-butyl 4-(2-(4-aminonaphthalen-1-yloxy)-2-methylpropyl)pyridin-2-ylcarbamate (28) (92 mg, 99%) as a purple oil: m/z 408 (M+H)+ (ES+).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][N:30]([CH3:36])[CH2:31][C:32]([NH:34][NH2:35])=O>>[CH3:29][N:30]([CH2:31][C:32]1[O:27][C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])[CH2:10]2)=[N:35][N:34]=1)[CH3:36]
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CN(C)CC(=O)NN
Product: CN(C)Cc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)o1

Procedure:
100 mg (0.249 mmol) of the compound from Example 44A and 42 mg (0.275 mmol) of 2-(dimethylamino)acetohydrazide were reacted according to the General Method 4. Yield: 13 mg (11% of theory).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]5[CH2:26][O:25][CH2:24]5)[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[N:27]1([C:2]2[N:7]=[C:6]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[C:21]([CH:23]6[CH2:26][O:25][CH2:24]6)[CH:22]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)[CH:5]=[CH:4][CH:3]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: C1CNCCNC1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)n1
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)c1
Yield: 18 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and 1,4-diazepane, 118 was obtained as an off-white solid (22.8 mg, 18%). 1H NMR (400 MHz, DMSO) δ 9.36-9.33 (s, 1H), 9.18-9.13 (t, J=4.0 Hz, 1H), 9.10-9.05 (s, 1H), 8.68-8.62 (d, J=5.1 Hz, 2H), 8.55-8.50 (s, 1H), 7.74-7.69 (dd, J=13.8, 5.6 Hz, 1H), 7.23-7.18 (d, J=7.7 Hz, 1H), 6.65-6.61 (d, J=8.5 Hz, 1H), 5.07-5.00 (dd, J=8.3, 6.1 Hz, 2H), 4.76-4.69 (t, J=6.3 Hz, 2H), 4.48-4.36 (m, 1H), 3.90-3.83 (t, J=5.8 Hz, 2H), 3.83-3.77 (d, J=5.3 Hz, 2H), 3.01-2.93 (m, 2H), 2.75-2.69 (m, 2H), 1.89-1.83 (m, 2H); MS (ESI) m/z: 428.2 [M+H]+
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[C:6](=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:8])[CH3:7]>C1COCC1.[Cu]I>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([C:6]([CH:1]1[CH2:3][CH2:2]1)([CH3:7])[CH3:8])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:14]
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: Br[Mg]C1CC1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)C1CC1
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
To a suspension of copper(I) iodide (7.61 g, 40.0 mmol) in THF (50 mL) at −50° C. was added cyclopropylmagnesium bromide (160 mL, 80.0 mmol, 0.5 M in THF) under nitrogen. After stirring for 15 minutes, the suspension was allowed to warm up and stirred at rt for 20 min before cooling back to −50° C. A solution of diethyl isopropylidenemalonate (4.0 g, 20.0 mmol) in THF (50 mL) was added, and the reaction was allowed to warm to rt over 3 h. The reaction mixture was then quenched with saturated sodium bicarbonate (200 mL), and filtered through Celite. The filtrate was extracted with ethyl acetate (3×250 mL). The combined extracts were dried over sodium sulfate and concentrated, and the resulting residue was purified by silica gel chromatography eluting with diethyl ether/hexanes (1:10) to afford 2-(1-cyclopropyl-1-methylethyl)malonic acid diethyl ester.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)C=CC=CC=1>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CNCCO1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of 1,1-dimethylethyl {[(2S)-4-(phenylmethyl)-2-morpholinyl]methyl}carbamate (4.9 g, 16 mmol) in ethanol (160 mL) was added 10% Pd/C (1.5 μg). The suspension was hydrogenated at 50 psi for 8 h. The reaction was filtered through a pad of Celite® and the pad was washed several times with methanol. The filtrate was concentrated to afford the title compound (3.35 g, 97%) as a colorless solid which was not purified further: LC/MS (ES) m/e 217 (M+H)+. The absolute stereochemistry of the title compound was determined by vibrational circular dichroism (VCD).