Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH2:27])[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH:25]([NH:27][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:26])[CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CC(N)c1cc(F)cc(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of cinnamic acid (44 mg), 1-(3-fluoro-5-morpholin-4-yl-phenyl)ethylamine, Preparation 24 (66 mg), DMAP (36 mg), EDC.HCl (120 mg), and Et3N (120 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification of the crude product by flash chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 78 mg of the title compound as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=1)=[O:8].[N:16]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][C:12]([N:19]2[CH2:20][CH2:21][N:16]([C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:31])[F:32])[CH2:17][CH2:18]2)=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C(NCCCCO)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Product: O=C(NCCCCO)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (4-hydroxybutyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (30% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.98, 7.75, 7.63, 7.57, 7.37, 6.99, 4.06, 3.88, 3.82-3.67, 3.52, 3.36, 1.70.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.IC>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:13])[N:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cnn1C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 110 mg (30%) of the title compound and 195 mg (53%) of the compound of Preparative Example 7.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12>>[CH2:1]([N:8]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[C:11]=2[CH:18]=[CH:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2[nH]ccc12
Reactant: NCc1ccccc1
Product: Nc1nccc2c1ccn2Cc1ccccc1
Temperature: 180 °C
Yield: 55 %

Procedure:
Benzylamine (1.8 mL, 16.4 mmol, 5 eq) was added to 4-chloro-1H-pyrrolo[2,3-b]pyridine (0.50 g, 3.3 mmol, 1.0 eq; see, generally, Cheng, C.-C. et al. J. Physical Chem. 2003, 107, 1459-1471, incorporated by reference in its entirety) in a sealed tube and the reaction mixture was heated at 180° C. for 8 h. The reaction mixture was purified by loading it directly onto a C-18 YMC 30×500 mm reverse phase column (eluting 20-90% aqueous methanol with 0.1% TFA over a 30 minute gradient) and the appropriate fractions were isolated and concentrated in vacuo. The residue was neutralized with saturated aq. NaHCO3 solution and the mixture was extracted with CHCl3. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the product (0.40 g, 55%) as a solid. 1H NMR (DMSO-d6) δ 7.51-7.52 (m, 1H), 7.16-7.36 (m, 6H), 6.63-6.68 (m, 2H), 6.09 (s, 2H); MS(ESI+) m/z 224 (M+H)+. Calculated: 224.1188, found: 224.1178
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:33]5[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[CH:34]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C#N)c(Cl)c1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (0.084 g, 0.20 mmol), 4-bromo-2-chlorobenzonitrile (0.043 g, 0.20 mmol), aqueous potassium carbonate (520 μL, 1M), FibreCat 1007 (7 mg), and DMF (1 mL) were combined. The mixture was heated at 80° C. for 18 hours. After cooling, the mixture was filtered and purified by preparative HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH2:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27]>>[CH2:26]([S:28]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:30])=[O:29])[CH3:27]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.5 g (1.4 mmol) of material from Example 50 and 7.6 μL (0.11 mmol) ethanesulfonyl chloride. MMR was consistent with the proposed compound.
Reaction SMILES: O=[C:2]1[O:3][CH2:4][CH2:5]/[C:6]/1=[CH:7]/[O-:8].[Na+].[NH2:10][C:11]([NH2:13])=[O:12]>C(O)C>[OH:3][CH2:4][CH2:5][C:6]1[C:7]([OH:8])=[N:10][C:11]([OH:12])=[N:13][CH:2]=1
Reactant: O=C1OCC/C1=C/[O-]
Reactant: NC(N)=O
Agent: [Na+]
Solvent: CCO
Product: OCCc1cnc(O)nc1O
Yield: 18.6 %

Procedure:
Sodium (Z)-(2-oxodihydrofuran-3(2H)-ylidene)methanolate (1.36 g, 10 mmole) was added to a solution of 600 mg. (10 mmole) of urea in 50 ml. of absolute ethanol, and the reaction mixture was boiled under reflux for 5 h with stirring. Concentration under vacuum gave a residue, which was crystallized from ethanol to yield 5-(2-hydroxyethyl)pyrimidine-2,4-diol (290 mg, 18.5%). LC-MS (m/z)=157 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:16]#[C:17][CH3:18]>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:18][C:17]#[CH:16])[CH:3]=1
Reactant: CC#CBr
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.4 %

Procedure:
3-Fluorophenol (5.10 g, 45.5 mmol) was dissolved in DMF (10 mL) and potassium carbonate (7.55 g, 54.6 mmol) was added and the mixture was stirred at ambient temperature for 30 minutes. Bromoprop-1-yne (5.05 mL, 45.5 mmol) was added and the reaction was stirred overnight at ambient temperature. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, concentrated under reduced pressure to give a yellow oil (7.27 g) that was used without further purification in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.30-7.23 (m, 1 H), 6.81-6.69 (m, 3 H), 4.70 (d, J=2.3 Hz, 2 H), 2.56 (t, 1 H); LCMS (m/z) ES+=151 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[N:16]=1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[NH2:22][C:17]1[N:16]=[C:15]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:20]=[C:19]([CH3:21])[N:18]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(F)c(C=O)c(F)c2)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
To (3,5-difluoro-4-formylphenyl)boronic acid (5.0 g, 26.9 mmol) and 4-chloro-6-methyl-2-pyrimidinamine (3.86 g, 26.9 mmol) were added 1,4-dioxane (100 mL) and saturated aqueous NaHCO3 (40 mL). The mixture was degassed with nitrogen for 10 minutes. Pd(Ph3P)4 (1.0 g, 0.87 mmol) was added and the reaction mixture was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, poured onto water and filtered. The solid was washed with water and EtOAc to provide a pale yellow solid (2.4 g). The combined filtrates were poured into a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on a SiO2 column (gradient: 100% CHCl3 to 90:10:1 CHCl3/CH3OH/NH4OH). Loading of the material into the column was complicated by the poor solubility properties of the residue. Hot dioxane was used to help solubilize the residue. Part of the material co-eluted with the solvent front. All the fractions containing the product (including the ones that co-eluted with the solvent front) were combined, concentrated and triturated with ˜1:1 mixture of EtOAc and hexanes to provide desired product as a yellow solid (1.6 g). This material was combined with the pale yellow solid obtained from the initial filtration and used without further purification. LC-MS (ES) m/z=250 [M+H]+.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:19])=[C:3](\[C:6]1[CH2:7][CH2:8][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH:11]=1)/[C:4]#[N:5].[Cl-].N1(C=[N+](C)C)C2C=CC=C[C:24]=2N=N1.[OH-].[Na+]>ClCCl>[CH2:12]([N:9]1[CH2:8][C:7]2[CH:24]=[N:1][C:2]([CH3:19])=[C:3]([C:4]#[N:5])[C:6]=2[CH2:11][CH2:10]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[N+](C)=Cn1nnc2ccccc21
Reactant: C/C(N)=C(\C#N)C1=CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ncc2c(c1C#N)CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a solution of (E)-3-amino-2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-but-2-enenitrile (15 g, 0.056 mole) in dichloromethane (200 mL), freshly prepared benzotriazol-1-ylmethylene-dimethyl-ammonium chloride (12 g, 0.068 mole) was added in one portion. The mixture was stirred for 24 h at ambient temperature. NaOH (2N, 200 mL) was added, and the resulting mixture was stirred vigorously for 5 min. The phases were separated and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The crude product was purified by column chromatography to give 7-benzyl-3-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile as a colorless oil (8.9 g, 53% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:35][CH:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:38]([CH:36]([CH3:37])[CH3:35])(=[O:40])=[O:39])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(=O)(=O)C(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 137.8 %

Procedure:
To a 10 mL round-bottomed flask, in an ice bath, fitted with a thermometer, and under a nitrogen atmosphere, of (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (150 mg, 0.3984 mmol, prepared in example 39) dissolved in methylene chloride (2.7 mL) was added triethylamine (0.07 mL, 0.478 mmol). Once the mixture was cooled to 0° C., 2-propanesulfonyl chloride (0.05 mL, 0.4382 mmol) was added by syringe, and the mixture was gradually warmed to room temperature, with stirring overnight. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under vacuum, yielding 265 mg viscous oil. Purification was conducted using a Chromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding the title compound (200 mg, 100%) as a slow crystallizing foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.O=[CH:46][CH2:47][NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:51]([O:50][C:49]([NH:48][CH2:47][CH2:46][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Yield: 67.7 %

Procedure:
The title compound was prepared according to the procedure described in Example 25 (Step a) using tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl}carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol), tert-butyl N-(2-oxoethyl)carbamate (Aldrich) (131 mg, 0.83 mmol) and NaBH(OAc)3 (Aldrich) (176 mg, 0.83 mmol) in CH2Cl2 (20 mL). Purification by silica gel chromatography (1:10 McOH:EtOAc) provided the title compound as a white foam (386 mg). MS (ESI, pos. ion) m/z: 760 (M+1); (ESI, neg. ion) m/z: 758 (M−1). Calc'd for C42H54ClN5O6: 759.38.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]O[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:21]>CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][NH:21][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)CCCC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CCCC2
Temperature: 115 °C
Yield: 50.7 %

Procedure:
A mixture of ethyl 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylate (3.48 g, 15.7 mmol) and ammonium acetate (2.41 g, 31.3 mmol) in N,N-dimethylformamide (25 mL) was heated at 115° C. for 6 hours. The mixture was concentrated in vacuo, ice water was added, then extracted 2× with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered through a small pad of Silica gel (1:19 methyl alcohol/dichloromethane), and the filtrate concentrated in vacuo to give ethyl 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylate (1.76 g). A solution of this ester in aqueous 5N sodium hydroxide (30 mL) and ethyl alcohol (6 mL) was heated at reflux for 1 hour, then cooled in an ice bath. The mixture was acidified with hydrochloric acid, and the precipitate collected, rinsed with water followed by diethyl ether and allowed to dry to give 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid (1.17 g). m.p. 225°-227° C.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.N1C=CC=CC=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>ClCCl>[CH2:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2][N:3]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:4]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccccc2CC1
Reaction time: 8 h

Procedure:
To a solution of 1.75 g of 2,3,4,5-tetrahydro-1H-3-benzazepine in 20 ml of dichloromethane was added 2.884 ml of pyridine. The reaction mixture was ice-cooled, and 1.705 ml of ethyl chloroformate which had been dissolved in 5 ml of dichloromethane was added dropwise thereto, followed by stirring overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 2.15 g of ethyl 1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a pale yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[CH:4][C:3]1=[O:8].FC(F)(F)C(O)=O.CO[CH2:18][N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][Si](C)(C)C>C(Cl)Cl>[CH2:25]([N:19]1[CH2:20][CH:4]2[C:3](=[O:8])[N:2]([CH3:1])[C:6](=[O:7])[CH:5]2[CH2:18]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CN1C(=O)C=CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 0 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
N-Methylmaleimide (23.3 g, 21 mmol; Aldrich) was dissolved in CH2Cl2 (400 mL) in a 3-neck flask, chilled to 0° C. under nitrogen, and treated with trifluoroacetic acid (1.6 mL, 21 mmol; Aldrich). A solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (49.8 g, 21 mmol; Aldrich) in CH2Cl2 (60 mL) was then added slowly at a rate to maintain the temperature below about 5° C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred for 24 h. The solution was concentrated under vacuum, and the residue was diluted with CH2Cl2 (125 mL), washed with saturated aqueous NaHCO3 (2×100 mL) and brine (2×100 mL). The organic phase was concentrated under vacuum to afford the title compound as a white solid (51.2 g, 21 mmol; 100% yield): 1H NMR (300 MHz, CDCl3) δ ppm 7.14-7.37 (m, 5H), 3.57 (s, 2H), 3.28 (d, J=10.2 Hz, 2H), 3.13-3.21 (m, 2H), 3.01 (s, 3H), 2.32-2.42 (m, 2H); MS (DCI/NH3) m/z 245 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][C:30](O)=[O:31])=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][C:30]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:19])=[O:31])=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Product: O=C(Cc1ccc2c(c1)OCO2)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(benzo[d][1,3]dioxol-5-yl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.41 (m, 1H), 8.01-7.95 (m, 2H), 7.72 (m, 1H), 7.63 (m, 4H), 6.96 (d, J=1.6, 1H), 6.88 (d, J=7.9, 1H), 6.84 (dd, J=8.0, 1.6, 1H), 5.99 (s, 2H), 3.61 (s, 2H); MS (APCI+) M/Z 434 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH2:2][C:3]1[CH:8]=[N:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1)(=[O:23])=[O:22]
Reactant: N#Cc1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(C#N)nc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.3 %

Procedure:
To a solution of 5-(hydroxymethyl)picolinonitrile (1.59 g, 11.9 mmol) in 80 mL of DCM was added diisopropylethylamine (3.2 mL), followed by a solution of methanesulfonyl chloride (1.49 g, 13.0 mmol) in 20 mL of DCM at 0° C. The solution was stirred at 0° C. for 40 min and washed with 5% citric acid, sat. NaHCO3 (aq.) and brine. After concentration, the residue was purified by silica gel chromatography (elution with 0-30% EtOAc/Hex) to afford (6-cyanopyridin-3-yl)methyl methanesulfonate (2.33 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14].C([N-]C(C)C)(C)C.[Li+].C[O:35][C:36](=O)[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[N:39][CH:38]=1>O1CCCC1>[CH2:13]([N:15]([CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][C:21](=[C:36]([OH:35])[C:37]2[CH:38]=[N:39][CH:40]=[C:41]([CH3:43])[CH:42]=2)[C:20]1=[O:25])[CH2:16][CH3:17])[CH3:14]
Reactant: CCN(CC)CN1CCCCC1=O
Reactant: COC(=O)c1cncc(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCN(CC)CN1CCCC(=C(O)c2cncc(C)c2)C1=O
Temperature: 25 °C
Yield: 13.2 %

Procedure:
To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30 min and was re-cooled to −78° C. A solution of 1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) in tetrahydrofuran (10 mL) was added to the lithium diisopropylamide via syringe. The reaction mixture was maintained at −78° C. for 1 h and was treated with a solution of 5-methylnicotinic acid methyl ester (2.12 g, 14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixture was allowed to warm to rt and was maintained overnight. The reaction mixture was quenched with water (30 mL) and was extracted with ether (2 x). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography [1/0 to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide 560 mg (13%) of 1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one. To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (101 mL) was added conc. hydrochloric acid (2 L) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was allowed to cool to rt, diluted with isopropyl alcohol, and allowed to stand at 0° C. The product was isolated by filtration, thus providing 400 mg (85%) of 5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.