Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:6][C:3]=1[C:4]#[N:5].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([OH:34])[CH3:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:34][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH3:33])[N:9]=1
Reactant: CC(O)c1ccc(F)cc1
Reactant: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(Cl)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C#N)c(OC(C)c3ccc(F)cc3)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To an oven-dried round bottom flask was added toluene (1 mL), the product of Step D of Example 114 (0.050 g; 0.134 mmol); 1-(4-flourophenyl)ethanol (0.070 mL; 0.536 mmol), and cesium carbonate (0.218 g; 0.670 mmol). The reaction mixture was heated at 100° C. and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, then it was partitioned between ethyl acetate and 2N aq. NaOH solution. The organic portion was separated and washed with more 2N aq. NaOH solution (2×), brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford 0.051 g of the desired product: m/e=355 (M-1-(4-flourophenyl)ethyl group) Rt=4.9 min on LCMS.
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:37]=[CH:36][C:10]([C:11]([C:13]2[C:14]3[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=3[S:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=O)=[CH:9][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C1COCC1.ClCCl>[OH:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:13]2[C:14]3[CH:35]=[CH:34][CH:33]=[CH:32][C:15]=3[S:16][C:17]=2[C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:22][CH:23]=2)=[CH:36][CH:37]=1
Reactant: COC(=O)COc1ccc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCCOc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To the product (1 g, 1.94 mmol) of Example 28 dissolved in anhydrous THF (80 mL) was added LAH (0.47 g, 12.4 mmol) at 0-5° C. under nitrogen. The reaction mixture was stirred for 2 hours and quenched with ice-cold NaOH (0.5 M) solution. The organic layer was extracted with ethyl acetate, combined, dried and concentrated in vacuo. To this residue (0.88 g, 1.8 mmol) dissolved in dichloromethane (˜50 mL) was added triethylsilane (1.73 mL, 10.8 mmol) and TFA (0.42 mL, 5.4 mmol). The reaction mixture was stirred for 1.5 hours before it was washed with dilute NaOH solution and brine until neutral. The combined organic layers were dried with Na2SO4 and concentrated. The residue was purified by column chromatography (20% CH3OH in dichloromethane) to yield 0.53 g (63%) of title compound.
Reaction SMILES: [CH:1]([NH2:3])=[CH2:2].[CH:4]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH2:5].C(=O)([O-])[O-].[K+].[K+].[N+:25]([C:28]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:29]=1F)([O-:27])=[O:26]>CN(C)C=O>[CH:1]([NH:3][C:29]1[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:28]=1[N+:25]([O-:27])=[O:26])=[CH2:2].[CH:4]([N:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH2:5]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C=CN
Agent: C=Cn1c2ccccc2c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
1 gram of a copolymer comprising vinylamine/N-vinylcarbazole (25/75 mole percent) is dissolved in 50 milliliters of anhydrous dimethylformamide (DMF). 0.184 grams potassium carbonate is then suspended in this polymer solution and thereafter 1 milliliter of 2,4-dinitrofluorobenzene (Sanger's reagent) added by dropwise addition. Immediately after the addition of Sanger's reagent a yellow color develops within the solution and becomes more intense as the reaction proceeds. The flask containing the solution is then heated over a steam bath for about 11/2 hours at which time the polymer precipitated from the DMF by the addition of water. The precipitate is separated from the solution by filtration and purified by washing with warm dilute aqueous potassium hydroxide solution. This washing procedure is repeated several times until the filtrate is colorless. The polymer is then dried in a vacuum oven at about 70°C. The number average molecular weight of the product is in the range of about 100,000.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=2)=[N:14][CH:15]=1.Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:11]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCOc1ccc(-c2ncc(-c3ccc(O)c(F)c3F)cn2)cn1
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCCCCCC)nc3)nc2)c(F)c1F
Yield: 61 %

Procedure:
The etherification of 12 mmol of 5-(2,3-difluoro-4-hydroxyphenyl)-2-(6-hexyloxypyridin-3-yl)pyrimidine using 13.2 mmol of 1-bromooctane in 100 ml of DMF is carried out analogously to the procedure indicated for Example 3. The crude product is chromatographed on silica gel 60 using dichloromethane as eluent and is recrystallized from n-heptane and toluene, giving 3.6 g (61%) of colorless crystals, whose analytical data correspond to those of the compound obtained as described in 1a).
Reaction SMILES: O.[NH:2]1[C:6]([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][CH:16]3[CH:11]([CH2:12][CH:13]([C:19]([OH:21])=[O:20])[NH:14][CH2:15]3)[CH2:10]2)=[N:5][N:4]=[N:3]1.Cl>C(O)CCCCCCCCC>[CH2:6]([O:20][C:19]([CH:13]1[CH2:12][CH:11]2[CH:16]([CH2:17][CH2:18][CH:9]([CH2:8][CH2:7][C:6]3[NH:2][N:3]=[N:4][N:5]=3)[CH2:10]2)[CH2:15][NH:14]1)=[O:21])[CH2:7][CH2:8][CH2:9][CH2:18][CH2:17][CH2:16][CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1
Agent: Cl
Solvent: O
Solvent: CCCCCCCCCCO
Product: CCCCCCCCCCOC(=O)C1CC2CC(CCc3nnn[nH]3)CCC2CN1

Procedure:
A solution of 2.5 g (8.4 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid monohydrate in 50 ml decyl alcohol saturated with hydrogen chloride (g) is heated at 120° C. overnight. The mixture is concentrated in vacuo and the residue purified by SPE (Oasis HLB) to afford the title compound.
Reaction SMILES: Cl.C([O:4][C:5](=[O:19])[CH2:6][CH2:7][CH2:8][N:9]([CH2:17][CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)C>O1CCOCC1.O>[CH2:17]([N:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:19])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=1)[CH3:18]
Reactant: CCOC(=O)CCCN(CC)c1cccc(C)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCN(CCCC(=O)O)c1cccc(C)c1
Temperature: 95 °C
Reaction time: 12 h
Yield: 109.5 %

Procedure:
4N Solution (100 ml) of hydrogen chloride in dioxane and water (20 ml) was added to the compound (14.1 g) obtained in Step 1, and the mixture was stirred at 95° C. for 12 hours. The solvent was evaporated to give the title compound (13.7 g).
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[N:14]1([CH:20]=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[N:3]1[C:4]2=[C:13]3[C:8](=[CH:7][CH:6]=[CH:5]2)[CH2:9][CH2:10][CH2:11][N:12]3[C:2]=1[N:17]1[CH2:18][CH2:19][N:14]([CH:20]=[O:21])[CH2:15][CH2:16]1
Reactant: O=CN1CCNCC1
Reactant: Clc1nc2cccc3c2n1CCC3
Product: O=CN1CCN(c2nc3cccc4c3n2CCC4)CC1
Yield: 64.5 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (20.00 g) in 1-piperazinecarboxaldehyde (25.00 g) was stirred at 120° C., under nitrogen, for 1.5 hrs. The reaction mixture was quenched with dilute sodium bicarbonate solution (300 ml) and extracted with chloroform. The organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel; 25:1 dichloromethane-methanol). The appropriate fractions were collected and evaporated. The residue was recrystallized twice from ethyl acetate to give 18.1 g (64%) of product, mp 138°-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)[CH3:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CCOc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCOc1ccccc1NN(C)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 41.5 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.00 g, 6.8 mmol), 2-ethoxyphenylboronic acid (Combiblock; 1.12 g, 6.8 mmol), copper(II) acetate (1.24 g, 6.8 mmol) and triethylamine (960 μL, 6.8 mmol) in 1,2-dichloroethane (15 mL) was heated in an oil bath at 50° C. overnight. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 20-25% ethyl acetate/hexanes, to give N′-(2-ethoxy-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (751 mg, 38%) as an off-white solid.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]1[CH2:15][CH:14]([C:16]([OH:18])=[O:17])[N:13]([C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[C:12]1=[NH:27].[CH3:28]O>>[ClH:1].[CH3:28][O:17][C:16]([CH:14]1[CH2:15][N:11]([C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:3])[C:12](=[NH:27])[N:13]1[C:19]1[C:20]([CH3:26])=[CH:21][CH:22]=[CH:23][C:24]=1[CH3:25])=[O:18]
Reactant: Cc1cccc(C)c1N1CC(C(=O)O)N(c2c(C)cccc2C)C1=N
Reactant: CO
Agent: Cl
Product: COC(=O)C1CN(c2c(C)cccc2C)C(=N)N1c1c(C)cccc1C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Dry, gaseous hydrochloric acid is introduced into a solution of 1.7 g (4.55 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acid hydrochloride, obtained as described in Example 33, in 20 ml of dry methanol at 0° to +5° C. After one hour the introduction of the gas is stopped, and the mixture is allowed to stand at +5° C. for 24 hours. The fluffy insolubles floating in the solution are filtered off, and the solvent is evaporated in vacuo. The residue is triturated with dry diethyl ether, the separated precipitate is filtered off, washed with diethyl ether, and dried. 1.6 g (90.9%) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine-4-carboxylic acid methylester hydrochloride are obtained as a colourless, hygroscopic crystalline substance; m.p.: 113°-115° C. (in sealed tube).
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([OH:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C1(C)C(C)=CC=CC=1>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:27]3[CH2:26][CH2:25][C:24]([C:21]4[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=4)([OH:30])[CH2:29][CH2:28]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: Cc1ccccc1C
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(O)(c3ccc(Cl)cc3)CC1)O2
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 28.4 %

Procedure:
A suspension of 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine (1.4 g) and 4-(4-chlorophenyl)-4-hydroxypiperidine (1.3 g) in xylene (10 mL) was stirred under nitrogen gas at 120° C. for 1.5 hours and, then, refluxed for 16 hours. Thereafter, 0.85 g of 4-(4-chlorophenyl)-4-hydroxypiperidine was added and the mixture was refluxed for 24 hours. After cooling, the reaction mixture was filtered and washed with diethyl ether. The filtrate was extracted with 1N-hydrochloric acid and the aqueous layer was made weakly acidic with saturated aqueous sodium hydrogen carbonate (NaHCO3). This aqueous layer was washed with diethyl ether and made weakly basic with saturated aqueous NaHCO3. This solution was extracted with ethyl acetate and the organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from diethyl ether/hexane to provide 0.58 g of the title compound. Yield 28%.
Reaction SMILES: [AlH4-].[Li+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10](OCC)=[O:11])[CH2:6][CH2:5]1>C1COCC1>[OH:11][CH2:10][CH:7]1[CH2:8][CH2:9][CH:4]([OH:3])[CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(O)CC1
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a suspension of lithium tetrahydroaluminate (3.11 g, 81.9 mmol) in THF (158 mL) was added a solution of ethyl 4-hydroxycyclohexanecarboxylate (9.40 g, 54.6 mmol) in THF (20 mL) at 0° C. After stirring for 30 min at same temperature, the reaction was quenched with water (10 mL) dropwise, then 15% NaOH solution (10 mL) and water (30 mL). After stirring for 10 min, the reaction mixture was filtered through a pad of Celite, the organic layer was wash with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate/hex) to give the desired product as white solid (6.9 g, 97%).
Reaction SMILES: C[O-].[Na+].[O:4]=[C:5]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[O:8][C:7]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:6]1.[CH:27](OCC)=[O:28].O>C1COCC1>[OH:28][CH:27]=[C:6]1[C:7]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[O:8][C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:5]1=[O:4]
Reactant: CCOC=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ncccc1O2
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1cccnc1C(=O)C2=CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a suspension of sodium methoxide (594 mg, 11.0 mmol) in THF (5 mL) was added a suspension of tert-butyl 4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (1.0 g, 3.1 mmol) in THF (10 mL), followed by ethyl formate (2.5 mL, 31 mmol) and the reaction mixture was stirred at 25° C. for 3 hours. Additional sodium methoxide (170 mg, 3.1 mmol) and ethyl formate (0.25 mL, 3.1 mmol) were added and the reaction mixture was stirred at 25° C. for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate (4×). The aqueous layer was saturated with solid NaCl and was extracted with ethyl acetate (5×). The organic layers were combined and dried over sodium sulfate. The precipitate formed was filtered and washed with ether (2×). The solid product was dissolved in hot dichloromethane/MeOH (1:1) and filtered, and the filter cake was rinsed with additional hot dichloromethane/MeOH (1:1) (4×) to dissolve all product and remove solid sodium sulfate. The combined filtrates were evaporated to afford tert-butyl 3′-(hydroxymethylene)-4′-oxo-3′,4′-dihydrospiro-[piperidine-4,2′-pyrano[3,2-b]pyridine]-1-carboxylate (560 mg, 52%) as a yellow solid. ESI-MS m/z talc. 346.2, found 347.5 (M+1)+; Retention time: 0.98 minutes (3 min run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([O:19]C1C=CC=CC=1)=O)[CH2:7][CH2:6][CH2:5]2.[NH2:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:13][CH3:14])[O:15][CH3:16])[N:8]([C:17]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][N:28]=1)=[O:19])[CH2:7][CH2:6][CH2:5]2
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Oc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C#N)cn1
Reaction time: 2 h

Procedure:
A solution of phenyl 6-bromo-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 11, 640 mg, 1.57 mmol) and 6-aminonicotinonitrile (206 mg, 1.73 mmol) in THF (10 ml) at −10° C. was treated with LHMDS (1M in THF, 1.89 ml, 1.89 mmol) and stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl. The org. layer was washed with water (2×) and brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was dissolved in a small quantity of DCM and then, MeOH was added to precipitate the product. The white solid was collected by filtration and washed with MeOH to obtain the title compound as a white solid. (UPLC-MS 1) tR 1.18 min; ESI-MS 432.0, 434.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][C:20]([NH:23][N+]([O-])=O)=[CH:19][CH:18]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1.NN>[Pd].C(O)C>[Cl:1][C:2]1[N:11]2[C:5]([CH2:6][N:7]([C:16](=[O:27])[C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(N[N+](=O)[O-])cc1)N1Cc2ccc(Cl)n2Cc2ccccc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3ccc(Cl)n3Cc3ccccc32)cc1

Procedure:
A mixture of 1 mmol of 3-chloro-10,11-dihydro-10-(4-nitroaminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine, 2.5 mmol of anhydrous hydrazine, 50 mg of palladium on carbon and 10 ml of ethyl alcohol is refluxed for 1.5 hours. The mixture is filtered through diatomaceous earth and the filtrate concentrated to dryness to give the desired product as a solid.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[CH:26]=NC=C[N:22]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].O[C@@H:37]1CC[N+:39](C)(C(C2C=NC=CN=2)C(=O)N)[CH2:38]1.[Br-].OC1CC[N@@+](C)(CC(=O)NC2N=NC=CC=2)C1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17]([C:21]2[N:22]=[N:39][CH:38]=[CH:37][CH:26]=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CC[C@@H](O)C1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: C[N@@+]1(CC(=O)Nc2cccnn2)CCC(O)C1
Agent: [Br-]
Product: C[N+]1(C(C(N)=O)c2cccnn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 1) by replacing (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-yl-carbamoylmethyl)-pyrrolidinium bromide (Intermediate B) with (R)-3-hydroxy-1-methyl-1-(pyridazin-3-ylcarbamoylmethyl)-pyrrolidinium bromide (Intermediate F).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: Clc1ccc(-c2ccccc2Cl)nn1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3ccccc3Cl)nn12

Procedure:
As in Example 36, a mixture of 5.5 g. of 3-chloro-6-(o-chlorophenyl) pyridazine, 3.6 g. of acetylhydrazine in 75 ml. of n-butanol is refluxed for 72 hrs. to give 2.2 g. or product as off-white crystals, m.p. 146°-148° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].CO.[Cl-].[NH4+]>O1CCCC1.O>[F:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16]
Reactant: N#Cc1cccc(Oc2cccc(F)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: NCc1cccc(Oc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.2 %

Procedure:
Next, to a solution of lithium aluminum hydride (139 mg, 3.68 mmol) in tetrahydrofuran (3.0 mL) was added a solution of the resulting 3-(3-fluoro-phenoxy)-benzonitrile (313 mg, 1.47 mmol) in tetrahydrofuran (1 mL) on an ice bath, and the solution was stirred at room temperature for 18 hours. A mixture solvent of methanol and water (9:1) was added to the reaction solution, an aqueous solution of saturated ammonium chloride was further added thereto, followed by stirring at room temperature for 10 minutes, then, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, then, the solvent was evaporated to obtain the title compound (285 mg, 89%) as a yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2)cc1
Yield: 78.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), biphenyl-4-carbonyl chloride (0.098 g; 0.445 mmol), and triethylamine (0.131 mL; 0.934 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 10% ethyl acetate in dichloromethane) furnished 0.125 g (79%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.