Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([OH:18])([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:23]CCCCC>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][C:11]([O:18][CH3:23])([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: COC(=O)C1(O)CCN(c2ncc(Br)cn2)CC1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1(C(=O)O)CCN(c2ncc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 57 %

Procedure:
A solution of methyl 1-(5-bromopyrimidin-2-yl)-4-hydroxypiperidine-4-carboxylate (0.2 g, 0.63 mmol) in DMF (25 mL) was cooled to 0° C. followed by portion wise addition of NaH (60% dispersion in mineral oil, 0.05 g, 1.08 mmol) and the mixture stirred at 0° C. for 45 min followed by addition of MeI (0.20 mL, 3.16 mmol). The temperature of the reaction was slowly raised to rt and left to stir for 4 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 3% EtOAc:hexane to obtain the product as an off-white solid (0.12 g, 57% yield). MS: 330.18 [M+H]+.
Reaction SMILES: [Mg].C(I)C.[CH2:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Br)=[CH:10][C:9]=1[SiH:19]([CH3:21])[CH3:20])[CH:6]=[CH2:7].[CH2:22]=[O:23].[NH4+].[Cl-]>C1COCC1>[CH2:5]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH2:22][OH:23])=[CH:10][C:9]=1[SiH:19]([CH3:21])[CH3:20])[CH:6]=[CH2:7]
Reactant: C=CCc1c([SiH](C)C)cc(Br)c2ccccc12
Reactant: C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: C=CCc1c([SiH](C)C)cc(CO)c2ccccc12
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a vigorously stirred suspension of activated magnesium turning (480 mg, 20 mmol) in dry THF (70 mL) were added a piece of 12 and ethyl iodide (50 μL). The reaction mixture was heated to reflux until the red color disappeared. Heating (65° C.) of the suspension was continued while a solution of 1-allyldimethylsilyl-4-bromo-naphthalene (1 Scheme 26, 3.0 g, 10 mmol) in THF (20 mL) was added over a period of 15 min. Upon completion of the addition, the gray solution was heated further for 10 min and transferred to a separate flask containing. paraformaldehyde (700 mg) in THF (20 mL) via cannula. After stirring the reaction mixture at 50° C. for 30 min, concentrated NH4Cl (10 mL) was added to the solution, and the reaction mixture was concentrated. The residue was extracted with ethyl acetate (70 mL) and brine (30 mL), and the organic layer was dried (Na2SO4), concentrated. The crude product was purified by column chromatography (1:5 ethyl acetate/hexanes) to afford a colorless oil (1.8 g, 75%); 1H NMR (300 MHz, CDCl3) δ 0.58 (s, 6 H), 2.08 (d, J=7.50 Hz, 2 H), 3.21 (s, OH, 1 H), 4.93-5.03 (2 H), 5.04 (s, 2 H), 5.89 (m, 1 H), 7.47 (d, J=7.20 Hz, 2 H), 7.53-7.64 (2 H), 7.69 (d, J=6.90 Hz, 1 H), 8.11 (d, J=8.80 Hz, 1 H), 8.23 (d, J=8.80 Hz, 1 H), 13C NMR (75 MHz, CDCl3) −1.50 (2 C), 24.6, 63.5, 114.1, 124.5, 124.8, 125.9, 126.8, 129.1, 131.4, 133.7, 135.0, 137.3, 137.5, 138.3.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[N:28]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH:33]2[CH2:38][OH:39])[CH2:31][CH2:30][CH2:29]1>>[N:28]1([C@@H:32]2[CH2:37][CH2:36][N:35]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:34][C@H:33]2[CH2:38][OH:39])[CH2:29][CH2:30][CH2:31]1
Reactant: OCC1CNCCC1N1CCC1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: OC[C@@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC[C@H]1N1CCC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using (4-azetidin-1-yl-piperidin-3-yl)-methanol in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compounds were separated by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=O)=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C1(C)C(C)=CC=CC=1.C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]23[CH2:8][CH2:9][C:10](=[O:12])[N:17]2[CH2:16][CH2:15][NH:18]3)=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: NCCN
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1C
Product: O=C1CCC2(c3ccc(Cl)cc3)NCCN12
Temperature: 25 °C
Yield: 81.4 %

Procedure:
To a solution of 3-(4-chlorobenzoyl)propionic acid (40 g, 190 mmol) in xylene (250 mL) were added ethylenediamine (22.6 g, 376 mol), and 12M hydrochloric acid (0.500 mL, 6 mmol). The reaction mixture was stirred at reflux under Dean-Stark for 12 h, and cooled to RT. The solid was collected by filtration and washed with xylene to give the crude residue. This was dissolved in DCM (400 ml) and filtered. The filtrate was concentrated in vacuo to give 36.6 g (62%) of the racemic title compound as a beige solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:19]1([Si:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCOCC.C1C=CC=CC=1>[C:32]1([Si:25]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCOCC
Product: c1ccc([Si](c2ccccc2)(c2ccccc2)C2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
To a solution of 17 g of fluorene (102.4 mmol) in 300 mL of dry ether was added 46 mL of 2.3M n-butyllithium dropwise over a period of 20 minutes. The mixture was refluxed for 3 hours, cooled in an ice bath, and treated in one portion with a solution of 24 g (81.46 mmol) of triphenylsilyl chloride in 100 mL of dry benzene. The mixture was refluxed for 24 hours, cooled to room temperature, and washed with sat'd NH4Cl (100 mL), brine (150 mL), and water (150 mL). The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo to give a yellow residue which was triturated with methanol to afford 34.18 g (98.9%) of the crude silane as an off-white solid. Recrystallization from EtOAc--EtOH (4:1) gave 27.46 g (79.5%) of the pure triphenylsilane as white needles, m.p. 182°-193° C.; 1H NMR (CDCl3): δ 4.72 (s, 1H, CH), 6.82-7.90 (m, 23H, aryl).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10]([CH3:12])=[CH:9][CH2:8][N:7]1C(OC(C)(C)C)=O)=[O:5])[CH3:2].[ClH:20]>C(OCC)(=O)C>[ClH:20].[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C:10]([CH3:12])=[CH:9][CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(C)=CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CC(C)=CCN1
Reaction time: 2 h

Procedure:
A stirred, ice-cooled solution of the product from (g) above (3.13 g, 11.62 mmol) in ethyl acetate (30 ml) was satured with hydrogen chloride over 0.5 hour and then stood at room temperature for a further 2 hours. The solvent was evaporated under reduced pressure and the residue crystallised from a mixture of ether and ethanol to afford the title compound (2.20 g) as white crystals, m.p. 108°-109° C. Rf 0.35 (SS 3),
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:22]([CH2:24][CH3:25])=[O:23])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=[O:28])C.OO>O>[Cl:1][C:2]1[C:3]([S:22]([CH2:24][CH3:25])(=[O:28])=[O:23])=[C:4]([C:8]2[N:20]([CH3:21])[C:11]3=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCS(=O)c1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Agent: OO
Solvent: O
Product: CCS(=O)(=O)c1c(Cl)cccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 80 °C

Procedure:
A mixture of 2-(3-chloro-2-ethylsulfinylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (0.48 g) and acetic acid (12 ml) was stirred with heating at 80° C., and then 30% of an aqueous solution of hydrogen peroxide (6 ml) was added dropwise. The mixture was heated to 100° C., and stirred with heating for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.21 g of 2-(3-chloro-2-ethylsulfonylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 90).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[CH2:26]Br)[CH3:17]>>[CH2:16]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[CH2:26][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1)[CH3:17]
Reactant: CCOC(=O)c1cccnc1CBr
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: CCOC(=O)c1cccnc1CN1CCC(c2c[nH]c3ccccc23)CC1
Yield: 92.4 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.5 g (2.5 mmol) of 3-piperidin-4-yl-1H-indole and 0.65 g (3.25 mmol) of 2-bromomethyl-nicotinic acid ethyl ester. After the standard purification, 0.84 g (92% of yield) of 2-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-nicotinic acid ethyl ester were obtained.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1>C(O)(=O)C.[Pd].[Pt](=O)=O>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:11][NH:12][CH2:13][CH:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:19]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cncc(-c2ccc(OC(F)F)cc2)c1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)C1CNCC(c2ccc(OC(F)F)cc2)C1
Reaction time: 24 h

Procedure:
A solution of 8.6 g (30.9 mmol) of methyl 5-[4-(difluoromethoxy)phenyl]nicotinate in concentrated acetic acid (112 ml) was admixed with 841 mg of palladium/carbon (10% palladium) and 1.12 g of platinum(IV) oxide. This was followed by hydrogenation under a hydrogen atmosphere at standard pressure for 24 h. The reaction solution was concentrated under reduced pressure. The residue was taken up in water, acidified (pH=1) with 1 N hydrochloric acid, extracted with diethyl ether, then basified (pH>10) with saturated aqueous sodium hydrogencarbonate solution and extracted repeatedly with ethyl acetate. The combined filtrates were dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 6.6 g (74% of theory)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([CH:26]([N:28]([CH3:30])[CH3:29])[CH3:27])[C:21](OCC)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]>O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]([CH:26]([N:28]([CH3:30])[CH3:29])[CH3:27])[CH2:21][OH:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)N(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C(CO)c1ccc(Cl)c(Cl)c1)N(C)C

Procedure:
To a suspension of 10 g. of lithium aluminum hydride in 300 ml. of diethyl ether, 18.7 g. of ethyl 2-(3,4-dichlorophenyl)-3-dimethylaminobutyrate is added dropwise with stirring. The mixture is refluxed for 40-45 hours and after cooling with an ice bath, 50 ml. of water is added very slowly. After filtering off and thoroughly washing out the inorganic salts, the dried organic filtrate is evaporated and the residue is distilled in vacuo at 115° C/0.4 mm Hg to yield 13 g. of the title compound. The hydrochloride salt melts at 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1.O.[NH2:20][NH2:21]>CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([NH:20][NH2:21])=[O:12])=[CH:9][C:8]=2[O:17][CH3:18])[CH:6]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-n2cnc(Cl)c2)c(OC)c1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)NN)ccc1-n1cnc(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxybenzoate (25.5 mg) in methanol (1 mL) was added hydrazine monohydrate (0.019 mL) at room temperature, the mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (12.7 mg).
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:27]([NH2:28])=[CH:26][C:9]2[CH2:10][C@@H:11]3[C:16]([CH3:18])([CH3:17])[C@:15]([CH3:19])([C:8]=2[CH:7]=1)[CH2:14][CH2:13][N:12]3[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22].C(O)(=O)C>O>[F:23][C:21]([F:24])([F:22])[C:20]([N:12]1[CH2:13][CH2:14][C@:15]2([CH3:19])[C:16]([CH3:17])([CH3:18])[C@H:11]1[CH2:10][C:9]1[CH:26]=[C:27]3[N:28]=[N:1][NH:5][C:6]3=[CH:7][C:8]=12)=[O:25]
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)[C@H]2Cc3cc4nn[nH]c4cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of NaNO2 (330 mg) in water (2 mL) is slowly added to a flask charged with a stir bar, 1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (650 mg), and acetic acid (15 mL) and chilled in an ice bath. The resulting mixture is stirred in the cooling bath for 2 h and at ambient temperature for 1 h. Then, the solution is poured into ice-cold water and the precipitate formed is separated by filtration and dried to afford the title compound that is used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:22])([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(OCc2ccccc2)c1
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Using the procedure described in Example 93, Part A, 3-benzyloxyaniline (10 mmol) and 2-nitrobenzoyl chloride (11 mmol) yielded 3.1 g (89%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[CH:21]=1)(=[O:3])[CH3:2].C([O:24]CC)C>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[CH:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=3[O-:24])[C:8]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccn1)=CC(C)(C)O2
Product: CC(=O)c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C)(C)O2

Procedure:
In an analogous manner to that described in the first paragraph of Example 3, from 6-acetyl-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-(6-acetyl-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 165°-167° C. (from diethyl ether).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[NH:22]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12]([C:14]3[C:15]([CH3:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:11][C:4]=2[CH:3]=1)[NH2:23]
Reactant: Cc1ccccc1C(=O)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1ccccc1C(=O)N1CCc2nnc(NN)cc2C1

Procedure:
13.0 g of 3-chloro-5,6,7,8-tetrahydro-6-(o-toluoyl)pyrido[4,3-c]pyridazine and 100 cc of hydrazine hydrate are reacted as described in Example 4. Reaction time 2 hours. The bis[3-hydrazino-5,6,7,8-tetrahydro-6-(o-toluoyl)pyrido[4,3-c]pyridazine]trisfumarate has a M.P. of 98°-100° (decomp., from 95% ethanol).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>CCO>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=3)[C:13](=[O:14])[C:12]3[C:11](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:10]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: CSc1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: CSc1ccc(-n2c(-c3ccc(C)nc3)nc3ccccc3c2=O)cc1
Yield: 19 %

Procedure:
A mixture of 6-methylnicotinaldehyde (0.36 g, 3.0 mmol), 2-amino-N-(4-(methylthio)phenyl)benzamide (3.0 mmol), and anyhydrous CuCl2 (0.80 g, 6.0 mmol) in anyhydrous EtOH was refluxed for 6 hours. After concentration in vacuo, the residue was redissolved in EtOAc and washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 20% MeOH in CH2Cl2, followed by 40% to 100% of 92:7:1 CHCl3/MeOH/concentrate NH4OH in CH2Cl2, afforded the title compound (19%). 1H-NMR (300 MHz, DMSO-d6): δ8.42 (s, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.87-7.97 (m, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.56-7.73 (m, 2H), 7.31 (d, J=8.3 Hz, 2H), 7.10-7.26 (m, 3H), 2.43 (s, 3H), 2.41 (s, 3H). MS (APCI) m/z: 360 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([NH2:19])=[O:18])=[N:4][C:5]2[C:10]([C:11]=1[C:12]([F:15])([F:14])[F:13])=[CH:9][C:8]([Cl:16])=[CH:7][CH:6]=2.[C:20](CC(=O)C)(=O)[CH3:21]>OS(O)(=O)=O>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[C:3]3[C:17](=[O:18])[NH:19][C:20]([CH3:21])=[N:1][C:2]3=[C:11]([C:12]([F:13])([F:15])[F:14])[C:10]=2[CH:9]=1
Reactant: CC(=O)CC(C)=O
Reactant: NC(=O)c1nc2ccc(Cl)cc2c(C(F)(F)F)c1N
Agent: O=S(=O)(O)O
Product: Cc1nc2c(C(F)(F)F)c3cc(Cl)ccc3nc2c(=O)[nH]1
Temperature: 100 °C
Yield: 55 %

Procedure:
3-Amino-6-chloro-4-(trifluoromethyl)-2-quinolinecarboxamide (12, 172 mg, 0.594 mmol) was dissolved acetylacetone (5.9 mL). Three drops of H2SO4 were added and the reaction was heated to 100° C. for 30 minutes. The reaction was cooled to rt and the copious cream precipitate was collected and washed with cold CH3OH to provide the desired product (103 mg, 55%) requiring no further purification. 1H NMR (d6-DMSO, 300 MHz) δ12.73 (br s, NH), 8.35 (d, J=9.2 Hz, 1 H), 8.29 (s, 1H), 7.97 (dd, J=2.2, 9.1 Hz, 1H), 2.44 (s, 3H); 19F NMR (CDCl3, 300 MHz) δ−51.34; IR (KBr) νmax 3442, 3060, 2920, 1706, 1629, 1608, 1560, 1485, 1336, 1329, 1198, 1144, 1114, 961, 837, 710 cm−1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:28][CH:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:24])=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NC1CCOCC1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NC3CCOCC3)cn2)cn1
Yield: 73 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (46 mg, 0.126 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (41 mg, 73%) which was obtained as a white foam after purification by chromatography (silica, 0-10% methanol in dichloromethane). MS: m/e=448.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])/[CH:5]=[CH:6]/[Sn](CCCC)(CCCC)CCCC)[CH3:2].[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1I>CN(C)C=O.O>[NH2:26][C:27]1[N:32]=[C:31]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][CH3:41])[C:34]=2[F:42])[N:30]=[C:29]([C:43]([O:45][CH3:46])=[O:44])[C:28]=1/[CH:6]=[CH:5]/[Si:4]([O:3][CH2:1][CH3:2])([O:20][CH2:21][CH3:22])[O:23][CH2:24][CH3:25]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1I
Reactant: CCCC[Sn](/C=C/[Si](OCC)(OCC)OCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: CCO[Si](/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC)(OCC)OCC
Temperature: 90 °C
Reaction time: 120 h
Yield: 5.4 %

Procedure:
Tetrakis triphenylphosphine palladium(0) (160 mg, 0.14 mmol, 0.10 equiv) and (E)-triethoxy(2-(tributylstannyl)vinyl)silane (990 mg, 2.1 mmol, 1.5 equiv) were sequentially added to a stirred solution of methyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-iodopyrimidine-4-carboxylate (600 mg, 1.4 mmol, 1.0 equiv) in N,N-dimethylformamide (5.5 mL) at room temperature. The heterogeneous yellow mixture was heated at 90° C. and stirred for 5 d. The cooled reaction mixture was diluted with water (300 mL) and extracted with diethyl ether (3×100 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated under vacuum. The product was purified by acid free reverse phase column chromatography (5% acetonitrile to 100% acetonitrile gradient) to provide the title compound as a yellow glass (38 mg, 6% yield): IR (thin film) 3315 (w), 3069 (w), 2974 (w), 1657 (s) cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=9, 8 Hz, 1H), 7.29 (d, J=18.5 Hz, 1H), 7.21 (dd, J=9, 2 Hz, 1H), 6.06 (d, J=18.5 Hz, 1H), 5.39 (br s, 2H), 3.98 (d, J=1 Hz, 3H), 3.92 (s, 3H), 3.89 (q, J=7 Hz, 6H), 1.26 (t, J=7 Hz, 9H); ESIMS m/z 500 [(M+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCOCC1>[C:12]1([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnccc1Nc1ccccc1
Yield: 69.3 %

Procedure:
4-Chloro-3-nitropyridine (1.50 g, 9.46 mmol) and aniline (2.0 ml, 21.9 mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylamine was added thereto, followed by reaction at 80° to 90° C. for 2 hours. Then, the solvent was removed by distillation under reduced pressure, and 10 ml of hexane was added to the residue to wash it. The solvent was removed by decantation. The residue was further similarly treated with 10 ml of ether. The residue was purified by silica gel column chromatography [eluent: hexane:ethyl acetate=2:1 (v/v)] to obtain 1.41 g of a yellow solid (yield: 68.8%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH3:18])[C:3]=1[O:20][CH:21]([CH3:23])[CH3:22].[CH3:24][CH2:25][O:26][C:27]([CH:29](P(OCC)(OCC)=O)[F:30])=[O:28].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:18])=[C:29](/[F:30])\[C:27]([O:26][CH2:25][CH3:24])=[O:28])[C:3]=1[O:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(=O)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-3-isopropoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-112, 262 mg, 0.69 mmol) and triethyl 2-fluoro-2-phosphonoacetate (669 mg, 2.76 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.73 mL, 2.76 mmol) in THF to produce the title compound after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).